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Antioxidants for female subfertility (Review)
Showell MG, Mackenzie-Proctor R, Jordan V, Hart RJ
Showell MG, Mackenzie-Proctor R, Jordan V, Hart RJ.

Antioxidants for female subfertility.
Cochrane Database of Systematic Reviews 2017, Issue 7. Art. No.: CD007807.
DOI: 10.1002/14651858.CD007807.pub3.
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TABLE OF CONTENTS
HEADER......................................................................................................................................................................................................... 1
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2
SUMMARY OF FINDINGS.............................................................................................................................................................................. 4
BACKGROUND.............................................................................................................................................................................................. 7
OBJECTIVES.................................................................................................................................................................................................. 8
METHODS..................................................................................................................................................................................................... 8
RESULTS........................................................................................................................................................................................................ 11
Figure 1.................................................................................................................................................................................................. 12
Figure 2.................................................................................................................................................................................................. 16
Figure 3.................................................................................................................................................................................................. 19
Figure 4.................................................................................................................................................................................................. 21
Figure 5.................................................................................................................................................................................................. 22
Figure 6.................................................................................................................................................................................................. 24
Figure 7.................................................................................................................................................................................................. 26
Figure 8.................................................................................................................................................................................................. 29
Figure 9.................................................................................................................................................................................................. 31
Figure 10................................................................................................................................................................................................ 33
Figure 11................................................................................................................................................................................................ 34
DISCUSSION.................................................................................................................................................................................................. 34
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 36
ACKNOWLEDGEMENTS................................................................................................................................................................................ 36
REFERENCES................................................................................................................................................................................................ 38
CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 46
DATA AND ANALYSES.................................................................................................................................................................................... 110
Analysis 1.1. Comparison 1 Antioxidant(s) versus placebo or no treatment/standard treatment, Outcome 1 Live birth; 113
antioxidants vs placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments)...........
Analysis 1.2. Comparison 1 Antioxidant(s) versus placebo or no treatment/standard treatment, Outcome 2 Live birth; type of 114
antioxidant.............................................................................................................................................................................................
Analysis 1.3. Comparison 1 Antioxidant(s) versus placebo or no treatment/standard treatment, Outcome 3 Live birth; 115
indications for subfertility....................................................................................................................................................................
Analysis 1.4. Comparison 1 Antioxidant(s) versus placebo or no treatment/standard treatment, Outcome 4 Live birth; IVF/ICSI.... 116
Analysis 1.5. Comparison 1 Antioxidant(s) versus placebo or no treatment/standard treatment, Outcome 5 Clinical pregnancy; 116
antioxidants vs placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments)...........
type of antioxidant...............................................................................................................................................................................
IVF/ICSI...................................................................................................................................................................................................
Analysis 1.9. Comparison 1 Antioxidant(s) versus placebo or no treatment/standard treatment, Outcome 9 Adverse events....... 122
Analysis 2.1. Comparison 2 Head-to-head antioxidants, Outcome 1 Live birth; type of antioxidant (natural conceptions and 123
undergoing fertility treatments)..........................................................................................................................................................
Analysis 2.2. Comparison 2 Head-to-head antioxidants, Outcome 2 Clinical pregnancy; type of antioxidant (natural conceptions 124
and undergoing fertility treatments)...................................................................................................................................................
Analysis 2.3. Comparison 2 Head-to-head antioxidants, Outcome 3 Adverse events....................................................................... 124
Analysis 3.1. Comparison 3 Pentoxifylline versus placebo or no treatment/standard care, Outcome 1 Live birth; pentoxifylline 125
vs placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments)................................
Analysis 3.2. Comparison 3 Pentoxifylline versus placebo or no treatment/standard care, Outcome 2 Clinical pregnancy; 125
pentoxifylline vs placebo or no treatment/standard treatment (natural conceptions and undergoing fertility treatments).........
Analysis 3.3. Comparison 3 Pentoxifylline versus placebo or no treatment/standard care, Outcome 3 Clinical pregnancy; type 126
of antioxidant........................................................................................................................................................................................
Antioxidants for female subfertility (Review) i

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Analysis 3.4. Comparison 3 Pentoxifylline versus placebo or no treatment/standard care, Outcome 4 Clinical pregnancy; 126
Analysis 3.5. Comparison 3 Pentoxifylline versus placebo or no treatment/standard care, Outcome 5 Clinical pregnancy; IVF/ 127
ICSI.........................................................................................................................................................................................................
Analysis 3.6. Comparison 3 Pentoxifylline versus placebo or no treatment/standard care, Outcome 6 Adverse events................ 127
ADDITIONAL TABLES.................................................................................................................................................................................... 128
APPENDICES................................................................................................................................................................................................. 128
WHAT'S NEW................................................................................................................................................................................................. 137
HISTORY........................................................................................................................................................................................................ 137
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 137
DECLARATIONS OF INTEREST..................................................................................................................................................................... 138
SOURCES OF SUPPORT............................................................................................................................................................................... 138
DIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 138
INDEX TERMS............................................................................................................................................................................................... 138
Antioxidants for female subfertility (Review) ii

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[Intervention Review]
Antioxidants for female subfertility
Marian G Showell1, Rebecca Mackenzie-Proctor2, Vanessa Jordan1, Roger J Hart3
1Department of Obstetrics and Gynaecology, University of Auckland, Auckland, New Zealand. 2Department of Obstetrics and
Gynaecology, Auckland City Hospital, Auckland, New Zealand. 3School of Women's and Infants' Health, The University of Western
Australia, King Edward Memorial Hospital and Fertility Specialists of Western Australia, Subiaco, Perth, Australia
Contact address: Marian G Showell, Department of Obstetrics and Gynaecology, University of Auckland, Park Road Grafton, Auckland,
1142, New Zealand. m.showell@auckland.ac.nz.
Editorial group: Cochrane Gynaecology and Fertility Group

Publication status and date: Edited (no change to conclusions), published in Issue 10, 2017.
Citation: Showell MG, Mackenzie-Proctor R, Jordan V, Hart RJ. Antioxidants for female subfertility. Cochrane Database of Systematic
Reviews 2017, Issue 7. Art. No.: CD007807. DOI: 10.1002/14651858.CD007807.pub3.
ABSTRACT
Background
A couple may be considered to have fertility problems if they have been trying to conceive for over a year with no success. This may affect
up to a quarter of all couples planning a child. It is estimated that for 40% to 50% of couples, subfertility may result from factors affecting
women. Antioxidants are thought to reduce the oxidative stress brought on by these conditions. Currently, limited evidence suggests that
antioxidants improve fertility, and trials have explored this area with varied results. This review assesses the evidence for the effectiveness
of different antioxidants in female subfertility.
Objectives
To determine whether supplementary oral antioxidants compared with placebo, no treatment/standard treatment or another antioxidant
improve fertility outcomes for subfertile women.
Search methods
We searched the following databases (from their inception to September 2016) with no language or date restriction: Cochrane Gynaecology
and Fertility Group (CGFG) specialised register, the Cochrane Central Register of Studies (CENTRAL CRSO), MEDLINE, Embase, PsycINFO,
CINAHL and AMED. We checked reference lists of appropriate studies and searched for ongoing trials in the clinical trials registers.
Selection criteria
We included randomised controlled trials (RCTs) that compared any type, dose or combination of oral antioxidant supplement with
placebo, no treatment or treatment with another antioxidant, among women attending a reproductive clinic. We excluded trials comparing
antioxidants with fertility drugs alone and trials that only included fertile women attending a fertility clinic because of male partner
infertility.
Data collection and analysis

Two review authors independently selected eligible studies, extracted the data and assessed the risk of bias of the included studies. The
primary review outcome was live birth; secondary outcomes included clinical pregnancy rates and adverse events. We pooled studies
using a fixed-effect model, and calculated odds ratios (ORs) with 95% confidence intervals (CIs) for the dichotomous outcomes of live birth,
clinical pregnancy and adverse events. We assessed the overall quality of the evidence by applying GRADE criteria.
Main results
We included 50 trials involving 6510 women. Investigators compared oral antioxidants, including combinations of antioxidants, N-acetyl-
cysteine, melatonin, L-arginine, myo-inositol, D-chiro-inositol, carnitine, selenium, vitamin E, vitamin B complex, vitamin C, vitamin D
Antioxidants for female subfertility (Review) 1
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+calcium, CoQ10, pentoxifylline and omega-3-polyunsaturated fatty acids versus placebo, no treatment/standard treatment or another
antioxidant.
Very low-quality evidence suggests that antioxidants may be associated with an increased live birth rate compared with placebo or no
treatment/standard treatment (OR 2.13, 95% CI 1.45 to 3.12, P > 0.001, 8 RCTs, 651 women, I2 = 47%). This suggests that among subfertile
women with an expected live birth rate of 20%, the rate among women using antioxidants would be between 26% and 43%.
Very low-quality evidence suggests that antioxidants may be associated with an increased clinical pregnancy rate compared with placebo
or no treatment/standard treatment (OR 1.52, 95% CI 1.31 to 1.76, P < 0.001, 26 RCTs, 4271 women, I2 = 66%). This suggests that among
subfertile women with an expected clinical pregnancy rate of 22%, the rate among women using antioxidants would be between 27% and
33%. Heterogeneity was moderately high.
There was insufficient evidence to determine whether there was a difference between the groups in rates of miscarriage (OR 0.79, 95%
CI 0.58 to 1.08, P = 0.14, 18 RCTs, 2834 women, I2 = 23%, very low quality evidence). This suggests that, among subfertile women with an
expected miscarriage rate of 7%, use of antioxidants would be expected to result in a miscarriage rate of between 4% and 7%. There was
also insufficient evidence to determine whether there was a difference between the groups in rates of multiple pregnancy (OR 1.00, 95% CI
0.73 to 1.38, P = 0.98, 8 RCTs, 2163 women, I2 = 4%, very low quality evidence). This suggests that among subfertile women with an expected
multiple pregnancy rate of 8%, use of antioxidants would be expected to result in a multiple pregnancy rate between 6% and 11%. Likewise,
there was insufficient evidence to determine whether there was a difference between the groups in rates of gastrointestinal disturbances
(OR 1.55, 95% CI 0.47 to 5.10, P = 0.47, 3 RCTs, 343 women, I2 = 0%, very low quality evidence). This suggests that among subfertile women
with an expected gastrointestinal disturbance rate of 2%, use of antioxidants would be expected to result in a rate between 1% and 11%.
Overall adverse events were reported by 35 trials in the meta-analysis, but there was insufficient evidence to draw any conclusions.
Only one trial reported on live birth, clinical pregnancy or adverse effects in the antioxidant versus antioxidant comparison, and no
conclusions could be drawn.
Very low-quality evidence suggests that pentoxifylline may be associated with an increased clinical pregnancy rate compared with placebo
or no treatment (OR 2.07, 95% CI 1.20 to 3.56, P = 0.009, 3 RCTs, 276 women, I2 = 0%). This suggests that among subfertile women with an
expected clinical pregnancy rate of 25%, the rate among women using pentoxifylline would be between 28% and 53%.
There was insufficient evidence to determine whether there was a difference between the groups in rates of miscarriage (OR 1.34, 95%
CI 0.46 to 3.90, P = 0.58, 3 RCTs, 276 women, I2 = 0%) or multiple pregnancy (OR 0.78, 95% CI 0.20 to 3.09, one RCT, 112 women, very low
quality evidence). This suggests that among subfertile women with an expected miscarriage rate of 4%, the rate among women using
pentoxifylline would be between 2% and 15%. For multiple pregnancy, the data suggest that among subfertile women with an expected
multiple pregnancy rate of 9%, the rate among women using pentoxifylline would be between 2% and 23%.
The overall quality of evidence was limited by serious risk of bias associated with poor reporting of methods, imprecision and inconsistency.
Authors' conclusions
In this review, there was very low-quality evidence to show that taking an antioxidant may provide benefit for subfertile women, but
insufficient evidence to draw any conclusions about adverse events. At this time, there is limited evidence in support of supplemental oral
antioxidants for subfertile women.
PLAIN LANGUAGE SUMMARY
Vitamins and minerals for subfertility in women
Review question:
Do supplementary oral antioxidants compared with placebo, no treatment/standard treatment or another antioxidant improve fertility
outcomes for subfertile women (standard treatment includes less than 1 mg of folic acid).
Background:
Many subfertile women undergoing fertility treatment also take dietary supplements in the hope of improving their fertility. This can be a
very stressful time for women and their partners. It is important that these couples be given high-quality evidence that will allow them to
make informed decisions on whether taking a supplemental antioxidant when undergoing fertility treatment will improve their chances or
cause any adverse effects. This is especially important, as most antioxidant supplements are uncontrolled by regulation. This review aimed
to assess whether supplements with oral antioxidants increase a subfertile woman's chances of becoming pregnant and having a baby.
Search date:
The evidence is current to September 2016.
Study characteristics:

Informed decisions.

The review includes 50 randomised controlled trials that compare antioxidants with placebo or with no treatment/standard treatment, or
with another antioxidant, in a total of 6510 women.
Funding sources:
Funding sources were reported by only 14 of the 50 included trials.
Key results:
Very low-quality evidence suggests that antioxidants may be associated with an increased live birth and clinical pregnancy rate. Based on
these results, we would expect that out of 100 subfertile women not taking antioxidants, 20 would have a baby, compared with between
26 and 43 women per 100 who would have a baby if taking antioxidants. There was insufficient evidence to draw any conclusions about
the adverse effects of miscarriage, multiple births or gastrointestinal effects. Very low-quality evidence suggests that pentoxifylline may
also be associated with increased rates of clinical pregnancy, but there were only three trials in this analysis. In this case we would expect
that out of 100 subfertile women not taking pentoxifylline, 25 would become pregnant, compared with between 28 and 53 women per 100
who would become pregnant if taking pentoxifylline to improve their chances of getting pregnant. There was also insufficient evidence to
draw any conclusions about the adverse effects of pentoxifylline. Only one trial measured one antioxidant against another,so there was
no evidence available to draw any conclusion from this comparison.
Quality of the evidence:

The overall quality of evidence was limited by serious risk of bias associated with poor reporting of methods, imprecision and inconsistency.

SUMMARY OF FINDINGS

Summary of findings for the main comparison. Antioxidant(s) compared to placebo or no treatment/standard treatment for female subfertility
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Antioxidant(s) compared to placebo or no treatment/standard treatment for female subfertility
Patient or population: subfertile women who had been referred to a fertility clinic and might or might not be undergoing assisted reproductive techniques
Setting: fertility clinic
Intervention: antioxidant(s)
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Comparison: placebo or no treatment/standard treatment
Outcomes Anticipated absolute effects* (95% CI) Relative effect № of partici- Quality of the Comments
(95% CI) pants evidence
Risk with place- Risk with Antioxidan- (studies) (GRADE)
bo or no treat- t(s)
ment/standard
treatment
Live birth; antioxidants vs placebo or no 196 per 1,000 342 per 1,000 OR 2.13 651 ⊕⊝⊝⊝
treatment/standard treatment (natur- (262 to 433) (1.45 to 3.12) (8 RCTs) VERY LOW 1, 2
al conceptions and undergoing fertility
treatments)
Clinical pregnancy; antioxidants vs place- 220 per 1,000 301 per 1,000 OR 1.52 4271 ⊕⊝⊝⊝
bo or no treatment/standard treatment (270 to 332) (1.31 to 1.76) (26 RCTs) VERY LOW 1, 3, 5
(natural conceptions and undergoing fer-
tility treatments)
Adverse events - Miscarriage 68 per 1,000 55 per 1,000 OR 0.79 2834 ⊕⊝⊝⊝
(41 to 73) (0.58 to 1.08) (18 RCTs) VERY LOW 1, 2
Adverse events - Multiple pregnancy 80 per 1,000 80 per 1,000 OR 1.00 2163 ⊕⊝⊝⊝

Adverse events - Gastrointestinal distur- 24 per 1,000 37 per 1,000 OR 1.55 343 ⊕⊝⊝⊝
bances (12 to 112) (0.47 to 5.10) (3 RCTs) VERY LOW 1, 4, 5
*The risk in the intervention group (and its 95% confidence interval) is based on the mean 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: We are very confident that the true effect lies close to that of the estimate of the effect
4

Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is sub-
stantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
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1Downgraded two levels due to very serious risk of bias; at high risk of bias in two domains.
2Downgraded one level due to serious imprecision; the event rate is low (< 300).
3Downgraded two levels due to very serious inconsistency (I2 = 81%) with differing directions of effect.
4Downgraded two levels due to very serious imprecision; the event rate is very low (n = 11).
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5In practice, full downgrading not possible as evidence already graded as very low quality.

Summary of findings 2. Pentoxifylline compared to placebo or no treatment/standard care for female subfertility
Pentoxifylline compared to placebo or no treatment/standard care for female subfertility
Patient or population: subfertile women who had been referred to a fertility clinic and might or might not be undergoing assisted reproductive techniques
Setting: fertility clinic
Intervention: pentoxifylline
Comparison: placebo or no treatment/standard care
Outcomes Anticipated absolute effects* (95% CI) Relative effect № of partici- Quality of the Comments
(95% CI) pants evidence
Risk with place- Risk with Pentoxi- (studies) (GRADE)
bo or no treat- fylline
ment/standard care
Live birth; pentoxifylline vs placebo or no 250 per 1,000 339 per 1,000 OR 1.54 112 ⊕⊝⊝⊝
treatment/standard treatment (natural con- (185 to 538) (0.68 to 3.50) (1 study) VERY LOW 1, 2
ceptions and undergoing fertility treatments)
Clinical pregnancy; pentoxifylline vs placebo 245 per 1,000 401 per 1,000 OR 2.07 276 ⊕⊝⊝⊝

or no treatment/standard treatment (natur- (280 to 535) (1.20 to 3.56) (3 RCTs) VERY LOW 3, 4
al conceptions and undergoing fertility treat-
ments)
Adverse events - Miscarriage 43 per 1,000 57 per 1,000 OR 1.34 276 ⊕⊝⊝⊝
Adverse events - Multiple pregnancy 89 per 1,000 71 per 1,000 OR 0.78 112 ⊕⊝⊝⊝
(1 study) VERY LOW 1, 2
(19 to 233) (0.20 to 3.09)
5

Adverse events - Gastrointestinal distur- Not reported in any included study
bances
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*The risk in the intervention group (and its 95% confidence interval) is based on the mean 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
Better health.
Informed decisions.
Trusted evidence.
High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is sub-
stantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
1Downgraded one level due to questionable applicability: study table states that cause of infertility is male in 51 of 112 participants, although text states that the participants
were 112 infertile women.
2Downgraded two levels due to very serious imprecision; the event rate is very low (n = 33 for live birth, n = 14 for miscarriage, n=9 for multiple pregnancy), wide confidence
intervals.
3Downgraded two levels due to questionable applicability of one study (see footnote 1) and very serious risk of bias: all studies at unclear or high risk of bias in one or more
domains.
4Downgraded one level due to serious imprecision; the event rate is low (n = 87).


6

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BACKGROUND may include molecules that have unpaired electrons, which may
lead to the formation of free radicals. Free radicals may cause
Description of the condition further harmful reactions with lipids in membranes, amino acids
in proteins and carbohydrates within nucleic acids. An antioxidant
A couple that has tried to conceive for a year or longer without
molecule is thought to be capable of slowing or preventing the
success is considered to be subfertile (Evers 2002) or less fertile than
oxidation of other molecules and potentially of reducing the
a typical couple. The World Health Organization (WHO) (Zegers-
production of free radicals, which may cause this cellular damage.
Hochschild 2009) defines infertility as the “failure to achieve a
clinical pregnancy after 12 months or more of regular unprotected Two major types of free radicals have been identified: reactive
sexual intercourse”. Levels of infertility in 2010 were similar to those oxygen species (ROS) and reactive nitrogen species (RNS). Reactive
in 1990 in most of the world, apart from declines in Sub-Saharan oxygen species are products of normal cellular metabolism and
Africa and in South Asia (Mascarenhas 2012). Forty to fifty per cent consist of oxygen ions, free radicals and peroxides. The addition
of cases of subfertility are due to causes in women. Influencing of one electron to oxygen forms the superoxide anion radical,
factors include ovulatory failure, tubal damage, endometriosis, which then can be converted to hydroxyl radical, peroxyl radical
poor egg quality and unexplained subfertility. It is suggested that or hydrogen peroxide. Free radicals seek to participate in chemical
up to 25% of couples who are planning a baby have difficulty (Boivin reactions that relieve them of their unpaired electron, resulting
2007; Hart 2003). in oxidation (Ruder 2008; Tremellen 2008). The presence of ROSs
within the ovary and the endometrium has significant physiological
To overcome these fertility problems, many couples undergo
and pathological implications for women when they try to
assisted fertility techniques (assisted reproductive techniques
conceive. Oxidative stress (OS) is a result of an imbalance between
(ART)). These include ovulation stimulation, intrauterine
the amount of ROS and the quantity of natural antioxidants present
insemination (IUI), in vitro fertilisation (IVF) and intracytoplasmic
within the body, and results in overwhelming the body’s natural
sperm injection (ICSI).
defence mechanism. Both oxidative stress and ROS can attack
Women use antioxidant supplements in preparation for ART and/ lipids, proteins DNA and affect metabolic pathways (chemical
or simultaneously with the treatment, and some women use transformations in the cells) (Agarwal 2012). Natural antioxidants
supplements alone with no ART in an attempt to improve their present in the body include catalase, glutathione peroxidase,
fertility. superoxide dismutase and glutathione reductase, vitamins C and E,
ferritin and transferrin (Gupta 2007).
Description of the intervention
Indirect evidence from smoking and alcohol trials suggests that
Antioxidants are biological and chemical compounds that reduce these factors have a negative impact on female fertility, potentially
oxidative damage (imbalance between creation of reactive through the generation of excessive oxidative stress (Agarwal 2012;
oxygen species and the body's ability to detoxify). They are a Ruder 2008). Other lifestyle factors such as diet, disease, pollution,
group of organic nutrients that include vitamins, minerals and stress and allergies also contribute to increased levels of free
polyunsaturated fatty acids (PUFAs). Some of the predominant radicals (Agarwal 2012).
antioxidants used in female subfertility are N-acetyl-cysteine;
melatonin; vitamins A, C and E; folic acid; myo-inositol; zinc and The global vitamin and supplement market has grown
selenium. They may be administered as a single antioxidant or as exponentially and has been reported in 2016 as being worth
combined therapy. over USD 140 billion, growing from USD 96 billion in 2012
(Global Supplement report 2016; Reportlinker.com 2010). In
PUFAs are classified into omega-3, omega-6 and omega-9. Omega-9 2009 sales of vitamins and dietary supplements in the United
is synthesised by animals, but omegas-3 and -6 need to be Kingdom "totalled £674.6 million, a growth of about 16% over
supplemented in the diet. The main sources of omega-6 are the previous five years, with the two biggest selling areas being
vegetable oils. Sources of omega-3 are vegetable and fish oils. The multivitamins (£138.6 million) and fish oils (£139.1 million)" (NHS
ratio of omega-6 to omega-3 has risen in recent times (as a result News 2011). Multivitamin sales have increased steadily since 2009,
of increased intake of vegetable oils) to the point where there is with reported sales in 2015 of GBP 414 million, with sales to
a reduced need for intake of omega-6 and an increased need for women accounting for the largest group (Mintel 2016). Vitamins
intake of omega-3 (Wathes 2007). and supplements are dispensed through various retail outlets,
including health food shops, online retailers, health centres, fitness
Pentoxifylline is a conventional medicine, a tri-substituted clubs, supermarkets and pharmacies.
xanthine derivative usually prescribed for intermittent claudication
(cramping) (Drugs.com 2013). Pentoxifylline is also used in fertility In an effort to enhance fertility, couples are increasingly resorting
treatment, as it is known to have a strong antioxidant effect by to ART; however, these techniques do not cure the causes of
generating reactive oxygen species (Vircheva 2010). It has been subfertility, but rather overcome some of its barriers. Adjunct
shown to benefit men who have varicocoele-associated infertility measures, including courses of dietary supplements such as oral
(engorged vein in the scrotum) (Oliva 2009). antioxidants, may be beneficial (Ebisch 2007). However, most
antioxidant supplements are uncontrolled by regulation, and thus
The amino acid L-arginine also has antioxidant properties that aid their effects may be unpredictable in the population.
in the inflammatory response and act against oxidative damage (Ko
2012). How the intervention might work
When oxidative damage occurs, toxins are produced as a Antioxidants are said to have an important role in the regulation of
consequence of all cells using oxygen to survive. Toxic end-products all processes involved in the birth of a healthy baby (Gupta 2007).

Informed decisions.

The local development of oxidative stress will have significant METHODS

adverse effects on these processes. Conditions with which the
adverse effects of oxidative stress may be associated in subfertile Criteria for considering studies for this review
women include endometriosis, hydrosalpinges (dilated fallopian
Types of studies
tubes), polycystic ovarian syndrome (PCOS), fetal malformations
and potentially unexplained subfertility (Agarwal 2012; Ruder 2008; Inclusion criteria
Zhao 2006).
• Randomised controlled trials (RCTs).
At the time of conception, oxidative stress can lead to cell • Cross-over trials are included; however, we used only first-phase
membrane lipid peroxidation, cellular protein oxidation and DNA data in the analysis. Achieving outcomes such as pregnancy and
damage, causing a negative effect upon the oocyte (immature live birth would preclude entry of couples into the next trial
egg cell), the embryo and implantation (Ruder 2008). Antioxidants phase (Dias 2006).
would be expected to counteract the negative impact of oxygen-
free radicals by acting as free radical scavengers. Exclusion criteria
• Any quasi-randomised trials.
Supplementary antioxidants may have several methods of action.
Fertility benefits of vitamin E include improvement in epithelial Types of participants
growth in blood vessels and in the endometrium (Ledee-Bataille
2002). Higher vitamin D levels are associated with an increased Inclusion criteria
likelihood of successful pregnancy and may be of particular benefit • Trials that included subfertile women who had been referred to
to women with PCOS in lowering hyperandrogenism (androgen a fertility clinic and might or might not be undergoing assisted
excess) (Thomson 2012). Myo-inositol helps ovarian function reproductive techniques (ART) such as in vitro fertilisation
and decreases hyperandrogenism and insulin resistance (Nestler (IVF), intrauterine insemination (IUI) or intracytoplasmic sperm
1998); L-arginine improves endometrial blood flow (Takasaki injection (ICSI).
2009); N-acetyl-cysteine is needed for fertile cervical mucus and
ovulation (Badawy 2007); and PUFAs influence prostaglandin Exclusion criteria
(lipid compounds with hormone-like effects) synthesis and
steroidogenesis (creation of steroid hormones), and also play a • Trials enrolling only fertile women attending a fertility clinic
role in the composition of cell membranes of the sperm and exclusively as the result of male partner infertility.
oocyte, which is important during fertilisation (Wathes 2007). • Trials enrolling women exclusively with Vitamin D deficiency.
Cohort studies have shown some evidence suggesting that in
some instances taking a multivitamin tablet may increase fertility Types of interventions
(Haggarty 2006) or even regulate ovulation (Charvarro 2008). Inclusion criteria
Why it is important to do this review • Any type of oral antioxidant supplementation versus control:
placebo (plus or minus a co-intervention) or no treatment/
There is currently limited evidence as to whether antioxidants standard treatment (standard treatment includes folic acid < 1
improve fertility, and ongoing trials in this area show varied results. mg);
This review assesses the effectiveness of different antioxidants and
• Individual or combined oral antioxidants versus any antioxidant
different dosages. This is an update of a review first published in
(head-to-head trials); or
2013 (Showell 2013)
• Pentoxifylline versus control (placebo or no treatment/standard
Subfertile women are highly motivated to explore all avenues of treatment).
treatment in their desire to have a healthy baby. Antioxidants
are mostly unregulated and are readily available for purchase by On clinical advice, we analysed trials that used folic acid (standard
consumers. Research has suggested that a significant number of treatment) and those that included a co-intervention (a fertility
women undergoing fertility treatment are taking oral supplements drug such as clomiphene citrate or metformin) in both arms in the
in the expectation that this will improve their chances of conception antioxidant versus placebo or no treatment/standard treatment
(O'Reilly 2014; Stankiewicz 2007). Consumer perception is that comparison and not in the head-to-head comparison, as the
antioxidant therapy is not associated with harm and is associated controls were not considered to be active treatments. We analysed
only with benefit. It is important to establish whether or not this pentoxifylline trials as a separate comparison, as it was not possible
therapy does improve fertility and whether it is associated with any to separate the antioxidant effects from the other medical effects of
harm. the drug.
Exclusion criteria
OBJECTIVES
• Interventions that included antioxidants alone versus fertility
To determine whether supplementary oral antioxidants compared drugs as controls. These fertility drugs included metformin and
with placebo, no treatment/standard treatment or another clomiphene citrate.
antioxidant improve fertility outcomes for subfertile women.

Informed decisions.

Types of outcome measures • Google, using the keywords 'antioxidants female infertility' and
'antioxidants female subfertility';
Primary outcomes
• Database for Abstracts of Reviews of Effects (DARE) for other
Live birth rate per woman randomly assigned: if live birth data were reviews on this topic;
unavailable and the trial reported ongoing pregnancy, we reported • 'Grey' literature (unpublished and unindexed), through the
ongoing pregnancy as live birth (footnoted in the forest plot). We openGREY database (www.opengrey.eu/); (Appendix 8).
define live birth as delivery of a live fetus after 20 completed weeks
of gestation, and ongoing pregnancy as evidence of a gestational We also contacted known experts and personal contacts for
sac with fetal heart motion at 12 weeks, confirmed with ultrasound. information on any unpublished materials, and we checked the
citation lists of appropriate papers for any relevant references.
Secondary outcomes
• Clinical pregnancy rate per woman (as confirmed by the Data collection and analysis
identification of a gestational sac on ultrasound at seven or more We conducted data collection and analysis in accordance with the
weeks' gestation). Cochrane Handbook for Systematic Reviews of Interventions (Higgins
• Any adverse effects reported by the trial. We subgrouped these 2011).
events by the type of adverse event reported.
Selection of studies
Search methods for identification of studies
Two review authors (MGS and RM-P) independently reviewed
We searched for all reports, published and unpublished, that titles and abstracts of trials for eligibility. We obtained the full
described RCTs investigating oral antioxidant supplementation for texts of trials that we considered for inclusion. We sought further
subfertile women and its impact on live birth, pregnancy and information from the authors of trials that did not contain sufficient
adverse events rates. We used both indexed and free-text terms, information to make a decision about eligibility. We resolved
and applied no language or date restrictions. any disagreements by reference to a third review author. We
documented the selection process with a PRISMA flow chart (see
Electronic searches Figure 1).
We searched the following databases: Data extraction and management
• The Cochrane Gynaecology and Fertility Group's (CGFG) Two review authors (MGS and RM-P) independently extracted data
specialised register of controlled trials from inception to from the included trials using a data extraction form. We compared
September 2016 (Appendix 1). This register contains published the two sets of extracted data and resolved discrepancies by
and unpublished trials and conference abstracts; discussion. The review authors screened the trials to ensure that
• Cochrane Central Register of Studies (CENTRAL CRSO) (from there were no duplicate publications.
inception to September 2016) (Appendix 2);
We designed the data extraction forms to extract information
• MEDLINE (1946 to September 2016) (Appendix 3);
on study characteristics and outcomes. We have included this
• Embase (1980 to September 2016) (Appendix 4); information and presented it in the Characteristics of included
• PsycINFO (from 1806 to September 2016) (Appendix 5); studies and the Characteristics of excluded studies tables, in
• AMED (Allied and Complementary Medicine) (1985 to September keeping with the guidance provided by the Cochrane Handbook
2016) (Appendix 6); for Systematic Reviews of Interventions (Higgins 2011). If any
• CINAHL (1982 to September 2016) (Appendix 7). information on trial methodology or any trial data were missing,
we contacted the study authors by email and by post. The
The MEDLINE search was limited by the Cochrane highly predominant questions for trial authors concerned live birth
sensitive search strategy filter for identifying randomised trials, data, clinical pregnancy, methods of randomisation and allocation
which appears in the Cochrane Handbook of Systematic Reviews concealment.
of Interventions (Version 5.1.0, Chapter 6, 6.4.11) (Higgins
2011). We combined the Embase and CINAHL (OVID platform Assessment of risk of bias in included studies
only) searches with trial filters developed by the Scottish We assessed the included studies for risks of bias using
Intercollegiate Guidelines Network (SIGN) (www.sign.ac.uk/ the Cochrane 'Risk of bias' tool, to assess selection bias
mehodology/filters.html#random). (sequence generation and allocation concealment); performance
bias (blinding of participants and personnel); detection bias
Searching other resources
(blinding of outcome assessors); attrition bias (completeness of
(last searched September 2016) outcome data); reporting bias (selective outcome reporting); and
other potential sources of bias. Two review authors (MGS and RM-
• International trial registers: the ClinicalTrials database, a service P) assessed the included studies according to these six criteria,
of the US National Institutes of Health (clinicaltrials.gov/ resolving any disagreements by discussion with a third review
ct2/home) and the World Health Organization International author. We sought published protocols.
Trials Registry Platform search portal (www.who.int/trialsearch/
Default.aspx); We took care to search for within-study selective reporting, for
• Web of Knowledge for conference proceedings and published example trials failing to report outcomes such as live birth or
trials; reporting them in insufficient detail to allow inclusion. Where

Informed decisions.

protocols were available, we assessed studies for differences We combined data from primary studies using a fixed-effect model
between study protocols and published results. in the following comparisons:
In cases where included studies failed to identify the primary • Antioxidants versus control (placebo or no treatment/standard
outcome of live birth but did report pregnancy rates, we carried treatment);
out an informal assessment to determine whether pregnancy rates • Antioxidants versus antioxidants or head-to-head stratification
were similar to those in studies that reported live birth. by type of antioxidant; and
Measures of treatment effect • Pentoxifylline versus control (placebo or no treatment/standard
treatment).
We expressed the dichotomous data for live birth, pregnancy rate,
miscarriage and adverse events as Mantel-Haenszel odds ratios We displayed increases in the odds of a particular outcome, which
(ORs) with 95% confidence intervals (95% CIs). may be beneficial (e.g. live birth) or detrimental (e.g. adverse
effects), graphically in meta-analyses to the right of the centre line,
Unit of analysis issues and decreases in the odds of a particular outcome to the left of the
centre line.
We analysed the outcomes of live birth, pregnancy and adverse
events per woman randomly assigned, counting multiple births as The aim was to define analyses that were comprehensive and
one live birth event. mutually exclusive, so that we could slot all eligible study results
into one stratum only. We specified comparisons so that any trials
Dealing with missing data
falling within each stratum could be pooled for meta-analysis.
In cases where trial data were missing, we first sought information Stratification allowed for consideration of effects within each
from the original trial investigators. Details of authors contacted stratum, as well as or instead of an overall estimate for comparison.
and the questions asked of them are contained in Characteristics
of included studies. In addition, and where possible, we performed In trials with multiple arms, we pooled intervention groups versus
analyses on all outcomes on an intention-to-treat basis, i.e. to the control group.
include in the analyses all women randomly assigned to each
If individuals had been randomly re-assigned after failed cycles, we
group and to analyse all women in the group to which they were
did not pool the data in a meta-analysis.
allocated, regardless of whether or not they received the allocated
intervention. Subgroup analysis and investigation of heterogeneity
Assessment of heterogeneity We conducted the following subgroup analyses:
We considered whether the clinical and methodological • Type of control, placebo or no treatment;
characteristics of included studies were sufficiently similar for
• Type of antioxidant, whether individual or combined (three or
meta-analysis to provide a clinically meaningful summary. We
more antioxidants combined);
assessed statistical heterogeneity according to the guidelines
set out in the Cochrane Handbook for Systematic Reviews of • Trials that enrolled women with different indications for
Interventions (Higgins 2011). We examined heterogeneity between infertility (i.e. PCOS, endometriosis, unexplained infertility or
the results of different trials by visually examining the forest plots poor responders); and
and the overlap of confidence intervals (poor overlap suggested • Trials that enrolled women who were also undergoing IVF or
heterogeneity), by considering the P value (a low P value or a ICSI.
large Chi2 statistic relative to the degree of freedom suggests
If we detected substantial heterogeneity, we explored possible
heterogeneity), and by identifying the I2 statistic. If I2 was 50%
explanations by performing sensitivity analyses.
or higher, we assumed high heterogeneity, and conducted a
sensitivity analysis. A high I2 statistic suggests that variations in Sensitivity analysis
effect estimates were due to differences between trials rather than
to chance alone. We conducted sensitivity analyses (using the random-effects model
in RevMan software) on the primary outcomes if we detected a high
Assessment of reporting biases degree of heterogeneity (where the I2 statistic was 50% or more),
excluding studies:
The search strategies covered multiple sources, without language
or publication restrictions. We were alert to the possibility of • with a high risk of bias, or
duplication of data. We used a funnel plot to explore the possibility
• that used antioxidants plus folic acid versus standard treatment
of small-study effects in cases where estimates of intervention
(folic acid < 1 mg); or
effect can be more beneficial in smaller studies (Higgins 2011).
• that used antioxidants plus a fertility drug (a co-intervention)
Data synthesis versus placebo plus a fertility drug.
We conducted statistical analysis of the data using Review Manager Overall quality of the body of evidence: 'Summary of findings'
5 (RevMan 2014). We considered pregnancy outcomes to be tables
positive, and higher numbers of pregnancy rates to be a benefit. We
considered the outcomes of miscarriage and adverse events to be We produced a 'Summary of findings' table, using GRADEpro GDT
negative effects, and higher numbers harmful. software (GRADEpro GDT 2015) and Cochrane methods (Higgins
2011) for the main review comparison (Antioxidant(s) compared to

Informed decisions.

placebo or no treatment/standard treatment). This table evaluates we placed into the 'Awaiting classification' section of the review. We
the overall quality of the body of evidence for the main review found 12 ongoing trials in searches of the clinical trial registers (see
outcomes (live birth, clinical pregnancy and adverse events), using Ongoing studies).
GRADE criteria (study limitations, i.e. risk of bias, consistency of
effect, imprecision, indirectness and publication bias). We have 2017 Update
included an additional 'Summary of findings' table for the main We assessed 926 abstracts (after 222 duplicates were removed) for
review outcomes for the comparison of pentoxifylline compared inclusion from the title and abstract found in a search dated from
to placebo or no treatment/standard care. Two review authors, April 2013 to September 2016. We assessed 39 of these papers in full
working independently, made judgements about evidence quality text. One study was published in Persian (Mohammadbeigi 2012)
('high', 'moderate', 'low' or 'very low'). and required translation (see Acknowledgements). We excluded
15 articles (14 studies) of the 39, and included 24 (23 studies).
RESULTS Of the latter, six were from the seven trials placed in 'Awaiting
classification' in the original review, while Salem 2012 was excluded
Description of studies
due to inappropriate intervention and control. See the PRISMA flow
Results of the search chart (Figure 1). For the current update four of the 12 previously
ongoing trials are now included (Bentov 2014; Mohammadbeigi
2013 version of the review
2012; Unfer 2011; Youssef 2015). The conference abstract of the
The search retrieved 2127 abstracts and titles, which we screened included study Aboulfoutouh 2011 in the original review became
to identify trials that met our inclusion criteria. We retrieved the full a secondary reference of Youssef 2015 in the update and Rezk
texts of 67 trials for appraisal. Only one study (Bonakdaran 2012) 2004, formerly an excluded study, is now included as a secondary
was not published in English, with the full text in Persian; however, reference of Rizk 2005. Pourghassem 2010 was found to be the
the English abstract contained enough information to show that it same trial as the excluded Ardabili 2012. We excluded Pasha 2011
did not meet the inclusion criteria, and we therefore excluded it. Of due to an ineligible population. We added two trials (NCT03023514;
the 67 studies assessed, we included 27 and excluded 39. Please see NCT02058212) after the search in September 2016, so eight trials
Characteristics of included studies and Characteristics of excluded remain ongoing (Fernando 2014; NCT01019785; NCT03023514;
studies for study details. A repeat search in April 2013 revealed NCT02058212; IRCT201112148408N1; CTRI/2012/08/002943;
seven studies (Carlomagno 2012; Choi 2012; Mohammadbeigi 2012; NCT01782911; NCT01267604).
Rosalbino 2012; Salehpour 2012; Schachter 2007; Salem 2012) that


Informed decisions.

Figure 1. Study flow diagram.

Informed decisions.

We include 23 new trials in the 2017 update: Battaglia 1999; 2007; Unfer 2011) included women with PCOS (four trials in the
Bentov 2014; Brusco 2013; Carlomagno 2012; Cheraghi 2016; original review and 17 in the update). Other participants in the trials
Choi 2012; Colazingari 2013; Daneshbodi 2013; Deeba 2015; El were enrolled for endometriosis, ovulation failure, tubal blockages
Refaeey 2014; Ismail 2014; Keikha 2010; Lesoine 2016; Maged 2015; and unexplained subfertility. One trial included women aged 35 to
Mohammadbeigi 2012; Pacchiarotti 2016; Panti Abubakar 2015; 42 years with poor oocyte quality and poor response (Rizzo 2010).
Polak de Fried 2013; Razavi 2015; Rosalbino 2012; Salehpour 2012; Seven trials included women with more than one fertility problem:
Schachter 2007; Valeri 2015. these reasons included a percentage of male partner subfertility,
unexplained subfertility, ovulatory problems, poor responders,
Fifty trials are now included in this updated review (Characteristics PCOS, tubal blockages and endometriosis (Agrawal 2012; Aleyasin
of included studies) and 50 have been excluded (Characteristics of 2009; Batioglu 2012; Battaglia 1999; Brusco 2013; Griesinger 2002;
excluded studies). Westphal 2006). Four trials included a small percentage of women
whose subfertility was caused by the male partner (Aleyasin 2009;
Included studies
Creus 2008; Balasch 1997; Griesinger 2002).
Fifty trials met the criteria for inclusion. Fourteen were based
in Italy (Battaglia 1999; Battaglia 2002; Brusco 2013; Carlomagno One trial enrolled only women who were aged over 40 (Valeri 2015)
2012; Ciotta 2011; Colazingari 2013; Gerli 2007; Lisi 2012; Papaleo and one (Gerli 2007) included participants in whom "infertility was
2009; Pacchiarotti 2016; Rizzo 2010; Rosalbino 2012; Unfer 2011; an ailment in only half of the participants in each group". The author
Valeri 2015). Ten were based in Iran (Alborzi 2007; Aleyasin 2009; of this trial states that there was "no difference in the proportions
Cheraghi 2016; Daneshbodi 2013; Keikha 2010; Mohammadbeigi of infertile women in the groups".
2012; Rashidi 2009; Razavi 2015; Salehpour 2009; Salehpour 2012),
Twenty-seven studies included women undergoing IVF/ICSI
seven in Egypt (Badawy 2006; El Refaeey 2014; Ismail 2014; Maged
(Aleyasin 2009; Batioglu 2012; Battaglia 1999; Battaglia 2002;
2015; Rizk 2005; Nasr 2010; Youssef 2015), four in Turkey (Batioglu
Bentov 2014; Brusco 2013; Carlomagno 2012; Cheraghi 2016; Choi
2012; Cicek 2012; Eryilmaz 2011; Ozkaya 2011), three in Korea (Choi
2012; Ciotta 2011; Colazingari 2013; Eryilmaz 2011; Griesinger
2012; Kim 2006; Kim 2010), two in Spain (Creus 2008; Balasch 1997)
2002; Kim 2006; Kim 2010; Lesoine 2016; Lisi 2012; Ozkaya 2011;
and one each in the UK (Agrawal 2012), Hungary/Austria (Griesinger
Pacchiarotti 2016; Papaleo 2009; Polak de Fried 2013; Rizzo
2002), Mexico (Mier-Cabrera 2008) USA (Westphal 2006), Canada
2010; Rosalbino 2012; Salehpour 2009; Unfer 2011; Valeri 2015;
(Bentov 2014), Bangladesh (Deeba 2015), Germany (Lesoine 2016),
Youssef 2015). Eleven studies included women undergoing natural
Nigeria (Panti Abubakar 2015) Israel (Schachter 2007) and Argentina
intercourse or ovulation induction with timed intercourse or IUI
(Polak de Fried 2013).
(Agrawal 2012; Badawy 2006; Cicek 2012; Deeba 2015; El Refaeey
We tried to contact authors of all the included trials to obtain 2014; Ismail 2014; Maged 2015; Mohammadbeigi 2012; Panti
further details and clarification. However we could not obtain data Abubakar 2015; Rizk 2005; Salehpour 2012). The remaining 12
for meta-analysis from 14 trials (Carlomagno 2012; Choi 2012; studies enrolled women who were either having no adjunctive
Colazingari 2013; Daneshbodi 2013; Deeba 2015; Keikha 2010; Kim treatment or each trial included a number of differing treatments,
2006; Kim 2010; Lesoine 2016; Mohammadbeigi 2012; Ozkaya 2011; i.e. some women having IVF while others were having IUI, and only
Razavi 2015; Rosalbino 2012; Valeri 2015), and one did not report on one trial enrolled women undergoing laparoscopic ovarian drilling
the outcomes included in this review (Salehpour 2009). In one trial (Nasr 2010).
(Gerli 2007) (see Table 1), only half of the participants declared that
Further details of inclusion and exclusion criteria are available in
they wanted to become pregnant before the study began; we have
the Characteristics of included studies table.
therefore included this trial, but have not used the data in the meta-
analysis (see Characteristics of included studies). Interventions
Duration of treatment ranged from 12 days (Battaglia 2002) to A variety of antioxidants were used in the included trials.
nearly two years (Alborzi 2007). One trial (Bentov 2014) was Comparisons covered antioxidants versus placebo, no treatment or
terminated before the end due to the publication of a paper standard treatment (folic acid < 1 mg), head-to-head comparisons
(Levin 2012) describing the negative effects of polar body biopsy, (antioxidant versus antioxidant) and pentoxifylline versus placebo,
an adjunctive treatment in this trial, on the development of the no treatment or standard treatment.
embryo. The trial began in 2010 and ran until 2012, enrolling 39
women. Comparison antioxidants versus placebo, no treatment and
standard treatment included the following: combinations of
Participants antioxidants; L-arginine, vitamin E, myo-inositol, D-chiro-inositol,
carnitine, selenium, vitamin B complex, vitamin C, vitamin D
The trials randomly assigned 6510 subfertile women who were
+calcium, CoQ10, and omega-3 polyunsaturated fatty acids. They
attending a fertility clinic and might or might not be undergoing
were labelled as Octatron® (Youssef 2015), multiple micronutrients
ART procedures such as IVF, IUI or ICSI. The age range of randomly-
(Agrawal 2012; Deeba 2015; Ozkaya 2011; Panti Abubakar 2015)
assigned participants was 18 to 44 years; Battaglia 1999 enrolled
and Fertility Blend (Westphal 2006). The time that women received
women who were between 37 and 44 years.
treatment or control in these trials ranged from two-and-a-half
Twenty-one trials (Brusco 2013; Cheraghi 2016; Choi 2012; menstrual cycles to six months. Four of these trials (Agrawal 2012;
Colazingari 2013; Daneshbodi 2013; El Refaeey 2014; Ismail 2014; Deeba 2015; Panti Abubakar 2015; Westphal 2006) enrolled women
Keikha 2010; Lesoine 2016; Maged 2015; Mohammadbeigi 2012; undergoing ovulation induction with timed intercourse, and two
Nasr 2010; Pacchiarotti 2016; Panti Abubakar 2015; Papaleo 2009; (Ozkaya 2011; Youssef 2015) included women undergoing IVF/ICSI.
Razavi 2015; Rizk 2005; Rosalbino 2012; Salehpour 2012; Schachter More details of these combination antioxidants are given in the

Informed decisions.

Characteristics of included studies. The remaining 44 trials gave Agrawal 2012, Cicek 2012 and Schachter 2007 reported on ongoing
single antioxidants, including two types of inositols and vitamin B pregnancy, which we used as a surrogate for live birth.
complexes. The duration of treatment in these trials ranged from 12
days to two years. Clinical pregnancy
Thirty-six trials reported on clinical pregnancy rates in the text of

The comparison 'antioxidants versus antioxidants' included only the trial reports or through direct communication with the authors
three trials (Colazingari 2013; Keikha 2010; Unfer 2011). Two of (Agrawal 2012; Aleyasin 2009; Badawy 2006; Balasch 1997; Batioglu
these three trials looked at the effects of myo-inositol versus 2012; Battaglia 1999; Battaglia 2002; Bentov 2014; Brusco 2013;
D-chiro-inositol, while Keikha 2010 looked at N-acetyl- cysteine Carlomagno 2012; Cheraghi 2016; Choi 2012; Cicek 2012; Creus
versus vitamin C. Only Unfer 2011 could be used in the meta- 2008; Deeba 2015; El Refaeey 2014; Eryilmaz 2011; Gerli 2007;
analysis, as Colazingari 2013 and Keikha 2010 did not report on Griesinger 2002; Ismail 2014; Kim 2010; Lisi 2012; Maged 2015; Nasr
live birth, clinical pregnancy or adverse events. The head-to-head 2010; Pacchiarotti 2016; Panti Abubakar 2015; Papaleo 2009; Polak
comparisons were included in an attempt to assess whether one de Fried 2013; Rashidi 2009; Rizk 2005; Rizzo 2010; Salehpour 2012;
antioxidant was more effective than another. Schachter 2007; Unfer 2011; Westphal 2006; Youssef 2015). One trial
In summary: reported only biochemical pregnancy or conception (Ciotta 2011)
and another four trials reported only 'pregnancy rates' (Alborzi
• 22 included trials compared antioxidants versus placebo 2007; Mier-Cabrera 2008; Mohammadbeigi 2012; Razavi 2015) (see
(Alborzi 2007; Badawy 2006; Battaglia 2002; Bentov 2014; data from these five trials in Table 2). Nine trials did not report
Cheraghi 2016; Choi 2012; Daneshbodi 2013; Griesinger 2002; any pregnancy outcomes (Colazingari 2013; Daneshbodi 2013;
Ismail 2014; Kim 2006; Lesoine 2016; Mier-Cabrera 2008; Keikha 2010; Kim 2006; Lesoine 2016; Ozkaya 2011; Rosalbino 2012;
Mohammadbeigi 2012; Nasr 2010; Ozkaya 2011; Panti Abubakar Salehpour 2009; Valeri 2015). We tried to contact authors of all the
2015; Polak de Fried 2013; Rizk 2005; Rosalbino 2012; Salehpour trials that did not report clinical pregnancy rates.
2009; Salehpour 2012; Westphal 2006);
Adverse events
• 21 trials compared antioxidants with 'no treatment' or standard
treatment (Agrawal 2012; Batioglu 2012; Battaglia 1999; Brusco The following adverse events were reported:
2013; Carlomagno 2012; Cicek 2012; Ciotta 2011; Deeba 2015; El
Refaeey 2014; Eryilmaz 2011; Gerli 2007; Lisi 2012; Maged 2015; • Miscarriage: 24 trials either reported on miscarriage, or we
Pacchiarotti 2016; Papaleo 2009; Rashidi 2009; Razavi 2015; calculated the numbers from the differences between live birth
Rizzo 2010; Schachter 2007; Valeri 2015; Youssef 2015); and clinical pregnancy rates (Agrawal 2012; Aleyasin 2009;
• three trials compared one antioxidant with another antioxidant Badawy 2006; Balasch 1997; Battaglia 1999; Battaglia 2002;
(head-to-head comparisons) (Colazingari 2013; Keikha 2010; Bentov 2014; Choi 2012; Cicek 2012; Creus 2008; El Refaeey
Unfer 2011); 2014; Eryilmaz 2011; Ismail 2014; Nasr 2010; Pacchiarotti 2016;
• two trials compared pentoxifylline with placebo (Balasch 1997; Papaleo 2009; Panti Abubakar 2015; Polak de Fried 2013; Rizzo
Creus 2008); 2010; Rizk 2005; Schachter 2007; Unfer 2011; Westphal 2006;
Youssef 2015). We did not include the data from Rizk 2005 in the
• one trial compared pentoxifylline plus vitamin E with no
meta-analysis for miscarriage, as no pregnancies were reported
treatment (Aleyasin 2009);
in the control group, and adding these miscarriage data would
• 11 trials compared antioxidants plus a co-intervention with have skewed the analysis.
a placebo or no treatment plus a co-intervention at the
• Multiple pregnancy: 10 trials reported on multiple pregnancy
same dosage (Badawy 2006; Cheraghi 2016; El Refaeey 2014;
(Aleyasin 2009; Badawy 2006; El Refaeey 2014; Ismail 2014;
Maged 2015; Pacchiarotti 2016; Rashidi 2009; Razavi 2015; Rizk
Nasr 2010; Pacchiarotti 2016; Polak de Fried 2013; Rizk 2005;
2005; Rizzo 2010; Salehpour 2012; Schachter 2007). The co-
Salehpour 2012; Youssef 2015). We did not include Rizk 2005
interventions used were clomiphene citrate and metformin;
in the meta-analysis for multiple pregnancy, as no pregnancies
• In one trial, the control was unspecified (Kim 2010), and we tried occurred in the control group, and adding these data would
unsuccessfully to contact this author by email and by post. have skewed the analysis. Nasr 2010 reported no multiple
pregnancies in the antioxidant or placebo groups, so we did not
Seven trials (Cheraghi 2016; Griesinger 2002; Maged 2015;
include this study in the meta-analysis;
Pacchiarotti 2016; Rashidi 2009; Rosalbino 2012; Schachter 2007)
were multi-arm and fit into more than one of the above categories. • Gastrointestinal disturbances: Three trials reported on nausea
In one trial (Cheraghi 2016) all women were prescribed the oral (Cicek 2012; Maged 2015; Westphal 2006). No cases of
contraceptive pill as a pretreatment to ICSI. gastrointestinal disturbances were reported in treatment or
control groups in Cicek 2012;
Outcomes • Ectopic pregnancy: Two trials reported ectopic pregnancies
Live birth
(Agrawal 2012; Aleyasin 2009);
• Ovarian hyperstimulation syndrome (OHSS): three trials
The primary outcome for this review was live birth. Ten trials reported on OHSS (Kim 2006; Papaleo 2009; Rizk 2005).There
reported on live birth (Agrawal 2012; Aleyasin 2009; Battaglia 2002; were no cases of OHSS in treatment or control groups in Papaleo
Bentov 2014; Cicek 2012; Nasr 2010; Panti Abubakar 2015; Polak 2009 or Rizk 2005. Kim 2006 did not provide data for OHSS;
de Fried 2013; Schachter 2007; Unfer 2011). We sent emails and
• Preterm birth: One trial (Nasr 2010) reported on preterm birth.
letters to authors of all other included trials to ask whether they
had any data on live birth. We received live birth data from Battaglia
2002, Panti Abubakar 2015, and Polak de Fried 2013 by email.
Informed decisions.

We tried to contact authors of all the trials that did not report were because the population did not meet criteria for inclusion
adverse events. We could not assume that there were no adverse in this review (Aflatoonian 2014; Ardabili 2012; Baillargeon
events in trials where these were not reported. 2004; Benelli 2016; Bonakdaran 2012; Cheang 2008; Ciotta 2012;
Costantino 2009; Elgindy 2008; Elgindy 2010; Firouzabadi 2012;
Design Genazzani 2008; Hebisha 2016; Hernández-Yero 2012; Iuorno 2002;
All 50 included trials were of parallel-group design. One trial Jamilian 2016; Jamilian 2016a; Kamencic 2008; Kilicdag 2005;
(Rosalbino 2012) was a five-armed trial. Two trials (Griesinger 2002; Le Donne 2012; Li 2013; Moosavifar 2010; Nestler 1999; Nestler
Schachter 2007) were four-armed, which used different dosages of 2001; Nordio 2012; Oner 2011; Pasha 2011; Pizzo 2014; Santanam
vitamin C versus placebo and doses of vitamin B complex versus no 2003; Taheri 2015; Thiel 2006; Vargas 2011; Yoon 2010). Many of
treatment respectively, and four trials were three-armed (Cheraghi these trials recruited women with PCOS who were not attending a
2016; Maged 2015; Pacchiarotti 2016; Rashidi 2009). subfertility clinic and whose main concern was not pregnancy but
rather ways to control their symptoms of PCOS. Seven were quasi-
The sample size of the included trials ranged from 29 participants controlled trials and therefore were not randomised (Aksoy 2010;
(Lesoine 2016) to 804 participants (Badawy 2006). Fourteen trials Al-Omari 2003; Crha 2003; Henmi 2003; Nazzaro 2011; Papaleo 2007;
included in the meta-analysis (Agrawal 2012; Battaglia 2002; Bentov Tamura 2008). Nine had inappropriate treatment or control for
2014; Cicek 2012; Ciotta 2011; El Refaeey 2014; Eryilmaz 2011; inclusion (Asadi 2014; Elnashar 2007; Farzadi 2006; Hashim 2010;
Ismail 2014; Lisi 2012; Mier-Cabrera 2008; Nasr 2010; Pacchiarotti Immediata 2014; Papaleo 2008; Raffone 2010; Salem 2012; Twigt
2016; Papaleo 2009; Salehpour 2012) reported carrying out a power 2011). One (Elnashar 2005) was a conference abstract of another
calculation. excluded trial (Elnashar 2007). Two were secondary analyses (Pal
2016; Ruder 2014). One was a duplicate study (Ghotbi 2007) of the
Funding included study Alborzi 2007 and we excluded Nichols 2010 after
Funding sources were reported by only 14 of the 50 included the lead investigator confirmed that this trial had been abandoned
trials. One study (Bentov 2014) reported the support of before recruitment because of lack of funding. One trial Rezk 2004,
Ferring Pharmaceuticals and that one of the authors had a previously excluded, was now added as a sub-study of the included
consultancy agreement with Fertility Neutraceuticals, responsible study Rizk 2005.
for manufacturing and distribution of the CoQ10 product, and Ongoing trials
is also on the Science Advisory Board for Ferring. Valeri 2015
reported funding by a pharmaceutical company and three studies Twelve trials were ongoing in the original review; five of
(Carlomagno 2012; Lesoine 2016; Pacchiarotti 2016) included an these became included in the 2017 update (Agrawal 2012;
author who was an employee of a pharmaceutical company. Bentov 2014; Mohammadbeigi 2012; Unfer 2011; Youssef
Schachter 2007 reported that laboratory costs were partially 2015); two became excluded trials: Ardabili 2012 (formerly
supported by a company producing vitamins and supplements. known as Pourghassem 2010), and Pasha 2011. Five of the
One trial reports self-funding (Agrawal 2012), and eight reported 12 trials remain ongoing (NCT01019785; IRCT201112148408N1;
gaining funding from their institutions (Aleyasin 2009; Carlomagno CTRI/2012/08/002943; NCT01782911; NCT01267604).
2012; Cheraghi 2016; Creus 2008; Mier-Cabrera 2008; Razavi 2015;
Salehpour 2009; Westphal 2006). See details in Characteristics of In addition we identified 3 further ongoing trials: NCT03023514;
included studies. NCT02058212; Fernando 2014.
Excluded studies Risk of bias in included studies

We retrieved the full text of trials that were identified as potentially See Figure 2 for a summary of risk of bias in individual trials, and
eligible for inclusion (see Figure 1). We excluded 54 trials; 33 of these Figure 3 for a summary of each risk of bias item across all included
trials.


Informed decisions.

Figure 2. Methodological risk of bias summary: review authors' judgements about each methodological bias item
for each included study.

Informed decisions.


Figure 2. (Continued)

Informed decisions.




Informed decisions.

Figure 3. Methodological risk of bias graph: review authors' judgements about each methodological bias item
presented as percentages across all included trials.

Sequence Generation Blinding
All of the 50 included trials were randomised with a parallel We considered that the blinding status of participants could
design. Thirty-three trials described their methods of sequence influence findings for the outcomes of live birth, pregnancy
generation, which typically were computer-generated or used a and adverse effects, as antioxidants are easily available and it
random-number table (Agrawal 2012; Aleyasin 2009; Balasch 1997; would be possible for participants to self-medicate. Therefore if
Batioglu 2012; Battaglia 2002; Battaglia 1999; Bentov 2014; Cicek the participants were not blinded or the trial was not placebo-
2012; Ciotta 2011; Colazingari 2013; Creus 2008; El Refaeey 2014; controlled, or both, we considered the trial to be at high risk.
Eryilmaz 2011; Gerli 2007; Ismail 2014; Lesoine 2016; Lisi 2012; Thirty-two of the 50 included trials described some form of blinding
Maged 2015; Mier-Cabrera 2008; Mohammadbeigi 2012; Nasr 2010; of participants or investigators, or both. Four were triple-blinded,
Ozkaya 2011; Pacchiarotti 2016; Papaleo 2009; Polak de Fried 2013; with participants, clinicians/investigators and outcome assessors
Rashidi 2009; Razavi 2015; Rizzo 2010; Rosalbino 2012; Schachter blinded (Agrawal 2012; Badawy 2006; Battaglia 2002; Mier-Cabrera
2007; Unfer 2011; Valeri 2015; Youssef 2015). One trial (Panti 2008). Eight were double-blinded with blinding of participants
Abubakar 2015) used a coin toss. Sixteen trials simply reported and clinicians (Alborzi 2007; Bentov 2014; Ciotta 2011; Griesinger
the trial as randomised with no description of method (Badawy 2002; Razavi 2015; Rizk 2005; Salehpour 2009; Westphal 2006).
2006; Brusco 2013; Carlomagno 2012; Cheraghi 2016; Choi 2012; Twelve stated that they were double-blinded but did not declare
Daneshbodi 2013; Deeba 2015; Griesinger 2002; Keikha 2010; Kim who was blinded (Creus 2008; Cheraghi 2016; Carlomagno 2012;
2006; Kim 2010; Mier-Cabrera 2008; Rizk 2005; Salehpour 2009; Colazingari 2013; Daneshbodi 2013; Gerli 2007; Ismail 2014; Keikha
Salehpour 2012; Westphal 2006). Alborzi 2007 reported the method, 2010; Pacchiarotti 2016; Polak de Fried 2013; Unfer 2011; Valeri
but it remained unclear whether randomisation was performed by 2015). Eight were single-blinded: the participants were blinded
coin flip or with the use of odd and even numbers. We rated only in Balasch 1997, Panti Abubakar 2015 and Salehpour 2012; the
one trial (Brusco 2013) at high risk for this domain, due to lack of embryologists were blinded in Papaleo 2009 and Lesoine 2016;
explanation of the methods of randomisation and the unbalanced and the outcome assessors were blinded in Lisi 2012, El Refaeey
numbers in the treatment and control groups. We conducted a 2014 and Mohammadbeigi 2012. The remaining 18 trials did not
sensitivity analysis on the exclusion of trials that we considered to report any blinding; however, nine of these used 'no treatment'
be at high risk in any of the 'Risk of bias' domains. as the control so blinding for these trials is problematic (Aleyasin
2009; Battaglia 1999; Batioglu 2012; Brusco 2013; Carlomagno 2012;
Allocation Cicek 2012; Eryilmaz 2011; Maged 2015; Youssef 2015). Only Brusco
2013 stated that it was an open study. Valeri 2015 was also a no-
We judged 18 trials to be at low risk for allocation concealment
treatment trial but reported being double-blinded. Nine trials did
(Agrawal 2012; Alborzi 2007; Aleyasin 2009; Badawy 2006; Battaglia
not report on blinding (Choi 2012; Deeba 2015; Kim 2006; Kim 2010;
1999; Battaglia 2002; Bentov 2014; Colazingari 2013; Creus 2008;
Ozkaya 2011; Rashidi 2009; Rizzo 2010; Rosalbino 2012; Schachter
El Refaeey 2014; Griesinger 2002; Ismail 2014; Lisi 2012; Maged
2007).
2015; Razavi 2015; Rizk 2005; Schachter 2007; Youssef 2015). One
trial (Eryilmaz 2011) replied through email correspondence that no Incomplete outcome data
allocation concealment was used. The remainder either did not
describe any methods of allocation concealment or the description Eighteen trials had no losses to follow-up (Alborzi 2007; Aleyasin
was not clear. We tried unsuccessfully to contact these authors 2009; Badawy 2006; Batioglu 2012; Battaglia 1999; Brusco 2013;
regarding allocation concealment techniques. Ciotta 2011; Lesoine 2016; Lisi 2012; Maged 2015; Nasr 2010;
Papaleo 2009; Polak de Fried 2013; Rashidi 2009; Rizk 2005;

Informed decisions.

Rizzo 2010; Schachter 2007; Westphal 2006). Four trials reported remaining included trials. We therefore cannot confirm that on the
losses but used intention-to-treat (ITT) analysis (Agrawal 2012; basis of published reports alone the authors included all expected
Ismail 2014; Unfer 2011; Youssef 2015). Nine trials had losses and outcomes. However we considered a trial to be at low risk of
described from which groups they were lost, but did not use selective reporting if the outcomes reported in the Methods were
ITT in the reporting of trials; however, we used ITT for them in reported in the Results, and we rated 34 trials at low risk for
the meta-analysis (Balasch 1997; Battaglia 2002; Cheraghi 2016; this domain (Agrawal 2012; Alborzi 2007; Battaglia 1999; Battaglia
Creus 2008; El Refaeey 2014; Mier-Cabrera 2008; Pacchiarotti 2016; 2002; Bentov 2014; Brusco 2013; Cheraghi 2016; Cicek 2012; Ciotta
Panti Abubakar 2015; Salehpour 2012). Cheraghi 2016 explained 2011; Colazingari 2013; Creus 2008; Daneshbodi 2013; El Refaeey
the losses but was considered at high risk for attrition, as the 2014; Eryilmaz 2011; Griesinger 2002; Ismail 2014; Lesoine 2016; Lisi
losses were over 25% of the randomised women. Bentov 2014 had 2012; Maged 2015; Nasr 2010; Ozkaya 2011; Pacchiarotti 2016; Panti
explained loss to follow-up but reported data as percentages, so Abubakar 2015; Polak de Fried 2013; Razavi 2015; Rizk 2005; Rizzo
it is unclear if ITT was used. This trial was also terminated before 2010; Rosalbino 2012; Salehpour 2009; Salehpour 2012; Schachter
finishing enrolment, and we therefore rated it at high risk for this 2007; Unfer 2011; Valeri 2015; Youssef 2015).
domain. Salehpour 2009 had also explained losses, but because
outcomes reported in the trial were different from outcomes in Failure to report live birth in subfertility trials is common, and
this review, we could not include this study in the meta-analysis. is a major source of bias (Clarke 2010); it should be the default
Three trials (Cicek 2012, Eryilmaz 2011 and Griesinger 2002) had primary outcome in fertility trials. Only eight trials reported live
losses to follow-up with no explanation of which groups were birth (Aleyasin 2009; Battaglia 2002; Bentov 2014; Cicek 2012; Nasr
affected, however we took data from these trials as totals were 2010; Panti Abubakar 2015; Polak de Fried 2013; Unfer 2011). Two
given after dropouts, and we assumed that the groups were equal trials (Agrawal 2012; Schachter 2007) reported ongoing pregnancy,
on allocation. The remaining 14 trials were not included in the which we took to be live birth in the analysis. Mier-Cabrera 2008 and
meta-analysis: Gerli 2007 had more than 30% dropouts from the Papaleo 2009 stated that they would report live birth, but reported
treatment group, and data were unavailable for the 13 other trials only pregnancy. Adverse events were not well reported in most
(Carlomagno 2012; Choi 2012; Colazingari 2013; Daneshbodi 2013; studies.
Deeba 2015; Keikha 2010; Kim 2006; Kim 2010; Mohammadbeigi
A funnel plot for clinical pregnancy (Figure 4) was symmetrical,
2012; Ozkaya 2011; Razavi 2015; Rosalbino 2012; Valeri 2015). We
except for an absence of studies in the lower left of the pyramid.
tried to contact authors when the data were unavailable.
This suggests a small-study effect, indicating the potential for
Selective reporting publication bias whereby small unpublished studies with negative
results were not represented. Estimates of the intervention effect
Trial protocols were available for four trials (Bentov 2014; tend to be more beneficial in smaller studies and thus introduce the
Mohammadbeigi 2012; Unfer 2011; Youssef 2015) through the potential for selective reporting and publication bias.
clinical trials registries, but these were unavailable for the 46


Informed decisions.

Figure 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 Effects of interventions
We rated two trials (Balasch 1997; Bentov 2014) at high risk in See: Summary of findings for the main comparison
this domain, for women receiving varying adjunctive treatments Antioxidant(s) compared to placebo or no treatment/standard
and early termination of the study, respectively. See details in treatment for female subfertility; Summary of findings 2
Characteristics of included studies. Pentoxifylline compared to placebo or no treatment/standard care
for female subfertility
Reasons for studies with data included within the review but not
in the analysis 1. Antioxidant supplement versus placebo, no treatment/
Gerli 2007 (see Table 1) was not incorporated into the analysis, standard treatment
as only half the women randomly assigned reported a desire to Primary outcome: Live birth
become pregnant. Ninety-two women were randomly assigned,
1.1 Live birth; antioxidants versus placebo or no treatment/standard
45 to the treatment group and 47 to the control group. Twenty-
treatment
three from the treatment group and 19 from the control wished
to conceive; four from the treatment group and one from the See Analysis 1.1.
control group became pregnant. This trial also had more than 30%
dropouts from the treatment group. Antioxidants were associated with an increased live birth rate
compared with placebo or no treatment (odds ratio (OR) 2.13, 95%
Rashidi 2009 reported on clinical pregnancy, but there were no confidence interval (CI) 1.45 to 3.12, P > 0.001, 8 RCTs, 651 women,
events in either the antioxidant or the no-treatment arms of the I2 = 47%, very low-quality evidence) (Figure 5). This suggests that
trial. among subfertile women with an expected live birth rate of 20%,
the rate among women using antioxidants would be between 26%
and 43% (Summary of findings for the main comparison).


Informed decisions.

Figure 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 eight trials that reported live birth (Agrawal 2012; Battaglia control (these were in both the intervention and control arms, with
2002; Bentov 2014; Cicek 2012; Nasr 2010; Panti Abubakar 2015; an antioxidant in addition in the intervention), there was still an
Polak de Fried 2013; Schachter 2007), the OR for live birth was 2.13 association between increased live birth rate in the intervention
and for clinical pregnancy was 2.18. When we pooled all 26 studies arm, compared with placebo or no treatment (OR 2.15, 95% CI
that reported clinical pregnancy, the OR for clinical pregnancy 1.38 to 3.32, P < 0.001, 7 RCTs, 549 women, I2 = 60%), although
was lower, at 1.52. This suggests that the clinical pregnancy rate heterogeneity was moderately high.
in the eight trials that reported live birth may have been an
overestimation of the effect of the antioxidants, and hence that 1.2 Live birth; type of antioxidant
the live birth rate in these trials is may also be an overestimate See Analysis 1.2.
(Summary of findings for the main comparison).
We considered each type of antioxidant separately. Only two
The test for subgroup differences showed no evidence of a comparisons included more than one trial.
difference between the placebo and no-treatment subgroups (Chi2
= 0.09, df = 1, P = 0.76, I2 = 0%). 1.2.1 Nasr 2010; compared N-acetyl-cysteine with placebo (OR 3.00,
95% CI 1.05 to 8.60, P = 0.04, 60 women).
Sensitivity analyses
1.2.2 Battaglia 2002; compared L-arginine with placebo (OR 0.43,
1. We conducted a sensitivity analysis, restricted to trials without 95% CI 0.09 to 2.09, P = 0.30, 37 women).
a high risk of bias in any domain. We removed two trials from
the analysis: Bentov 2014, with a high risk of bias due to early 1.2.3 Bentov 2014; compared CoQ10 with placebo (OR 0.82, 95% CI
termination of the trial, and Cicek 2012 due to the trial being 0.19 to 3.54, P = 0.79, 39 women).
unblinded and with unexplained group attrition. After removal
there remained an association with increased live birth rate when 1.2.4 Polak de Fried 2013; compared Vitamin D with placebo (OR
compared to placebo or no treatment (OR 2.47, 95% CI 1.60 to 3.82, 0.79, 95% CI 0.21 to 3.02, P = 0.73, 52 women).
P < 0.001, 6 RCTs, 509 women, I2 = 54%). 1.2.5 Schachter 2007, a four-armed trial with two arms comparing a
2. When the two arms of Schachter 2007 were removed from Vitamin B complex with no treatment and Vitamin B complex plus
the analysis, due to the use of folic acid or a fertility drug as a metformin versus metformin (also considered to be 'no treatment'),
showing no association with increased live birth rate compared to
Informed decisions.

no treatment (OR 2.07, 95% CI 0.93 to 4.57, P = 0.07, 102 women, I2 1.4 Live birth; IVF/ICSI
= 0%). See Analysis 1.4.
1.2.6 Agrawal 2012 compared combined antioxidants with Four trials (Battaglia 2002; Bentov 2014; Polak de Fried 2013;
no treatment, and Panti Abubakar 2015 compared combined Schachter 2007) compared antioxidants with placebo or no
antioxidants with placebo. Combined antioxidants were associated treatment in women having IVF/ICSI treatment and reporting live
with an increased live birth rate compared with placebo or no birth. Antioxidants were not associated with an increased live birth
treatment (OR 6.76, 95% CI 2.79 to 16.41, P < 0.001, 2 RCTs, 258 rate compared with placebo or no treatment in women undergoing
women, I2 = 0%). IVF/ICSI (OR 1.21, 95% CI 0.69 to 2.11, P = 0.51, 4 RCTs, 230 women,
I2= 8%).
1.2.7 Cicek 2012 compared Vitamin E to no treatment (OR 1.43, 95%
CI 0.50 to 4.10, P = 0.51, 103 women). Secondary outcome: Clinical pregnancy
1.3 Live birth rate; indications for subfertility Only 26 of the 50 included trials presented or provided data
See Analysis 1.3. that could be used in this meta-analysis. We have not included
all data in the reports, as some were obtained through direct
1.3.1 Polycystic ovary syndrome contact with the trialist (see Characteristics of included studies).
We could not use the data for the remaining 24 trials in the meta-
Three trials reported on women with PCOS: Panti Abubakar analysis, as they provided either only 'pregnancy' or biochemical
2015; Nasr 2010; and Schachter 2007 (a four-armed trial, which pregnancy data (see Table 2), only bio-markers or embryo/oocyte
contributed to two comparisons in this analysis). Antioxidants were numbers, or insufficient information in the reports, which were
associated with an increased live birth rate compared with placebo mainly conference abstracts. We tried to contact these authors to
or no treatment in women with PCOS (OR 3.34, 95% CI 1.90 to obtain the clinical pregnancy data and some responded saying that
5.86, P < 0.001, 3 RCTs, 362 women, I2 = 28%). Each trial included they did not have the data, while others did not respond at all.
different antioxidants: 'N-acetyl-cysteine', combined antioxidants
and Vitamin B complex. 1.5 Clinical pregnancy; antioxidants versus placebo or no treatment/
standard treatment
1.3.2 Tubal subfertility See Analysis 1.5.
One trial (Battaglia 2002) enrolled women with tubal subfertility Antioxidants were associated with an increased clinical pregnancy
undergoing IVF (OR 0.43, 95% CI 0.09 to 2.09, P = 0.30, 37 women). rate compared with placebo or no treatment (OR 1.52, 95% CI 1.31
1.3.3 Varying indications to 1.76, P < 0.001, 26 RCTs, 4271 women, I2= 66%, very low-quality
evidence) (Figure 6). This suggests that among subfertile women
One trial (Agrawal 2012) enrolled women with various causes of with an expected clinical pregnancy rate of about 22%, the rate
subfertility (OR 4.50, 95% CI 1.46 to 13.86, P = 0.009, 58 women). among women using antioxidants would be between 27% and 33%
(Summary of findings for the main comparison). Heterogeneity was
1.3.4 Unexplained subfertility moderately high.
One trial (Cicek 2012) enrolled women with unexplained subfertility

(OR 1.43, 95% CI 0.50 to 4.10, P = 0.51, 103 women)


Informed decisions.

1.5 Clinical pregnancy; antioxidants vs placebo or no treatment/standard treatment (natural conceptions and
undergoing fertility treatments).

Informed decisions.


The test for subgroup differences showed no evidence of a or no treatment (these agents were in both the intervention and
difference between the placebo and no-treatment subgroups (Chi2 control arms, with an antioxidant in addition in the intervention
= 0.16, df = 1, P = 0.69, I2 = 0%). arm).
Sensitivity analyses When these eight trials were removed from the analysis (Badawy
2006; Cheraghi 2016; El Refaeey 2014; Ismail 2014; Maged 2015;
1. We conducted a sensitivity analysis, excluding trials with a high Rizk 2005; Salehpour 2012; Schachter 2007) there remained
risk of bias in any domain. an association between antioxidants and an increased clinical
Twelve trials (Batioglu 2012; Bentov 2014; Brusco 2013; Cheraghi pregnancy rate compared no treatment (OR 1.40, 95% CI 1.17 to
2016; Cicek 2012; El Refaeey 2014; Eryilmaz 2011; Lisi 2012; Maged 1.67, P < 0.001, 18 RCTS, 2682 women, I2 = 39%). Two trials (Cheraghi
2015; Papaleo 2009; Youssef 2015; Westphal 2006) had a rating 2016; Schachter 2007) were multi-armed, but only those arms with
of high risk in any one or more of the 'Risk of bias' domains a fertility drug plus placebo/no treatment were removed in this
(see Characteristics of included studies). When these trials were analysis.
removed in a sensitivity analysis there remained an association 1.6 Clinical pregnancy; type of antioxidant
between antioxidants and an increased clinical pregnancy rate
when compared to placebo (OR 1.46, 95% CI 1.23 to 1.74, P < 0.001, See Analysis 1.6.
14 RCTs, 3100 women, I2 = 78%); heterogeneity was very high.
We considered each type of antioxidant separately (Figure 7).
2. We conducted a sensitivity analysis, excluding studies that used a
fertility drug (metformin or clomiphene) as a control plus a placebo


Informed decisions.

1.6 Clinical pregnancy; type of antioxidant.

Informed decisions.



1.6.1 N-acetyl-cysteine was not associated with an increased clinical 1.6.5 There was no clear evidence of a difference in clinical
pregnancy rate when compared with placebo, no treatment or pregnancy rates between ascorbic acid and placebo (OR 0.75, 95%
standard treatment (OR 1.22, 95% CI 0.92 to 1.63, P = 0.16, 6 RCTs, CI 0.50 to 1.14, P = 0.18, 619 women).
1354 women, I2 = 74%). Heterogeneity was very high, perhaps as
a result of the high risk of bias in Badawy 2006 and Rizk 2005, the 1.6.6 There was no clear evidence of a difference in clinical
unclear risk of bias in Cheraghi 2016 and Salehpour 2012, or the pregnancy rates between L-arginine and placebo or no treatment
additional treatment of laparoscopic drilling that women received (OR 1.05, 95% CI 0.32 to 3.46, P = 0.94, 2 RCTs, 71 women, I2 = 67%).
in Nasr 2010.
1.6.7 There was no clear evidence of a difference in clinical
1.6.2 Combined antioxidants (similar antioxidants were combined pregnancy rates between myo-inositol plus folic acid and placebo
in each trial) were associated with an increased clinical pregnancy or no treatment (OR 1.35, 95% CI 0.98 to 1.86, P = 0.07, 4 RCTs, 694
rate when compared to placebo or no treatment (OR 2.28, 95% CI women, I2 = 0%).
1.51 to 3.43, P < 0.001, 4 RCTs, 569 women, I2 = 74%). Heterogeneity
1.6.8 CoQ10 was associated with an increased clinical pregnancy
was very high, and two of the trials enrolled small numbers of
rate when compared to placebo or no treatment (OR 4.28, 95% CI
women.
1.79 to 10.26, P = 0.001, 2 RCTs, 149 women, I2 = 73%).
pregnancy rates between melatonin and placebo or no treatment 1.6.9 L-carnitine was associated with an increased clinical
pregnancy rate when compared to placebo (OR 82.05, 95% CI 10.92
(OR 1.29, 95% CI 0.91 to 1.83, P = 0.15, 4 RCTs, 568 women, I2 = 0%).
to 616.59, P < 0.001, 170 women).
pregnancy rates between Vitamin E and no treatment (OR 1.43, 95%
pregnancy rates between vitamin D and placebo (OR 0.83, 95% CI
CI 0.50 to 4.10, P = 0.51, 103 women).
0.25 to 2.76, P = 0.76, 52 women).

Informed decisions.

1.6.11 There was no clear evidence of a difference in clinical acid and no treatment (OR 1.38, 95% CI 0.90 to 2.12, P = 0.14, 389
pregnancy rates between vitamin B complex in the two arms of women).
Schachter 2007 and placebo or no treatment (OR 1.94, 95% CI 0.82
1.7 Clinical pregnancy rate; indications for subfertility
to 4.58, P = 0.13, 1 RCT, 102 women, I2 = 0%).
See Analysis 1.7. (Figure 8).
pregnancy rates between myo-inositol plus melatonin plus folic


Informed decisions.

1.7 Clinical pregnancy; indications for subfertility.

Informed decisions.

1.7.1 Polycystic ovary syndrome 1.8 Clinical pregnancy rate; IVF/ICSI
Antioxidants were associated with an increased clinical pregnancy See Analysis 1.8.
rate when compared with placebo, no treatment or standard
treatment in women with PCOS (OR 2.63, 95% CI 2.06 to 3.36, P < There was no clear evidence of a difference in clinical pregnancy
0.001, 11 RCTs, 1721 women, I2 = 73%). Heterogeneity was high, rates when antioxidants were compared with placebo, no
probably due to the different antioxidants used. treatment or standard treatment in women undergoing IVF/ICSI (OR
1.19, 95% CI 0.98 to 1.43, P = 0.08, 15 RCTs, 2263 women, I2 = 0%).
1.7.2 Unexplained subfertility
Secondary outcome: Adverse events
There was no clear evidence of a difference in clinical pregnancy
rates when antioxidants were compared with placebo, no 1.9 Adverse events
treatment or standard treatment in women with unexplained See Analysis 1.9.
subfertility (OR 0.82, 95% CI 0.59 to 1.14, P = 0.23, 3 RCTs, 967
women, I2 = 0%). We subgrouped adverse event data according to the types of
events that occurred, as reported by the trials. These included
1.7.3 Tubal subfertility miscarriage, multiple pregnancy, gastrointestinal disturbances,
ectopic pregnancy and headache. There was no evidence to suggest
There was no clear evidence of a difference in clinical pregnancy
an association between antioxidants and adverse events, but
rates when antioxidants were compared with placebo, no
data were limited, with 17 trials reporting on miscarriage, seven
treatment or standard treatment in women with tubal subfertility
trials reporting on multiple pregnancy, and three reporting on
(OR 1.05, 95% CI 0.32 to 3.46, P = 0.94, 2 RCTs, 71 women, I2 = 67%). gastrointestinal upsets, one reporting ectopic pregnancy and one
reporting headache.
1.7.4 Varying indications
1.9.1 Miscarriage
There was no clear evidence of a difference in clinical
pregnancy rates when antioxidants were compared with placebo, There was no clear evidence of a difference in miscarriage rates
no treatment or standard treatment in women with varying when antioxidants were compared with placebo or no treatment
indications (OR 1.27, 95% CI 0.94 to 1.71, P = 0.12, 5 RCTs, 1004 (OR 0.79, 95% CI 0.58 to 1.08, P = 0.14, 18 RCTs, 2834 women,
women, I2 = 71%). I2 = 23%, very low-quality evidence) (Figure 9). This means that
given the rate of 7% miscarriages in the control population, the
1.7.5 Poor responders use of antioxidants would be expected to result in a miscarriage
rate of between 4% and 7% (Summary of findings for the main
There was no clear evidence of a difference in clinical pregnancy comparison). Most of the trials in this analysis were small, although
rates when antioxidants were compared with placebo, no one trial (Badawy 2006) enrolled 804 women. There were no events
treatment or standard treatment in women who were poor in one of the studies (Battaglia 2002).
responders (OR 1.88, 95% CI 0.64 to 5.47, P = 0.25, 1 RCT, 65 women).


Informed decisions.

1.9 Adverse events.

Informed decisions.

1.9.2 Multiple pregnancy 2.2 Clinical pregnancy; type of antioxidant
There was no clear evidence of a difference in multiple pregnancy One trial (Unfer 2011) reported on clinical pregnancy in this
rates when antioxidants were compared with placebo or no comparison. Clinical pregnancy rates were higher in the myo-
treatment (OR 1.00, 95% CI 0.73 to 1.38, P = 0.98, 8 RCTs, 2163 inositol group than in the D-chiro-inositol group (OR 3.86, 95% CI
women, I2 = 4%, very low-quality evidence) (Figure 9). This means 1.25 to 11.89, P = 0.02, 84 women).
that if the multiple pregnancy rate in the control population is 8%,
use of antioxidants instead would be expected to result in a multiple Secondary outcome: Adverse events
pregnancy rate between 6% and 11% (Summary of findings for the See Analysis 2.3.
main comparison). There were no events in one of the studies (Nasr
2010) 2.3 Adverse events
1.9.3 Gastrointestinal disturbances 2.3.1 Miscarriage
Three trials reported on gastrointestinal disturbances (Cicek 2012; One trial (Unfer 2011) reported on the miscarriage rate in this
Maged 2015; Westphal 2006). There was no clear evidence of comparison. There was no clear evidence of a difference between
a difference in gastrointestinal disturbances when antioxidants the myo-inositol group and the D-chiro-inositol group (OR 1.30,
were compared with placebo or no treatment (OR 1.55, 95% 95% CI 0.27 to 6.20, P = 0.74, 84 women).
CI 0.47 to 5.10, P = 0.47, 3 RCTs, 343 women, I2 = 0%, very
low-quality evidence) (Figure 9). This means that with a rate 3. Pentoxifylline supplement versus placebo, no treatment/
of 2% gastrointestinal disturbances in the control population, standard treatment
use of antioxidants instead would be expected to result in a Primary outcome: Live birth
gastrointestinal disturbances rate between 1% and 11% (Summary
of findings for the main comparison). See Analysis 3.1.
1.9.4 Ectopic pregnancy 3.1 Live birth; pentoxifylline versus placebo or no treatment/standard
treatment
One trial (Agrawal 2012) reported on ectopic pregnancy. There was
no clear evidence of a difference between the groups (OR 2.90, 95% Only one trial (Aleyasin 2009) reporting live birth was included in
CI 0.11 to 74.13, P = 0.52, 58 women). the pentoxifylline comparison (OR 1.54, 95% CI 0.68 to 3.50, P = 0.30,
112 women, very low quality evidence). This trial enrolled women
1.9.5 Headache with varying indications for infertility, who were undergoing IVF/
ICSI. They were given pentoxifylline plus vitamin E versus no
One trial (Ismail 2014) reported on headache. There was no clear treatment.
evidence of a difference between the groups (OR 2.02, 95% CI 0.18
to 22.75, P = 0.57, 170 women). Secondary outcome: Clinical pregnancy
3.2 Clinical pregnancy; pentoxifylline versus placebo or no treatment/
2. Head-to-head antioxidants standard treatment
Only one trial (Unfer 2011) was included in the head-to-head See Analysis 3.2.
comparison. Myo-inositol was compared with D-chiro-inositol,
among women with polycystic ovarian syndrome undergoing IVF. Three trials reported on pentoxifylline versus placebo or no
treatment (Aleyasin 2009; Balasch 1997; Creus 2008). Pentoxifylline
Primary outcome: Live birth was associated with an increased clinical pregnancy rate compared
See Analysis 2.1. with placebo or no treatment (OR 2.07, 95% CI 1.20 to 3.56, P
= 0.009, 3 RCTs, 276 women, I2 = 0%, very low-quality evidence)
2.1 Live birth (Figure 10).This suggests that among subfertile women with an
Only one trial (Unfer 2011) reported on live birth. Live birth rates expected clinical pregnancy rate of 25%, the rate among women
were higher in the myo-inositol group than in the D-chiro-inositol using pentoxifylline would be between 28% and 53% (Summary of
group (OR 3.86, 95% CI 1.25 to 11.89, P = 0.02, 84 women). findings 2).
Secondary outcome: Clinical pregnancy

See Analysis 2.2.


Informed decisions.

Figure 10. Forest plot of comparison: 3 Pentoxifylline versus placebo or no treatment/standard care, outcome:
3.2 Clinical pregnancy; pentoxifylline vs placebo or no treatment/standard treatment (natural conceptions and
undergoing fertility treatments).

Sensitivity analysis for trials at high risk of bias in clinical pregnancy rates (OR 2.06, 95% CI 0.97 to 4.38, P = 0.06,
112 women).
When Aleyasin 2009 was removed from the analysis (with a high risk
of bias for blinding and selective reporting) there was no conclusive 3.4 Clinical pregnancy; indications for subfertility
evidence of an association between pentoxifylline and increased See Analysis 3.4.
clinical pregnancy rate (OR 2.07, 95% CI 0.94 to 4.56, P = 0.07, 2 RCTs,
164 women, I2 = 0%). 3.4.1 Clinical pregnancy rate; endometriosis
3.2.1 Clinical pregnancy; pentoxifylline versus placebo Pentoxifylline did not show an association with an increased
clinical pregnancy rate (OR 2.07, 95% CI 0.94 to 4.56, P = 0.07, 2 RCTs,
Two trials (Balasch 1997; Creus 2008) reported on pentoxifylline 164 women, I2 = 0%) in women with endometriosis.
versus placebo. There was no clear evidence of a difference
between the pentoxifylline and placebo in clinical pregnancy rates 3.4.2 Clinical pregnancy rate; varying indications
(OR 2.07, 95% CI 0.94 to 4.56, P = 0.07, 2 RCTs, 164 women, I2 = 0%).
Only one trial (Aleyasin 2009) enrolled women who presented with
3.2.2 Clinical pregnancy rate; pentoxifylline versus no treatment different indications within the trial. There was no clear evidence of
a difference between the groups (OR 2.06, 95% CI 0.97 to 4.38, P =
Aleyasin 2009 was the only trial in this subgroup. There was no clear 0.06, 112 women).
evidence of a difference between the groups (OR 2.06, 95% CI 0.97
to 4.38, P = 0.06, 112 women). 3.5 Clinical pregnancy rate; IVF/ICSI
3.3 Clinical pregnancy; type of antioxidant See Analysis 3.5.
See Analysis 3.3. Only one trial (Aleyasin 2009) enrolled women who were
undergoing IVF/ICSI. There was no clear evidence of a difference
3.3.1 Pentoxifylline only between the groups (OR 2.06, 95% CI 0.97 to 4.38, P = 0.06, 112
women).
Two trials (Balasch 1997; Creus 2008) reported on pentoxifylline
alone, with no clear evidence of a difference between the groups Secondary outcome: Adverse events
in clinical pregnancy rates (OR 2.07, 95% CI 0.94 to 4.56, P = 0.07, 2
RCTs, 164 women, I2 = 0%). 3.6 Adverse events
See Analysis 3.6

3.3.2 Pentoxifylline plus vitamin E
We subgrouped adverse event data according to the types of events
Only one trial (Aleyasin 2009) reported on pentoxifylline plus that occurred, as reported by the trials. These included miscarriage,
vitamin E, with no clear evidence of a difference between the groups multiple pregnancy and ectopic pregnancy. No evidence suggested

Informed decisions.

an association with antioxidants and adverse events, but data were with only three trials reporting on this outcome (OR 1.34, 95% CI
limited, with three trials reporting on miscarriage, one on multiple 0.46 to 3.90, P = 0.58, 3 RCTs, 276 women, I2 = 0%, very low-quality
pregnancy, and one on ectopic pregnancy. evidence) (Figure 11). This suggests that among subfertile women
with an expected miscarriage rate of 4%, the rate among women
3.6.1 Miscarriage using pentoxifylline would be between 2% and 15% (Summary of
findings 2).
No evidence suggested a difference in miscarriage rates between
antioxidants and placebo or no treatment, but data were limited

Figure 11. Forest plot of comparison: 3 Pentoxifylline versus placebo or no treatment/standard care, outcome: 3.6
Adverse events.

3.6.2 Multiple pregnancy 47% with a fixed-effect model). The heterogeneity may be due to
the trials enrolling women with differing indications for subfertility
Only one trial (Aleyasin 2009) reported on multiple pregnancy. and varying types of antioxidants.
There was no clear evidence of a difference between the groups
(OR 0.78, 95% CI 0.20 to 3.09, P = 0.73, 112 women, very low quality We conducted subgroup analyses, in accord with our protocol,
evidence). by type of comparison and type of antioxidant. The association
between antioxidants and an increased live birth rate persisted.
3.6.3 Ectopic pregnancy When we considered specific indications for subfertility, there was
an association between the use of antioxidants and increased
Only one trial (Aleyasin 2009) reported on ectopic pregnancy. There
live birth among women with polycystic ovary syndrome (PCOS).
was no clear evidence of a difference between the groups (OR 2.04,
However we found no clear association between antioxidants and
95% CI 0.18 to 23.13, P = 0.57, 112 women).
an increased live birth rate among women undergoing IVF or ICSI.
DISCUSSION We performed a sensitivity analysis excluding trials at high risk of
bias in any domain, and those that used folic acid or a fertility drug
Summary of main results as a control (these were in both the intervention and control arms
Effectiveness of antioxidants versus placebo or no treatment with an antioxidant in addition in the intervention, and classified
as no treatment). When these trials were removed from the
Very low-quality evidence indicates that for subfertile women the analysis there remained an association between antioxidants and
use of supplemental antioxidants may be effective in increasing an increased live birth rate, although heterogeneity was moderately
rates of live birth. Eight trials with a total of 651 women reported high.
on live birth (Summary of findings for the main comparison). The
differences between the trials (heterogeneity) were moderate (I2 =
Informed decisions.

Antioxidants were associated with an increased clinical pregnancy Overall completeness and applicability of evidence
rate when compared with either placebo or no treatment, although
the quality of this evidence was assessed as 'very low' (Summary Of the 50 trials included in this review, 36 reported on
of findings for the main comparison). Heterogeneity was high, but clinical pregnancy, but only 10 trials reported on live birth.
there was no evidence that the effects differed by type of control Miscarriage, harmful events and costs of the included trials
(placebo or no treatment). We conducted sensitivity analyses generally were not well reported. Twenty-four trials reported
excluding trials at high risk of bias and those using a standard or co- on miscarriage, 10 reported on multiple pregnancy, three trials
intervention agent as their control. There remained an association discussed gastrointestinal disturbances, two ectopic pregnancy,
between increased clinical pregnancy rates and antioxidants in the one headache, three ovarian hyperstimulation syndrome and
analysis when these trials were removed. one preterm birth. The trials were generally quite small, and
heterogeneity between them was moderately high overall.
When we considered individual antioxidant interventions
separately, both 'combined antioxidants' and CoQ10 showed We tried to assess which type of antioxidant might have a beneficial
an association between antioxidant and an increased clinical effect on the outcomes of interest in this review However, there
pregnancy rate, although heterogeneity in both groups was high. were only one or two trials for most interventions. Similarly, the
We found no association between melatonin, L-arginine, myo- indications for subfertility within the trials were representative of
inositol or vitamin B complex and clinical pregnancy rate, although the general subfertile population, but apart from trials on PCOS
these subgroups contained only three or fewer trials. (with 12 trials across all comparisons), there were very few trials
specific to one indication for subfertility (three for unexplained
When we considered specific 'indications for subfertility', we subfertility and two for tubal subfertility, two for endometriosis,
found an association between antioxidants and increased clinical one for male factor, one for poor responders), and when pooling
pregnancy in women with PCOS, but heterogeneity here was was possible within these indications, we had to take into account
very high, probably due to varying antioxidants. We found no that the women were also receiving different types of antioxidants
association between antioxidants and clinical pregnancy rates in and differing adjunctive interventions such as laparoscopic ovarian
women with unexplained subfertility, with tubal subfertility, with drilling, timed intercourse or IVF/ICSI. Apart from PCOS, it was
varying indications, or in trials that enrolled women with poor therefore difficult to show any benefit or harm from antioxidants
response. for a particular indication of subfertility.
There was no association between antioxidants and clinical Only one trial, with each arm using a different antioxidant, was
pregnancy rates in women undergoing IVF or ICSI. included in the head-to-head analysis, so we could reach no
conclusions about benefits or harms in this comparison.
There was insufficient evidence to draw any conclusions about
adverse events such as miscarriage, multiple pregnancy or In the pentoxifylline versus placebo/no treatment comparison
gastrointestinal disturbances when comparing antioxidants with there was evidence of association with clinical pregnancy, but as
placebo or no treatment/standard treatment. The quality of this agent is a medicine and has actions above and beyond the
evidence for miscarriage, multiple pregnancy and gastrointestinal reactive oxygen species-scavenging capabilities of antioxidants, it
disturbances was considered 'very low' (Summary of findings for is difficult to say that this result is due to the antioxidant action of
the main comparison). The outcomes of ectopic pregnancy and the drug.
headache were reported by only one trial in each group.
Quality of the evidence
Effectiveness of antioxidants versus antioxidants−head-to-
The quality of the evidence according to the 'Summary of findings'
head
tables (Summary of findings for the main comparison; Summary of
Only one trial reported on live birth, clinical pregnancy or adverse findings 2) was considered to be 'very low' for all outcomes in the
effects in this comparison, so meta-analysis was not possible. antioxidant versus placebo/no treatment and in the pentoxifylline
The findings of this one trial suggested that myoinisitol may be versus placebo/no treatment comparisons. Heterogeneity in many
associated with higher rates of live birth and clinical pregnancy of the analyses was quite high; three of the main analyses had low
than D-chiro-inositol. There was insufficient evidence to determine heterogeneity, with an I2 value of 0%, but heterogeneity for the
whether there was any difference between them in miscarriage live birth outcome in the antioxidant versus placebo/no treatment
rates. comparison was 47%, and 66% for clinical pregnancy.
Effectiveness of pentoxifylline versus placebo/no treatment The overall quality of evidence was limited by serious risks of
bias associated with poor reporting of methods, imprecision and
Only one trial reported on live birth for this comparison, so pooling
inconsistency, leading to a downgrading of the evidence. The risk
of data was not possible. Very low-quality evidence suggests
of bias within the evidence (because of methodological limitations)
that pentoxifylline may be associated with an increased clinical
was moderately high (see Figure 2; Figure 3 and Characteristics of
pregnancy rate; although, there were only three trials reporting
included studies). Not all trials described their sequence generation
on this outcome, two reported on pentoxifylline and one reported
or allocation concealment methods, and most trials randomly
on pentoxifylline plus vitamin E. There was no evidence of an
assigned only small numbers of women.
association between pentoxifylline and clinical pregnancy rates in
women with endometriosis, and insufficient evidence to reach any The funnel plot for clinical pregnancy (Figure 4) was not
conclusions about miscarriage rates. We deemed the evidence to symmetrical, which suggests that the high number of small studies
be of 'very low quality' (Summary of findings 2). may have had an excessively positive effect on the overall results.
This high risk of bias in the included trials is also described in
Informed decisions.

other antioxidant reviews (Lu 2012; Showell 2011) and seems to be antioxidants (beta-carotene, vitamin A, vitamin C and vitamin E)
common in this area of complementary medicine. to prevent gastrointestinal cancers and found that there may
be an increased risk of mortality for participants taking these
Potential biases in the review process antioxidants. The review authors found that selenium may have
preventative effects on gastrointestinal cancers. Neither review
There may have been some potential for bias in the review process,
supports the use of antioxidants as a preventative measure, and
as there were some changes to the protocol. These included
they call for tighter regulations. Bjelakovic 2008 suggests that
additions and deletions to inclusion/exclusion criteria and to the
antioxidants should be regulated as drugs.
subgroup analyses (see Differences between protocol and review).
None of these changes was made as a result of the findings of
AUTHORS' CONCLUSIONS
included studies, but rather to improve the structure of the review.
For this 2017 update we analysed trials that used an antioxidant Implications for practice
plus an antioxidant versus the same antioxidants plus placebo/
no treatment or standard treatment in the antioxidants versus no- In this review, there is very low-quality evidence to show that
treatment comparison, whereas in the original review we treated taking an antioxidant may provide benefit for subfertile women.
them as head-to-head. There is insufficient evidence to draw any conclusions about
adverse events. At this time, there is limited evidence in support of
Agreements and disagreements with other studies or supplemental oral antioxidants for subfertile women.
reviews
Implications for research
The results of our review are in agreement with those of other
published reviews. Sekhon 2010 and Grajecki 2012 concluded Further appropriately-powered and well-designed randomised
that, despite numerous advances made in this area and possible placebo-controlled trials are needed to assess any evidence
positive effects of antioxidants, there is a need for further for benefits or harms or both of supplemental antioxidants for
investigation using better-quality randomised controlled trials subfertile women. New trials should state a priori that they are
within a larger population to determine the efficacy and safety going to report and follow up on the outcomes of live birth, clinical
of these supplements. A Cochrane Review Pentoxifylline versus pregnancy and adverse events.
medical therapies for subfertile women with endometriosis (Lu
2012) stated that evidence was still insufficient to support the ACKNOWLEDGEMENTS
use of pentoxifylline in the management of premenopausal
The authors wish to thank the following people for providing
women with endometriosis in terms of subfertility and relief of
valuable information that assisted in the writing of this review:
pain outcomes. Another Cochrane Review, Antioxidants for male
subfertility (Showell 2014), found a small significant effect in favour Dr Mustafa Nazıroğlu for providing information on the trial Ozkaya
of antioxidants for pregnancy and live birth and no apparent 2011;
association with any reported adverse events; however, there were
too few similar trials to provide conclusive evidence. Aboubakr Elnashar for providing information on the trials Elnashar
2005 and Elnashar 2007;
A systematic review by Pacis 2015 did not find any evidence
to support the use of vitamin D in women undergoing ART. Dr Rina Agrawal for providing information on the trial Agrawal 2012
Another two systematic reviews (Irani 2014; Thomson 2012) looked and for informing me of her new ongoing trial;
at vitamin D for subfertile women with PCOS. They reported
that there is some evidence for the beneficial effects of vitamin Dr Mohamed Youssef for providing information on the trial
D supplementation on menstrual dysfunction, but the current Aboulfoutouh 2011 and for informing me that this trial is about to
evidence is limited and additional randomised controlled trials are be published;
required.
Dr Gianfranco Carlomagno for providing information on the trial
Another systematic review concentrating on women with PCOS Unfer 2011;
was prepared by Unfer 2016. This review looked specifically at the
effects of myo-inositol for PCOS, and the review authors concluded Dr Mariagrazia Stracquadanio for providing information on the trial
that myo-inositol provided a beneficial effect for PCOS; this was Ciotta 2011;
"mainly based on improving insulin sensitivity of target tissues, Dr Badawy for providing information on the trial Badawy 2006;
resulting in a positive effect on the reproductive axis...". Our current
review found no evidence for this, but a Cochrane protocol (Showell Dr Balasch for providing information on the trial Balasch 1997;
2016) has recently been published and will look specifically at the
use of inositols for subfertile women with PCOS. Dr Papaleo for providing information on the trial Papaleo 2009;
Two Cochrane Reviews (Bjelakovic 2008; Bjelakovic 2012) reported Dr Lisi for providing information on the trial Lisi 2012;
an increased risk of mortality associated with the use of
supplemental antioxidants. Bjelakovic 2012 found this association Dr Battaglia for providing data on the trial Battaglia 2002; and
with beta-carotene and possibly vitamin E and vitamin A,
Dr Eryilmaz for providing information on the trial Eryilmaz 2011
but not with vitamin C or selenium. The review included
healthy participants and participants with various stable diseases. Professor Joanne Barnes
The Cochrane Review Bjelakovic 2008 reported on the use of

Informed decisions.

Dr Vahid Seyfoddin for providing translation of the trial Jane Clarke, who initiated and conceptualised the review, extracted
Mohammadbeigi 2012 the initial pool of data and wrote the first draft of the review.
The Cochrane Gynaecology and Fertility Group. Dr Julie Brown assisted with assessing the trials for inclusion,
extracted the data, assisted with the data analysis and helped with
writing of the original review.

Informed decisions.

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Reproductive Medicine 2012; Vol. 10 Suppl 1:18 Abstract no:
Papaleo 2009 {published data only} O-30.
Papaleo E, Unfer V, Baillargeon J, Fusi F, Occhi F, De Santis L.
Salehpour S, Akbari Sene A, Saharkhiz N, Sohrabi M,
Myo-inositol may improve oocyte quality in intracytoplasmic
Moghimian F. N-acetyl-cysteine as an adjuvant to clomiphene
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patients with polycystic ovary syndrome. Iranian Journal
Polak de Fried 2013 {published data only} of Reproductive Medicine. Research and Clinical Center for
Infertitlity, 2012; Vol. 10:9.
Polak de Fried E, Bossi NM, Notrica JA, Vazquez Levin MH.
Vitamin-d treatment does not improve pregnancy rates * Salehpour S, Akbari Sene A, Saharkhiz N, Sohrabi MR,
in patients undergoing art: a prospective, randomized, Moghimian F. N-acetylcysteine as an adjuvant to clomiphene
double-blind placebo-controlled trial. Fertility and Sterility citrate for successful induction of ovulation in infertile patients
2013;100(Suppl):S493. with polycystic ovary syndrome. Journal of Obstetrics &
Gynaecology Research 2012;38:1182-6.
Rashidi 2009 {published data only}
Rashidi B, Haghollahia F, Shariata M, Zayeriia F. The effects Schachter 2007 {published data only}
of calcium-vitamin D and metformin on polycystic ovary Schachter M, Raziel A, Strassburger D, Rotem C, Ron-El R,
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Gynecology 2009;48(2):142-7. vitamins for the reduction of plasma homocysteine in insulin-
resistant polycystic ovary syndrome. Fertility & Sterility. 2007;
Razavi 2015 {published data only}
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Ghandi Y, et al. Selenium supplementation and the effects
on reproductive outcomes, biomarkers of inflammation, and

Informed decisions.

Unfer 2011 {published data only} double-blind placebo-controlled trial. Archives of Gynecology
Unfer V, Carlomagno G, Rizzo P, Raffone E, Roseff S. Myo-inositol and Obstetrics 2014;289(4):865-870.
rather than D-chiro-inositol is able to improve oocyte quality
Baillargeon 2004 {published data only}
in intracytoplasmic sperm injection cycles: a prospective,
controlled, randomized trial. European Review for Medical and Baillargeon JP, Iuorno MJ, Jakubowicz DJ, Apridonidze T, He N,
Pharmacological Sciences 2011;15(4):452-7. Nestler JE. Metformin therapy increases insulin-stimulated
release of D-chiro-inositol-containing inositolphosphoglycan
Valeri 2015 {published data only} mediator in women with polycystic ovary syndrome. Journal
Valeri C, Sbracia G, Selman H, Antonini G, Pacchiarotti A. of Clinical Endocrinology & Metabolism 2004; Vol. 89, issue
Beneficial effects of melatonin on oocytes and embryo quality 1:242-9.
in aged IVF patients. Human Reproduction 2015;30:i48-9.
Benelli 2016 {published data only}
Westphal 2006 {published data only} Benelli E, Del Ghianda S, Di Cosmo C, Tonacchera M. A
Westphal LM, Polan ML, Trant AS. Double-blind, placebo- combined therapy with myo-inositol and d-chiro-inositol
controlled study of Fertilityblend: a nutritional supplement improves endocrine parameters and insulin resistance in
for improving fertility in women. Clinical and Experimental PCOS young overweight women. International Journal of
Obstetrics & Gynecology 2006;33(4):205-8. Endocrinology 2016; Vol. 2016:3204083.
Youssef 2015 {published data only} Bonakdaran 2012 {published data only}
Aboulfoutouh I, Youssef M, Khattab S. Can antioxidants Bonakdaran S, Khorasani ZM, Davachi B, Shakeri MT.
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2012;14(8):16-24.
* Youssef MA, Abdelmoty HI, Elashmwi HA, Abduljawad EM,
Elghamary N, Magdy A, et al. Oral antioxidants supplementation Cheang 2008 {published data only}
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1:38-42. chiro-inositol-containing inositol phosphoglycan mediator
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Informed decisions.

Elnashar 2007 {published data only} levels in patients with a luteal phase defect. Fertility & Sterility
Elnashar A, Fahmy M, Mansour A, Ibrahim K. N-acetyl cysteine 2003;80(2):459-61.
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Hernández-Yero 2012 {published data only}
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(Accessed 26.06.10). Tremellen K. Oxidative stress and male infertility - a clinical
perspective. Human Reproduction Update 2008;14(3):243-58.
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of randomized controlled trials. International Journal of
Ruder 2008
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Ruder EH, Hartman TJ, Blumberg J, Goldman MB. Oxidative
stress and antioxidants: exposure and impact on female fertility. Vircheva 2010
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Kubera M. In vivo effects of pentoxifylline on enzyme and
Sekhon 2010
non-enzyme antioxidant levels in rat liver after carrageenan-
Sekhon L, Gupta S, Kim Y, Agarwal A. Female infertility and induced paw inflammation.. Cell Biochemistry & Function
antioxidants. Current Women’s Health Reviews 2010;6:84-95. 2010;28(8):668-72.
Showell 2011 Wathes 2007
Showell MG, Brown J, Yazdani A, Stankiewicz MT, Wathes DC, Abayasekara DR, Aitken RJ. Polyunsaturated fatty
Hart RJ. Antioxidants for male subfertility. Cochrane acids in male and female reproduction. Biology of Reproduction
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10.1002/14651858.CD007411.pub2]
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Showell MG, Mackenzie-Proctor R, Brown J, Yazdani A, Mansour R, Nygren K, et al. International Committee for
Stankiewicz MT, Hart RJ. Antioxidants for male subfertility. Monitoring Assisted Reproductive Technology (ICMART) and
Cochrane Database of Systematic Reviews 2014, Issue 12. [DOI: the World Health Organization (WHO) revised glossary of ART
10.1002/14651858.CD007411.pub3] terminology, 2009. Fertility and Sterility 2009;92(5):1520-4.
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Brown J, Farquhar C. Inositol for subfertile women with Hobbs CA. Neural tube defects and maternal bio markers
polycystic ovary syndrome. Cochrane Database of Systematic of folate, homocysteine, and glutathione metabolism. Birth
Reviews 2016, Issue 9. [DOI: 10.1002/14651858.CD012378; Defects Research Part A: Clinical and Molecular Teratology
CD012378] 2006;76(4):230-6. [DOI: 10.1002/bdra.20240]
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attending a reproductive medicine unit in South Australia: a
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CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]


Informed decisions.

Agrawal 2012
Methods Prospective randomised trial
Participants Women attending a teaching hospital fertility clinic undergoing ovulation induction for timed inter-
course (N = 58). Mean age 32.2 years (range 19 to 40)
Inclusion criteria: anovulatory infertility, at least 12 months of unexplained infertility, PCOS, hypothy-
roidism or minimal endometriosis
Exclusion criteria: women whose partners had semen abnormalities and those who had been on multi-
vitamins (except folate) 6 weeks before recruitment
Women with tubal disease, moderate and severe endometriosis, medical disorders or haemoglo-
binopathies; smokers, those with excessive alcohol intake or BMI < 19 or > 34 kg/m2
Interventions 1. Multiple micronutrients (MMN): (n = 30) 1 tablet a day until completion of study (3 treatment cycles).
Women who became pregnant could continue if they wished.
These micronutrients consist of thiamine, riboflavin, niacin B3, vitamins B6 and B12, folate, vitamins C,
A and D, calcium, phosphorus, magnesium, sodium, potassium, chloride, iron, zinc, copper, selenium,
iodine, vitamin E, vitamin K, L-arginine, inositol, N-acetyl-cysteine, biotin, pantothenic acid
Mean age = 32.2 ± 0.65
2. Folic acid (n = 28): 1 tablet a day. Mean age = 32.5 ± 0.83
Women underwent ovulation induction with clomiphene citrate or human menopausal gonadotropin
approximately 4 weeks after starting MMN or folic acid and continued until end of study, which was 3
cycles even if pregnancy was attained.
Outcomes Clinical pregnancy
Ongoing pregnancy
Miscarriage
Ectopic pregnancy
Notes 2 women did not complete the study−1 from each group. Reasons given: 1 woman in the control
group stopped because she wanted to take the micronutrients, and 1 in the treatment group stopped
because of nausea
Trial is self-funded. Author stated in an email received 13th February that the trial was not funded.
Recruited between Febuary and August 2009
Location: London UK
Informed consent
Ethical approval
Sample size power calculation performed
ITT performed
Emailed author 12th January 2012about whether the women had IUI or timed intercourse. Author
replied on 7th February 2012 saying that all women underwent timed intercourse, not IUI. This email al-
so gave adverse event data (miscarriage and ectopic pregnancy data) for the first cycle. Dr Agrawal is
also currently recruiting for a new trial.
Emailed author on 9th August 2012 asking about any live birth data. Author replied saying that live
birth data were unavailable.
Risk of bias

Informed decisions.

Agrawal 2012 (Continued)
Bias Authors' judgement Support for judgement
Random sequence genera- Low risk "Third party randomization ... was carried out through the research and devel-
tion (selection bias) opment department of the University College London and the Royal Free Hos-
pitals using stratification..." "Participants were randomly allocated".
Email sent 12th January 2012 asking for methods of randomisation. Author
replied 13th February 2012 saying, "the subjects were randomised into 2
groups through computer randomisation".
Allocation concealment Low risk "Third party randomisation and allocation concealment was carried out
(selection bias) through the research and development department of the University College
London and the Royal Free Hospitals using stratification and numbered en-
velopes".
Blinding (performance Low risk "Women, caregivers and investigators were blinded to the treatment alloca-
bias and detection bias) tion".
All outcomes
Incomplete outcome data Low risk ITT was performed and explanations given for the 2 dropouts (1 from each
(attrition bias) group)
All outcomes
Selective reporting (re- Low risk Outcomes stated in the text are reported.
porting bias)
Other bias Low risk No other bias found

Alborzi 2007
Methods Randomised placebo-controlled trial
Participants Women with infertility (n = 88)
Mean age: Treatment: 29.7 years; Control: 28.3 years
Inclusion criteria: Infertility for at least 12 months with endometriosis (different stages) diagnosed by
laparoscopy
Exclusion criteria: women with other infertility factors including tubal obstruction
Interventions 1. Pentoxifylline 400 mg: 1 tablet twice a day for 12 months (n = 43)
2. Placebo (n = 45)
Duration: 12 months, 1-year follow-up
Outcomes Cumulative pregnancy rate
Recurrence of endometriosis
Notes Study approved by the Shiraz University of Medical Sciences Institutional Review Board
Trial conducted in Shiraz, Iran, from January 2002 to December 2003
Funding source not reported
Tried to contact the author regarding clinical pregnancy rate and live birth 12th February 2013, but no
reply

Informed decisions.

Alborzi 2007 (Continued)
Risk of bias
Random sequence genera- Unclear risk "They were assigned into 1 of 2 groups by simple randomisation. An indepen-
tion (selection bias) dent pharmacist generated the allocation and assigned the patients to their
groups. To do so, he gave each patient a number on the basis of the order of
her being referred to him. For example, the first patient was enlisted as num-
ber 1 and the second as number 2 and so on. He then assigned patients with
odd numbers into one group and patients with even numbers into another. He
decided which one should be the control group by flipping a coin".
There is a query as to whether this trial is adequately randomised. It could be

seen as block randomisation (cluster) or as alternate (in which case this study
would have been excluded). After discussion with the statistician, we decid-
ed to include this study because of the double-blind concealment−if dou-
ble-blinding was truly successful and nobody involved in recruitment affected
the sequence, then it is a third-party concealed allocation system that is pro-
tecting against selection bias, despite the lack of proper randomisation.
Allocation concealment Low risk An independent pharmacist generated the allocation and assigned the partici-
(selection bias) pants to their groups
Blinding (performance Low risk Double-blinded: "During this period, neither the clinicians nor the patients
bias and detection bias) knew who received the medication and who received the placebo. The only
All outcomes person who knew this was the pharmacist".
Incomplete outcome data Low risk No withdrawals or dropouts

(attrition bias)
All outcomes
Selective reporting (re- Low risk Both outcomes stated in Methods and reported on
porting bias)

Aleyasin 2009
Methods Randomised clinical trial
Participants "Infertile women undergoing standardised controlled ovarian hyperstimulation for ICSI-ZIFT [zygote in-
trafallopian transfer" (n = 112)
Table 1 p. 177 mentions cause of infertility to be male in 51 of 112.
Participants aged from 20 - 39 years; mean age 29.69, (treatment group mean age: 29.96; control group
mean age 29.41) with no previous history of IVF or ZIFT failure. Infertility duration from 1 - 20 years
Exclusion criteria: hypothalamic amenorrhoea, drug reactions, endometriosis and fibroids
Interventions 1. Pentoxifylline 400 mg and vitamin E 400 mg: 1 tablet of each twice a day (n = 56). Administered for 2
cycles before ICSI-ZIFT
2. No treatment (n = 56).
Duration: 2 cycles.
Outcomes Term delivery

Informed decisions.

Aleyasin 2009 (Continued)
Clinical pregnancy rate confirmed by beta human chorionic gonadotropin (hCG) at 14 days after em-
bryo transfer and transvaginal ultrasound 14 days after this
Miscarriage rate
Multiple pregnancy
Notes Conducted in 1 centre in Tehran, Iran; ethical approval gained and written consents obtained
Trial was carried out between April 2006 and April 2007
Funded by the institution
For sensitivity analysis performed because more than half (41/56) of women had male subfertile part-
ners or because both partners had fertility problems
Risk of bias
Random sequence genera- Low risk Computer-generated random number tables were used
tion (selection bias)
Allocation concealment Low risk Sealed opaque sequentially numbered envelopes

(selection bias)
Blinding (performance High risk Comparison group received no treatment. Authors stated "study not blind-
bias and detection bias) ed" (p. 176)
All outcomes

(attrition bias)
All outcomes
Selective reporting (re- High risk Cause of infertility is male in 51 of 112 participants (see Table 1 p. 177), al-
porting bias) though this is not mentioned in the text, where it says that the participants
were 112 infertile women

Badawy 2006
Methods Prospective randomised double-blind controlled trial
Participants Women attending a fertility outpatient clinic for management of unexplained fertility problems (n =
804)
Mean age: Treatment group: 27.9 years; Control group 28.1 years
Inclusion criteria: All women had at least 1 year of marriage without conception, unexplained subfertili-
ty and normal ovulating cycles; tubes were patent
Exclusion criteria: any known reason for subfertility
Timed intercourse
Interventions 1. N-acetyl-cysteine 1200 mg: 1 tablet a day plus clomiphene citrate 50 mg: 1 tablet twice a day for 5
days, starting on day 2 of the cycle (n = 404)

Informed decisions.

Badawy 2006 (Continued)
2. Placebo plus clomiphene citrate: 50 mg 1 tablet twice a day (n = 400)
Duration of treatment: 1 cycle
Timed intercourse
Outcomes Number and size of follicles
Hormonal profiles
Endometrial thickness
Clinical Pregnancy
Miscarriage
Multiple pregnancy
No loss to follow-up
Notes Conducted in 1 centre in Mansoura, Egypt. Ethical approval and informed consents obtained.
Trial ran from October 2003 to April 2005
Contacted author 13th February 2013 regarding methods of randomisation, but no reply
Risk of bias
Random sequence genera- Unclear risk No description of sequence generation apart from: "Patients were allocated
tion (selection bias) randomly to either the trial group".
Allocation concealment Low risk Sealed, opaque, sequentially-numbered, identical envelopes were used
(selection bias)
Blinding (performance Low risk Participants, investigators, outcome assessor and clinicians were blinded
bias and detection bias)
All outcomes

(attrition bias)
All outcomes
Selective reporting (re- Unclear risk Outcomes stated in the text−multiple pregnancy and miscarriage−reported
porting bias) on, although not initially stated as outcomes of interest

Balasch 1997
Methods Prospective randomised controlled trial. Pilot study
Participants Infertile women with asymptomatic minimal or mild endometriosis (n = 60).
Mean age: Treatment: 31.2 ± 3.8; Control: 32.4 ± 3.1

Informed decisions.

Balasch 1997 (Continued)
Inclusion criteria: at least 12 months of primary infertility, no previous pelvic surgery, minimal or mild
endometriosis confirmed by laparoscopy
Exclusion criteria: any previous pelvic surgery, pelvic disorders such as adhesions and tubal obstruc-
tions, in addition to endometriosis
Interventions 1. Pentoxifylline 400 mg: 1 tablet twice a day for 12 months (n = 30)
2. Placebo (n = 30).
12-month duration and 12-month follow-up. During this time, participants received treatment for infer-
tility problems (i.e. male problems, ovulatory problems, cervical mucus abnormalities, IUI, ovulation
induction)
Outcomes Pregnancy rates confirmed by ultrasound
Miscarriage rate
Notes 1 dropout from the treatment group and 3 from the control group−all due to refusal to start treatment
after randomisation. Number reported is 56. ITT is used for meta-analysis
Trial held from November 1993 to December 1995
Single-centre study conducted in Spain
Ethical approval and all consents obtained
Risk of bias
Random sequence genera- Low risk The investigators describe a random component in the sequence generation
tion (selection bias) process that was using a computer random number generator
Allocation concealment Unclear risk Allocation described as being "designated". Authors contacted regarding this
(selection bias) and confirmed concealment "computerised allocation"
Blinding (performance Low risk Women are described as being blinded. Authors contacted regarding other
bias and detection bias) blinded persons. They confirmed that participants were blinded, but investiga-
All outcomes tors, outcome assessors and clinicians were not
Incomplete outcome data Low risk Only a small number of dropouts−4 participants lost; 1 in treatment, 3 in con-
(attrition bias) trol. All explained−1 due to refusal and 3 due to failure to continue taking the
All outcomes medication. No ITT carried out
Selective reporting (re- Unclear risk Pregnancy rates were stated as the outcome of interest in the Methods section
porting bias) of the paper. However, miscarriage rates were given in the Results and were
not mentioned in the Methods. 1 participant in each study group became preg-
nant, then miscarried, then became pregnant again. The first 2 pregnancies
were not included in the analysis. Live births not reported
Other bias High risk Some women with other fertility issues apart from endometriosis were treat-
ed for these additional conditions (i.e. male factor (receiving bromocriptine),
oligo-ovulation (receiving ovulation induction and some additional IUI) poor
post-coital test, hyperprolactinaemia). Numbers of women in treatment and
numbers of controls in each of these categories are given. However, these
treatments may bias the results, as nearly double the control women in the
additional treatment group received IUI compared with the treatment group

Informed decisions.


Batioglu 2012
Methods Randomised controlled trial
Participants Women with primary infertility between 20 and 40 years undergoing IVF (n = 85)
Inclusion criteria: regular menstruation, no hormonal or non-hormonal drug therapy for less than 3
months and no systemic illness
Exclusion criteria: serious endometriosis, serious male factor (azoospermia) hypogonadism with an
FSH level < 13. Also participants with cycles cancelled were excluded.
Interventions 1. Melatonin 3 mg: 1 tablet a day (n = 40)
2. No treatment (n = 45).
Outcomes Primary outcome: number of morphologically mature oocytes retrieved (Mll oocytes)
Secondary outcome: fertilisation rate, embryo quality and pregnancy rate
Notes No information on miscarriage numbers

Funding sources not mentioned
Clinical pregnancy data (not chemical) used in the meta-analysis
Trial held in Turkey, study dates not reported
Risk of bias
Random sequence genera- Low risk Randomisation computer-assisted 1:1.

Allocation concealment Unclear risk No mention of allocation concealment

(selection bias)
Blinding (performance High risk Embyologist was the only person blinded
All outcomes
Incomplete outcome data Low risk ITT used. No dropouts were reported
(attrition bias)
All outcomes
Selective reporting (re- High risk Unclear why chemical pregnancy numbers are lower than clinical pregnancy
porting bias) numbers

Battaglia 1999
Participants Women attending fertility clinic having failed an IVF cycle (poor responders) (n = 34). Mean age: 40 ± 2.1
years, range 37 - 44 years. Undergoing IVF

Informed decisions.

Battaglia 1999 (Continued)
Inclusion: Infertile women with tubal infertility who had not taken hormonal treatments 4 months prior
to 1st IVF treatment
Exclusion: Intercurrent illness, BMI > 30, endometriosis, ovarian functional cyst or ovariectomy, regular
exercise, heavy smokers (> 10 a day), diastolic blood pressure > 90 mmHg
Interventions 1. Oral L arginine 16 g: 1 tablet a day (n = 17)
2. No treatment (n = 17)
Duration: from day 1 of the menstrual cycle to end of the IVF cycle
Outcomes Hormonal and biochemical evaluation
IVF cancellation rates
Oocyte and embryo number
Clinical pregnancy rates
Notes Conducted in Italy, study dates not reported
Risk of bias
Random sequence genera- Low risk Random-number table

Allocation concealment Low risk Sequentially-numbered sealed envelopes

(selection bias)
Blinding (performance Unclear risk Unclear

All outcomes
Incomplete outcome data Low risk No dropouts

(attrition bias)
All outcomes
Selective reporting (re- Low risk Outcomes reported

porting bias)

Battaglia 2002
Participants Women attending Modena University Infertility Clinic (n = 37)

Mean age (mean ± SD): 33.8 ± 3.1 years (range 28 - 37 years), mean duration of infertility 6.8 ± 3.8 (range
4 - 12 years).
Inclusion criteria: All participants were selected from among women who suffered from tubal infertili-
ty. They had regular menstrual cycles (28 ± 4 days), and their partners were fertile according to World
Health Organization standards

Informed decisions.

Battaglia 2002 (Continued)
Exclusion criteria: participants with intercurrent illness, BMI ≥ 30, endometriosis, ovarian functional
cyst, PCOS, unilateral ovarian resection or ovariectomy, participants who took regular exercise, heavy
smokers (> 10 cigarettes a day), those with hypertension (systolic blood pressure > 140 mm Hg and/or
diastolic pressure > 90 mm Hg) and women who had received hormonal treatments in the 4 months be-
fore the first IVF attempt
Interventions 1. L-arginine 4 grams: 4 times a day (n = 18)
2. Placebo (n = 19).
Both groups were undergoing IVF with long gonadotropin-releasing hormone (GnRH) agonist protocol
and pure FSH
Duration: 10, 12 days
Outcomes Clinical pregnancy rates
Side effects
Follicular number and diameter
Live birth
Notes Consent and ethical approval were obtained, and the trial was conducted in Modena, Italy, study dates
not reported
32 participants completed the trial, with 5 dropouts due to poor response.
Author was emailed 16th August 2012 and 12th Febrary 2013 with request for the number of live births
for each group. Author replied on 14th Febrary 2013, providing data for live birth and miscarriage
Risk of bias
Random sequence genera- Low risk "Random number table".

Allocation concealment Low risk "opening sequentially numbered sealed envelopes containing treatment allo-
(selection bias) cation".
Blinding (performance Low risk Investigtors, participants and outcome assessors were blinded
All outcomes
Incomplete outcome data Unclear risk 37 women were enrolled, and investigators stated "All 34 patients complet-
(attrition bias) ed the trial". Numbers given for dropouts from each group. We contacted the
All outcomes authors regarding this ITT not used. Five were said to be cancelled because of
"poor response".
Selective reporting (re- Low risk Key outcomes reported, including live birth
porting bias)


Informed decisions.

Bentov 2014
Methods Double-blind placebo-controlled randomised trial
Participants IVF/ICSI patients (n = 39)
Inclusion criteria: infertility requiring IVF–ICSI and age 35 – 43, mean age; CoQ10 39.0 ± 0.79 and place-
bo 39.1 ± 0.52
Exclusion criteria: body mass index (BMI) >38 kg/m2; early follicular phase (day 2 – 4) serum FSH level
20 mIU/mL; abnormal uterine cavity as evidenced by sonohysterogram or hysterosalpingography; any
current use of systemic steroid medication or any infertility treatment within 3 months of study enrol-
ment; any contraindication to being pregnant and carrying a pregnancy to term; contraindication for
the use of CoQ10, superfact, menopur, hCG, estrase, and progesterone suppositories; any ovarian or
abdominal abnormality that may interfere with adequate TVS evaluation; absence of 1 or both ovaries;
clinically relevant systemic disease (e.g. insulin-dependent diabetes, adrenal dysfunction, organic in-
tracranial lesion, PCOS, hyperprolactinemia, or hypothalamic tumor) or serious illness (neoplasia); his-
tory (within past 12 months) or current abuse of alcohol or drugs; administration of any investigational
drugs within 3 months before the study enrolment; any medical condition that may interfere with the
absorption, distribution, metabolism, or excretion of the study drugs; gastrointestinal diseases; malab-
sorption syndromes; and liver dysfunction; unexplained gynaecological bleeding; ejaculated sperm not
sufficient for ICSI; abnormal controlled ovarian hyperstimulation (COH) screening blood done for both
partners, including prolactin, thyroid stimulating hormone, HIV serology, hepatitis B and C serology,
rubella, group and screen, and syphilis serology before participation in the study; the concurrent use
of any of the following drugs: daunorubicin, doxorubicin, blood pressure medications, warfarin, timo-
lol, atorvastatin, cerivastatin, lovastatin, pravastatin, simvastatin, gemfibrozil, tricyclic antidepressant
medications (including amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine,
nortriptyline, protriptyline, and trimipramine), multivitamins, or any vitamin supplementation except
folic acid
Interventions 1. CoQ10 600 mg: 1 tablet a day with breakfast (n = 17)
2. Placebo - identical capsules containing rice oil and starch (n = 22)
Duration of treatment up to 3 cycles if pregnancy did not occur. All participants took either CoQ10 or
placebo for 2 months. On day 3 of the following cycle, they started ovarian stimulation for IVF while
continuing the consumption of the supplements.
Outcomes Primary outcome: number of euploid eggs per retrieval
Secondary outcome: cumulative pregnancy rate per retrieval and cumulative livebirth rate per retrieval
Notes 12 (5 dropouts) CoQ10 group and 15 (7 dropouts) in the placebo completed the study and 10 in the
CoQ10 and 14 of the placebo group completed an IVF/ICSI cycle. Overall there were 15 dropouts from
recruitment until the end of the study; 6 women withdrew from the study for personal reasons, 3 for
conceiving spontaneously, 2 for poor compliance, 1 for failing to achieve the target BMI, and 3 because
of poor ovarian response
Participant enrolment to the study began in 2010 and was terminated in June 2012 before sample size
reached, due to a paper published in May 2012 by Levin et al describing the negative effects of polar
body biopsy on embryogenesis.
In the CoQ10 group, 30.8% of the women were treated with the long luteal GnRH agonist protocol,
compared with 7.7% in the placebo group. The rest of the participants in both groups were treated with
the short microdose flare protocol
2 centres
Toronto, Canada
Trial registration no: NCT01048385
Informed consent

Informed decisions.

Bentov 2014 (Continued)
Ethics approval
Funding; Ferring Pharmaceuticals provided Menopur
Conflict of interests; one of the authors has a consultancy role with Fertility Neutraceuticals involved in
the manufacturing and distribution of CoQ10
Email sent to author regarding live birth, clinical pregnancy, dropouts and allocation concealment on
24th November 2015 'bentov@lunenfeld.ca', no reply.
Risk of bias
Random sequence genera- Low risk "Patients were assigned in chronological order according to the day of study
tion (selection bias) enrolment to a computer-generated randomization"
Allocation concealment Unclear risk "Each enrolled participant received a pre-assigned package containing either
(selection bias) placebo or CoQ10 for the duration of the study".
Blinding (performance Low risk "The study was a double blind, placebo-controlled, randomized trial". "Both
bias and detection bias) the physician and the patient were blinded regarding assignment of the pa-
All outcomes tients".
Incomplete outcome data High risk "At the point the study was terminated (June 2012), we had recruited a total of
(attrition bias) 39 patients who were evaluated and randomized (17 to the CoQ10 group and
All outcomes 22 to the placebo group). Only 27 had started the treatment with the supple-
ments (12 of the CoQ10 group and 15 of the placebo group). In all, 24 patients
completed the treatment cycle and had a polar body biopsy (PBBX) and em-
bryo transfer done (10 of the CoQ10 group and 14 of the placebo group). Six
patients withdrew from the study for personal reasons, three for conceiving
spontaneously, two for poor compliance, one for failing to achieve the target
BMI, and three because of poor ovarian response."
Selective reporting (re- Low risk Both primary and secondary outcomes reported in the Methods were reported
porting bias) in the results. Protocol available.
Other bias High risk "However, because of the premature termination of the study, the CoQ10
group had only one-third and the control group half of the target number".
Early termination of trial for embryo safety reasons may cause an overestima-
tion of the effect of the intervention

Brusco 2013
Methods Open-label RCT
Patients divided, according to a controlled randomized pattern, into two groups
Participants Women undergoing ICSI (n = 149)
Inclusion criteria: Age between 37 - 40 years; "The recruitment criteria include being under 40 years old,
at least one previous failed attempt with ICSI with low-quality oocyte recovery, diagnosis of PCOS (i.e.,
with oligomenorrhea, hyperandrogenism and pelvic ultrasonographic appearance characterized by
multiple anechoic areas) 8, diagnosis of “poor responders” (i.e., with poor ovarian response to hormon-
al stimulation, an age greater than 37 years and the need for high doses of FSH stimulation in previous
cycles). Only ICSI treatments arrived to the transfer of embryos in the uterus (Embryo-Transfer) and
carried out on Day +2/3 are included in the study".

Informed decisions.

Brusco 2013 (Continued)
Exclusion criteria: "Patients with a partner with a diagnosis of severe male infertility such as crypto-
zoospermia (i.e., retrieval of sperm in the semen after centrifugation) and azoospermia (i.e., eventual
retrieval of sperm from the testicle or epididymis) were excluded from the study."
Interventions 1. Myo-inositol 2000 mg, D-chiro-inositol 400 mg, and folic acid 400 mg: 1 of each tablet a day (n = 58)
2. Folic acid 400 mg: 1 tablet a day (n = 91)
Treatment duration 3 months before the ICSI cycle
Outcomes Oocyte quality
Embryo quality
Biochemical pregnancy
Clinical pregnancy
"Each patient was included only once; therefore, the results for each patient refer to a single treatment
cycle"
Notes Conducted in Perugia Italy
Trial duration between June 2012 and May 2013
Email sent to author regarding randomised pattern, allocation concealment and whether there were
any dropouts; gianfrancesco.brusco@ospedale.perugia.it; no reply.
No mention of ethics approval, consent or funding
Authors state "no conflicts of interest"
Risk of bias
Random sequence genera- High risk "According to a randomized pattern, the total number of patients was divid-
tion (selection bias) ed into two groups". "The two groups were homogeneous within the parame-
ters of inclusion adopted for the study". Numbers are very unequal between
the groups, with 58 in the intervention group and 91 in control

(selection bias)
Blinding (performance High risk "An open study"

All outcomes
Incomplete outcome data Unclear risk No dropouts mentioned and groups are unequal
(attrition bias)
All outcomes
Selective reporting (re- Low risk All outcomes were reported in the Results
porting bias)


Informed decisions.

Carlomagno 2012
Methods Double-blind RCT
Participants Women undergoing ICSI (n not stated)
Interventions 1. Myo-inostol 4 g and folic acid 400 μg: 1 tablet of each a day (n not stated)
2. Folic acid 400 μg: 1 tablet a day (n not stated)
Taken for 3 months before ICSI and throughout pregnancy
Outcomes Total rFSH units
Number of stimulation days
Fertilisation and cleavage rate
Embryo quality
Biochemical pregnancy rate
Clinical pregnancy rate
Conference abstract; percentages given but no total participant numbers available
Funding by an institutional grant. An author was an employee of a pharmaceutical company
Email sent to author 24th November 2015 Gianfranco.carlomagno@gmail.com; no reply.
Risk of bias
Random sequence genera- Unclear risk "Patients were randomly assigned to two groups; MI treated or placebo"
Allocation concealment Unclear risk Not mentioned

(selection bias)
Blinding (performance Low risk "Double blind"

All outcomes
Incomplete outcome data Unclear risk Not mentioned

(attrition bias)
All outcomes
Selective reporting (re- Unclear risk Unknown

porting bias)
Other bias Unclear risk Unknown

Cheraghi 2016
Methods Prospective randomised placebo-controlled pilot trial
Participants Infertile Iranian women with PCOS, aged from 25 - 35 years, undergoing ICSI treatment (N = 80)

Informed decisions.

Cheraghi 2016 (Continued)
Inclusion criteria: Women who met the Rotterdam criteria for PCOS
Exclusion criteria: Hypersensitivity to either MET (metformin) or NAC, infertility factors other than
anovulation, male infertility, pelvic organic pathologies, congenital adrenal hyperplasia, thyroid dys-
function, Cushing’s syndrome, hyperprolactinaemia, androgen-secreting neoplasia, diabetes mellitus,
consumption of medications affecting carbohydrate metabolism and hormonal analogues other than
progesterone 2 months prior to enrolment in the study and severe hepatic or kidney disease
Interventions 4 groups (n = 20 in each, 5 dropouts from each)
1. Placebo oral rehydration salts; 3 times a day
2. Metformin 500 mg: 1 tablet 3 times a day
3. NAC 600 mg: 1 tablet 3 times a day
4. Metformin 500 mg: 1 tablet 3 times a day + NAC 600 mg: 1 tablet 3 times a day
All treatments were administered for 6 weeks
Outcomes Oocyte and embryo quality
Endocrine parameters
Clinical pregnancy
Side effects
Notes Iran, study ran from July 2012 to February 2013
Need to clarify primary and secondary outcomes
Author emailed regarding RoB, live birth and miscarriage information; no reply
Funded by institutional grant
Risk of bias
Random sequence genera- Unclear risk State "random" but method not described
Allocation concealment Unclear risk Not stated

(selection bias)
Blinding (performance High risk Double-blinded placebo-controlled, but the placebo group received oral rehy-
bias and detection bias) dration salts, which are usually in solution, while the treatments were tablets
All outcomes
Incomplete outcome data High risk Dropouts accounted for, but > 25% dropout
(attrition bias)
All outcomes

porting bias)


Informed decisions.

Choi 2012
Methods Prospective, randomised controlled trial
Participants Infertile women with PCOS (n = 100) undergoing IVF/ICSI
Interventions 1. Calcium 400 mg + vitamin D 1000 IU: 1 of each tablet a day (n = 50)
2. Placebo (n = 50)
Given on the starting day of OC pretreatment, followed by controlled ovarian stimulation (COS) using
GnRH antagonist for IVF/ICSI. Calcium 400 mg/day with vitamin D 1000 IU/d or placebo was adminis-
tered once daily from the starting day of OC to the day of human chorionic gonadotropin (hCG) injec-
tion
Outcomes Total dose and days of rhFSH administered
Numbers of retrieved, mature and fertilised oocytes, and grade 1 or 2 embryos

FF TNF-a and IL-6 concentrations at oocyte retrieval
Embryo implantation rate
Miscarriage rate
Notes Korea, study dates not reported
Conference abstract
No data for clinical pregnancy or live birth stated in the conference abstract; emailed co-author CH
Kim; chnkim@amc.seoul.kr, asking about risk of bias, any full publication of the trial and whether they
had any clinical pregnancy and miscarriage data. No reply.
Risk of bias
Random sequence genera- Unclear risk "infertile patients with PCOS were randomized"
Allocation concealment Unclear risk Unknown

(selection bias)
Blinding (performance Unclear risk Unknown

All outcomes
Incomplete outcome data Unclear risk Unknown

(attrition bias)
All outcomes

porting bias)


Informed decisions.

Cicek 2012
Participants Women with a diagnosis of unexplained infertility undergoing ovulation induction and IUI (n = 107)
Inclusion criteria: no ovulatory problems, normal hysterosalpingography and laparoscopy. Normal se-
men sample
Exclusion criteria: endometriosis, hypertension, diabetes, uterine myoma, ovarian cyst, excessive alco-
hol, caffeine, chronic illness and smoking
Interventions 1. Vitamin E: 400 IU: one tablet per day from 3rd to 5th day of the menstrual cycle until the hCG injec-
tion. (n = 53)
4 women were lost to follow-up as a result of incorrect dose consumption (n = 3) and cycle cancellation
(n = 1). ITT not used in the trial
Outcomes Primary outcome: ongoing pregnancy rate
Secondary outcomes: biochemical and clinical pregnancy rate, number of follicles, endometrium thick-
ness, implantation rate
Notes Study was conducted between June 2011 and December 2011 in Turkey
Sample size calculated
Ethics approved and written consent obtained
Funding not reported, but authors say they have no conflict of interest
Emailed author 9th August 2012 regarding the number of women lost from treatment and/or control
group. Data added. Will perform sensitivity analysis for quality if we do not hear back from the author
regarding ITT. No reply
Risk of bias
Random sequence genera- Low risk Randomly assigned according to a randomisation table

(selection bias)
Blinding (performance High risk Not blinded as the control was no treatment
All outcomes
Incomplete outcome data High risk Reasons and numbers for attrition were given but unclear whether from treat-
(attrition bias) ment or control groups. ITT not used
All outcomes
Selective reporting (re- Low risk Nil known

porting bias)

Informed decisions.

Ciotta 2011
Participants Women with PCOS attending a fertility clinic−Gynaecological Endocrinology Clinics and Human Re-
production Pathophysiology Centre (n = 34)
Inclusion criteria: women with PCOS younger than 40 years
Exclusion criteria: concomitant endocrine and metabolic pathologies, such as hypothyroidism, hyper-
thyroidism, diabetes mellitus, androgen-secreting cancers, adrenal hyperplasia, Cushing's syndrome
Women received IVF or ICSI after evaluation of sperm analysis
Interventions 1. Myo-inisitol 2 g + folic acid 200 µg: 1 tablet of each twice a day (n = 16)
2. Folic acid 200 µg: 1 tablet twice a day (n = 18)
Treatment was given over 3 months
Outcomes Number of follicles
Number of oocytes retrieved
Number of embryos transferred
Embryo quality
Study states that there was "no difference in the total number of biochemical pregnancies detected",
but no data were provided. Author replied, giving the data for chemical pregnancies and stating that no
adverse events were reported
Notes Trial held in Catania, Italy
Contacted authors 21st November 2011 via letter and email regarding pregnancy data, allocation con-
cealment and who was blinded. Author responded 28th November 2011 Emailed the author 5th Febru-
ary 2012 requesting data on clinical pregnancies and whether the sealed envelopes were numbered. No
reply
Funding, ethics approval and power calculation not reported
Risk of bias
Random sequence genera- Low risk "According to a randomisation table, patients were divided into two groups".
Allocation concealment Unclear risk Author states that allocation was in "white sealed envelopes".
(selection bias)
Blinding (performance Low risk "the investigation was performed in a double-blind design". Author states,
bias and detection bias) "clinicians and patients were blinded".
All outcomes
Incomplete outcome data Low risk No women were lost to follow-up

(attrition bias)
All outcomes

porting bias)

Informed decisions.

Ciotta 2011 (Continued)

Colazingari 2013
Participants Women with PCOS attending an IVF clinic (n = 100)
Inclusion criteria: BMI <28 and FSH <10 IU/L with a diagnosis of PCOS according to Rotterdam 2003 and
a normal uterine cavity
Exclusion criteria: advanced stage (III or IV) endometriosis and those classified as poor responders or as
suffering from premature ovarian failure
Interventions 1. Myo-inositol 550 mg and DCI 13.8 mg: 1 tablet of each twice a day (INOFOLIC combi, soft gel, Lo.Li.
Pharma Roma, Italy; patented) (n = 47)
2. D-chiro-inositol 500 mg; 1 tablet twice a day (Interquim, s.a., Barcelona, Spain) (n = 53)
Treatment was given for 12 weeks before rFSH administration and throughout pregnancy
Outcomes Primary outcomes: number of morphologically mature oocytes, total IU of rFSH administered and the
number of grade 1 embryos
Secondary outcomes: E2 levels before hCG injection, the number of degenerated oocytes, maturation
rate, fertilisation rate and the number of embryos transferred
Notes The trial was registered on clinicaltrials.org (NCT1338844)
Conducted in Italy
No reproductive outcomes given in the data but pregnancy referred to in the text; emailed author re-
garding pregnancy outcomes 14th September 2016. Author replied on the 27th September 2016, saying
that there are no pregnancy data available but that the trial was double-blinded.
Risk of bias
Random sequence genera- Low risk "Patients were randomly assigned to a block of ten by a computer-generated
tion (selection bias) program"
Allocation concealment Low risk "The key to the coding of the treatments was kept by the Lo.Li. Pharma. Both
(selection bias) the participants and the research team were blinded. The randomization code
was not broken until the completion of the study"
Blinding (performance Low risk Double-blinded

All outcomes
Incomplete outcome data Low risk "One of the patients who was enrolled and assigned to the MI-DCI treated
(attrition bias) group decided to quit the IVF procedure due to personal reasons"
All outcomes
Selective reporting (re- Low risk All outcomes reported

porting bias)

Informed decisions.


Creus 2008
Participants Infertile women with mild to moderate endometriosis (n = 104) post-laparoscopic surgery
Inclusion criteria: at least 12 months with asymptomatic primary infertility, regular menstruation, aged
between 23 and 37 years with normal BMI. Women with other infertility factors were included if those
factors were correctable and were non-contributory
Exclusion criteria: women with other pelvic disorders such as adhesions and tubal obstructions in addi-
tion to endometriosis
Interventions 1. Pentoxifylline 400 mg: 1 tablet twice a day (n = 51)
2. Placebo (n = 53)
Other procedures given post-laparoscopy included biopsies, tubal dye perfusion and destruction of en-
dometriotic implants by cautery
Treatment was started with the first menses after laparoscopic surgery; then participants were ob-
served for 6 months. During this time, participants with other infertility factors were treated (e.g. male
problems or ovulatory defects). Treatments included IUI or ovulation induction, or both. Not all partici-
pants were treated or received the same treatment, thus the potential for bias.
Outcomes Pregnancy
Miscarriage
Notes 6 women dropped out: 4 from the treatment group and 2 from the control group. Reasons explained.
No ITT. Trial held in Barcelona, Spain
Work supported in part by the Comissionat per Universitat i Recerca-Generalitat de Catalunya
Authors were also involved in Balasch 1997
Author emailed 23rd November 2011 regarding live birth data. No reply.
Risk of bias
Random sequence genera- Low risk "Computer-generated randomisation list generated using the method of sim-
tion (selection bias) ple randomisation".
Allocation concealment Low risk "Concealment of treatment allocation was achieved with the use of sealed
(selection bias) opaque envelopes, each containing a unique study number and prepared in-
dependently by a secretary".
Blinding (performance Unclear risk Trial was blinded, not stated whether single, double or triple; "randomised
bias and detection bias) controlled blind trial".
All outcomes
Incomplete outcome data Low risk Small numbers of dropouts and reasons explained, no ITT
(attrition bias)
All outcomes

porting bias)

Informed decisions.

Creus 2008 (Continued)
Other bias Unclear risk Some women with other fertility issues apart from endometriosis were treat-
ed for these additional conditions (i.e. male factor (receiving bromocriptine),
oligo-ovulation (receiving ovulation induction and some additional IUI), poor
post-coital test, hyperprolactinaemia). Numbers of women in treatment and
control in each of these categories are given. However, treatments may bias
the results, as nearly double the control women in the additional treatment
group received IUI compared with the treatment group

Daneshbodi 2013
Participants Overweight and obese women with PCOS, aged 20 - 40 years, (n = 84) diagnosed depending on the Rot-
terdam Criteria
Interventions 1. Oral omega 3, 3 g: 1 tablet a day
2. Placebo
Duration of treatment 8 weeks
Outcomes Biochemical markers (FSH, LH, Prolactin)
Notes Conference proceeding
Conducted in Iran, study dates not reported
Author emailed regarding RoB and pregnancy data. No reply
Risk of bias
Random sequence genera- Unclear risk Not stated


(selection bias)
Blinding (performance Low risk Double-blinded (placebo control)

All outcomes
Incomplete outcome data Unclear risk Not stated

(attrition bias)
All outcomes

porting bias)


Informed decisions.

Deeba 2015
Participants Infertile women at Bangladesh fertility unit (n = 156) undergoing ovulation induction with clomiphene
citrate
Interventions 1. Multinutrient supplementation; unknown included antioxidants and dosage
2. Folic acid; unknown dosage
Outcomes Chemical pregnancy
Clinical pregnancy
Ovulation rate
Notes Conference abstract only, limited details
Set in Bangladesh, study dates not reported
Author emailed for RoB information and data. No reply
Risk of bias


(selection bias)
Blinding (performance Unclear risk Not stated

All outcomes
Incomplete outcome data Unclear risk Not stated

(attrition bias)
All outcomes
Selective reporting (re- Unclear risk Clinical pregnancy reported in Methods but not in the Results; this is a confer-
porting bias) ence abstract, so they may not have the data yet

El Refaeey 2014
Methods Prospective randomised controlled trial
Participants Women with clomiphene-citrate-resistant PCOS attending a fertility outpatient clinic (n = 110)
Inclusion criteria: diagnosis of PCOS. All women were previously treated with 150 mg clomiphene cit-
rate daily for 5 days per cycle, for 2 or 3 cycles with persistent anovulation or ovulate with very thin en-
dometrium (< 5 mm). All women had patent fallopian tubes

Informed decisions.

El Refaeey 2014 (Continued)
Exclusion criteria: women with hyperprolactinaemia, hypercorticism and thyroid dysfunction and
women receiving medications such as cholesterol-lowering drugs, beta-blockers and tricyclic antide-
pressants
Interventions 1. CoQ10 60 mg: 3 capsules a day + clomiphene citrate 150 mg: 1 tablet a day, from cycle days 2 – 6
starting on cycle day 2 and until the day of hCG administration (n = 55)
2. Clomiphene citrate 150 mg: 1 tablet a day from cycle day 2 for 5 days (n = 55)
The mean duration of CoQ10 treatment in the 1st cycle was 16.2 ± 2.1 days and in the 2nd cycle 17.1 ±
2.9 days
Outcomes Primary outcomes: number of growing and mature follicles, serum oestradiol, serum progesterone,
ovulation rate, endometrial thickness
Secondary outcomes: clinical pregnancy (ultrasound visualisation of gestational sac with pulsating fe-
tal pole) and miscarriage (spontaneous termination of a clinical pregnancy before 20 weeks of gesta-
tion)
Notes Timed intercourse
Sample size calculation done
4 dropouts from the intervention and 5 from the control group
Egypt
Trial duration January 2010 to January 2013
The study was approved by the departmental ethical committee and all participants gave informed
consent before inclusion in the trial (committee reference no. 231, approved December, 12 2009)
This trial is registered at ClinicalTrials.gov (ID NCT01910766)
Email to author regarding live birth data and allocation concealment sent 26th November 2015. No re-
ply.
Endometrial thickness; significant difference in favour of the treatment group vs control
Risk of bias
Random sequence genera- Low risk "Patients were randomly allocated using a computer generated random table"
Allocation concealment Low risk "sealed envelopes" "Allocation process was done by a third party (nurse)"
(selection bias)
Blinding (performance High risk "The physicians monitoring the cycles were blinded to the protocol of each
bias and detection bias) group"
All outcomes
Incomplete outcome data Low risk Dropouts accounted for from each arm
(attrition bias)
All outcomes
Selective reporting (re- Low risk All outcomes were reported as stated in the Methods
porting bias)

Informed decisions.


Eryilmaz 2011
Methods Randomised single-centre controlled clinical trial
Participants Women undergoing IVF with sleep disturbances (n = 63) from 24 - 38 years
Inclusion criteria: unexplained infertility, no ovulatory problems, normal hysterosalpingogram or la-

paroscopy and normal semen sample
Exclusion criteria: chronic drug usage, history of > 1 fertilisation failure, hypertension, diabetes, uterine
myoma, ovarian cyst and smoking
Interventions 1. Melatonin 3 mg; 1 tablet a day, taken at 22:00 to 23:00 from 3rd to 5th day of the menstrual cycle until
the hCG injection (n = 30)
Outcomes Primary outcome: oocyte quality
Secondary outcomes: fertilisation failure rate, number of follicles, number of oocytes retrieved, num-
ber of Mll oocytes, fertilisation rate, number of embryos transferred, embryo quality, implantation rate
and clinical pregnancy rate
Notes Trial held in Turkey
Ethics approved, written informed consent gained. Authors declare no conflicts of interest
Power calculation performed
Emailed author 9th August 2012 regarding which group or groups lost the 3 women. Data added. Tried
to contact the author again regarding live birth data 5th February 2013 Author replied on 7th February
2013 , saying that the 3 dropouts were from the treatment group, and that no allocation concealment
was performed and no live birth data were available because participants were mainly from rural sites
Risk of bias
Random sequence genera- Low risk Participants were randomly assigned according to a randomisation table
Allocation concealment High risk No allocation concealment

(selection bias)
Blinding (performance High risk No blinding as control is no treatment

All outcomes
Incomplete outcome data Low risk Dropouts explained

(attrition bias)
All outcomes

porting bias)


Informed decisions.

Gerli 2007
Methods Double-blind randomised trial
Participants Women with oligomenorrhoea or amenorrhoea and PCOS were recruited from gynaecology, endocrine
and fertility clinics. Women were < 35 years of age, mean age 29.7 (n = 92)
"Infertility was an ailment in only half of the patients in each group. There was no difference in the pro-
portions of infertile women with the groups".
Exclsion criteria: hyperprolactinaemia, hormone treatment, abnormal thyroid function, congenital

adrenal hyperplasia
Interventions 1. InfolicⓇ, a combination of myo-inositol 2g plus folic acid 400 μg: 1 tablet twice a day (n = 45). Mean
age 29.0
2. Folic acid 400 μg: 1 tablet twice a day (n = 47). Mean age 29.7
Duration: 16 weeks
Outcomes Ovulation frequency
Hormonal levels
Pregnancy
Notes "Ethical committee approval was obtained before the study, and written informed consent was given
by each patient".
Trial carried out in Italy, study dates not reported
Power calculation carried out
High dropouts, > 30% in the treatment group.
Included, but data not used, as half the participants did not want to conceive. Study is included on the
basis that half the participants were from a subfertility clinic
Authors contacted (May 2010) to request any pregnancy outcomes considered and to ask whether the
authors of the paper have the individual data on which women in each group were infertile. No reply as
of 12th June 2013
Risk of bias
Random sequence genera- Low risk "Randomisation was effected in a double blind fashion; patients received ei-
tion (selection bias) ther MYO combined with folic acid (Inofolic®) or only folic acid as placebo, ac-
cording to the code provided by computer-generated randomization."
Allocation concealment Unclear risk Not described

(selection bias)
Blinding (performance Unclear risk Described as "double-blind fashion" ("placebo control" however control is
bias and detection bias) folic acid therefore considered to be no treatment)
All outcomes
Incomplete outcome data High risk "The high dropout rate in the myo-inositol arm (more than 30%) is notable".
(attrition bias)
All outcomes

Informed decisions.

Gerli 2007 (Continued)
Selective reporting (re- High risk Only half the participants declared before the study that they wanted to con-
porting bias) ceive. No ITT for the pregnancy outcome. 1 miscarriage was reported but no
details of whether this occurred in the treatment or the control group. Miscar-
riage not prespecified as an outcome of interest

Griesinger 2002
Methods Prospective, randomised, placebo-controlled, group comparative, double-blind study
Participants Subfertile women having 1st IVF cycle aged < 40 years with mean age of 31.73 ± 4.4 years (n = 620)
10% described as male factor infertility, and associated data were not presented separately
Inclusion criteria: tubal, idiopathic and male infertility were included
Exclusion criteria: women with repeated IVF cycles and women with renal or gastrointestinal disease
Interventions 1. Ascorbic acid 1 g: 1 tablet a day (n = 172)
2. Ascorbic acid 5 g: 1 tablet a day (n = 153)
3. Ascorbic acid 10 g: 1 tablet a day (n = 136)
4. Placebo (n = 158)
Duration 1 cycle
Outcomes Clinical pregnancy rate confirmed by fetal heartbeat at 8 weeks
Implantation rate per embryo transfer
Notes 1 woman lost to follow-up−no explanation. Tried to contact author. No reply
10% of women had partners with male infertility
Trial conducted in 2 clinics in Budapest, Hungary (n = 237) and Vienna, Austria (n = 383)
No power calculation performed
Pregnancies were confirmed at 8 weeks with no further follow-up; authors contacted regarding this. No
reply as of 12th June 2013
No clarity regarding the number of treatment cycles involved in this study
Ethics approval not gained as "a study on vitamin supplementation is not subject to IRB approval".
Consent forms were signed.
Risk of bias
Random sequence genera- Unclear risk "This prospective randomised double-blind study". Method not described
Allocation concealment Low risk By an independent pharmacy in Vienna "prepared and coded by number".
(selection bias)

Informed decisions.

Griesinger 2002 (Continued)
Blinding (performance Low risk Women and clinicians were blinded: "double-blind study".
All outcomes
Incomplete outcome data Low risk 1 set of participant data noted as missing but not explained; authors contact-
(attrition bias) ed regarding this
All outcomes

porting bias)
Other bias Unclear risk Unequal baseline group numbers

Ismail 2014
Methods Randomised double-blind, placebo-controlled, parallel-group study
Participants Infertile women with PCOS. Mean age: Treatment group: 24.6 ± 3.2; Control group: 24.8 ± 2.7.Timed in-
tercourse (n = 170)
Inclusion criteria; < 35 years of age, presenting with primary or secondary infertility following regular
intercourse for at least 1 year and diagnosed with PCOS with no other abnormalities
Exclusion criteria; FSH values ≥ 10IU/ml
Interventions 1. Clomiphene citrate 250 mg: 1 tablet a day from day 3 to day 7 of the cycle plus oral-carnitine 3 g: 1
tablet a day from day 3 until the day of the first positive pregnancy test (n = 85)
2. Clomiphene citrate 250 mg: 1 tablet a day plus placebo (n = 85)
All participants received clomiphene citrate from day 3 until day 7 of the cycle.Timed intercourse
Outcomes Clinical pregnancy rate
Miscarriage
Multiple pregnancies
Ovulation rate
Days until hCG injection
Number of follicles
Number of pregnancies
Laboratory parameters
Notes All participants were counselled about their participation in the study. A signed informed consent was
obtained. Participants had the right to refuse to participate or to withdraw from the study at any time
without being denied their regular full clinical care. Personal information and medical data collected
were subject to confidentiality and were not made available to a third party.
Women’s Health Hospital, Assiut University, Assiut, Egypt
The study was conducted between January 2010 and March 2012
Sample size calculation done

Informed decisions.

Ismail 2014 (Continued)
"The authors have no conflict to disclose"
Email sent to author on 26th November 2015 regarding live birth data; author replied on 7th December
2015 saying there are no live birth data
Risk of bias
Random sequence genera- Low risk "computer-generated numbers"

"randomized according to computer-generated randomization tables to en-
sure an equal number of patients in each arm (1:1 ratio)".
Allocation concealment Low risk "using previously prepared sealed envelopes with computer-generated num-
(selection bias) bers"
"Throughout the trial, access to the randomization code was available only to
the pharmacist who manufactured the placebo and packed the envelopes and
was not available to any of the treating physicians or patients".
"The capsules were placed in sacks and then stored in envelopes numbered
from 1 to 170. The envelopes were numbered"
Blinding (performance Low risk "double blind"

All outcomes "The placebo capsules were specially manufactured to look identical to the L-
carnitine capsules".
Incomplete outcome data Low risk 18/170 dropouts with numbers per group and reasons given
(attrition bias)
All outcomes
Selective reporting (re- Low risk All outcomes stated in the Methods were reported
porting bias)

Keikha 2010
Methods Double-blinded randomised control trial
Participants Women aged 18 - 41 with PCOS which was clomiphene-resistant who attended fertility clinic in Iran (n =
93)
Interventions 1. Oral NAC 1.2 g: 1 tablet a day (n = 53)
2. Vitamin C (?dose) (n = 40)
Outcomes Oestradiol levels
Number of follicles > 18 mm
Notes Conducted in Iran, study began in 2010 (end unknown)

Informed decisions.

Keikha 2010 (Continued)
Unknown trial duration
Tried to contact author regarding pregnancy data, uneven number in each group. No reply.
Risk of bias


(selection bias)
Blinding (performance Unclear risk Double-blinded (another antioxidant, not placebo)

All outcomes
Incomplete outcome data High risk Uneven number in each group

(attrition bias)
All outcomes

porting bias)

Kim 2006
Participants Infertile women aged 25 - 39 years with PCOS undergoing IVF (n = 58)
Interventions 1. NAC 400 mg: 1 tablet twice a day (n = unknown)
2. Placebo (n = unknown)
Duration 13 - 15 weeks.
Outcomes Insulin sensitivity
Endocrine levels
Ovarian stimulation
Number and size of follicles
Number of retrieved oocytes
Number and quality of embryos transferred
Pregnancy rate
Miscarriage
Ovarian hyperstimulation syndrome rates

Informed decisions.

Kim 2006 (Continued)
Notes Conference abstract only
Trial held in Korea, study dates not reported
The authors contacted to request pregnancy outcome data and study protocol to appraise risk of bias
elements. No reply as of 14th September 2011
Risk of bias
Random sequence genera- Unclear risk "The patients randomly assigned..." No description of method of sequence
tion (selection bias) generation

(selection bias)

All outcomes

(attrition bias)
All outcomes

porting bias)

Kim 2010
Methods Prospective randomised controlled study
Participants Infertile women with a history of unexplained total fertilisation failure undergoing ICSI (n = 98). Ages
not given
Inclusion criteria: unknown
Exclusion criteria: unknown
Interventions 1. Omega-3-polyunsaturated fatty acids (o-3 PUFAs) 1000 mg: 1 tablet a day (n = unknown)
2. Unknown control (n = unknown)
Outcomes Total recombinant human (rh)FSH dose and days required
Numbers of oocytes retrieved
Number of oocytes fertilised
Embryo quality
Embryo implantation

Informed decisions.

Kim 2010 (Continued)
Notes Conference abstract only
Trial held in Korea, study dates not reported
Authors emailed 22nd November 2011regarding risk of bias, pregnancy data per woman, numbers in
intervention and control groups and inclusion/exclusion criteria. No reply
Risk of bias
Random sequence genera- Unclear risk "Prospective randomised controlled study"−no explanation given.

(selection bias)
Blinding (performance Unclear risk Unknownn.

All outcomes

(attrition bias)
All outcomes

porting bias)

Lesoine 2016
Methods vRandomised study
Participants Women with PCOS indicated by oligomenorrhoea and/or hyperandrogenism and/or hyperandrogaen-
emia and/or typical features of ovaries on ultrasound scan were enrolled in this study. At least 2 of the
above-mentioned criteria were present in all the participants
Women were undergoing IVF and aged < 40 years (n = 29)
Exclusion criteria: any other medical conditions causing ovulatory disorders such as hyperprolacti-
naemia or thyroidal disorders or Cushing syndrome
Interventions 1. Myo-inositol 4000 mg plus folic acid 400ug: 1 tablet per day (n = 14)
2. Placebo (n = 15)
Treatment was for 2 months prior to the IVF cycle and the trial ran for 4 months
Outcomes Number of retrieved oocytes
Ratio of follicles to retrieved oocytes
Fertilisation rate
Oocyte quality

Informed decisions.

Lesoine 2016 (Continued)
Amount of FSH units used
Days of stimulation
Notes Conducted in Germany, study dates not reported
Has an author who was an employee of a pharmaceutical company
Contact details; Pedro-Antonio Regidor (pedro-antonio.regidor@exeltis.com) email sent on 13th Octo-

ber 2016 asking whether the placebo group received folic acid, methods of randomisation, allocation
concealment, clinical pregnancy, live birth data and the length of the trial. Author replied 17th October
2016, no outcomes yet "but this is ongoing"
Risk of bias
Random sequence genera- Low risk "The method of randomization was a manual one. After fulfilling the including
tion (selection bias) criteria the patients were allocated to the previously defined randomisation
list"

(selection bias)
Blinding (performance Unclear risk Single-blinded. "The biologist which carried out the fertilization was the blind-
bias and detection bias) ed person. He did not know if the women were treated with myo-Inositol or
All outcomes not" (placebo used)
Incomplete outcome data Low risk All randomised women were analysed
(attrition bias)
All outcomes
Selective reporting (re- Low risk No apparent reporting bias

porting bias)

Lisi 2012
Methods Randomised open-label, multicentre pilot study
Participants Infertile women undergoing IVF/ICSI, mean age 34.4 ± 3.4 (n = 100)
Exclusion criteria: women with PCOS, with any endocrine or metabolic disease, taking any hormonal
treatment, with BMI > 30 kg/m2
Interventions 1. Myo-inositiol 4000 mg: "into two administrations per day" + folic acid 400 µg: 1 tablet a day (n = 50)
2. Folic acid 400 µg: 1 tablet a day (n = 50)
Duration of treatment 3 months, duration of trial 12 months
Outcomes Length of stimulation
Total quantity of gonadotropins required

Informed decisions.

Lisi 2012 (Continued)
Implantation rate
Clinical pregnancy
Notes Center for Reproductive Medicine Research, Clinica Villa Mafalda, Rome, Italy, study held from January
2011 to January 2012
Emailed author 13th February 2013 regarding randomisation, allocation concealment and live birth da-
ta. Professor Lisi replied, clarifying these questions.
Risk of bias
Random sequence genera- Low risk "Block randomisation in a computer-generated sequence" is written in the pa-
tion (selection bias) per and in further correspondence from the author ..."About randomization, a
computer software generated 100 numbers from 1 to 10,000, and the numbers
were stored in sealed envelopes and opened on the day of preparation and ex-
planation of the stimulation protocol to patients. Patients with odd number-
were assigned to folic acid, myo-inositol and rhFSH; patients with even num-
ber were assigned to folic acid and rFSH". Unsure whether this may be qua-
si-randomised. We sought further information from the author. Author replied,
"The envelope outside had 100 numbers in order and opened in that order;
numbers outside were different from numbers inside".
Allocation concealment Low risk Envelopes were numbered sequentially and were opaque
(selection bias)
Blinding (performance High risk Open-label, although outcome assessors were blinded participants were not
All outcomes
Incomplete outcome data Low risk No dropouts

(attrition bias)
All outcomes

porting bias)

Maged 2015
Methods Randomised study
Participants Women with PCOS (based on Rotterdam criteria, ESHRE/ASRM 2004), the diagnosis of PCOS is deter-
mined by the presence of 2 of the following conditions: oligo-ovulation or anovulation, hyperandro-
genism and polycystic ovaries detected by ultrasonography with the presence of 12 or more follicles
measuring 2 – 9mm in diameter, and/or at least 1 enlarged ovary (410 cm). None of the participants had
history of clomiphene citrate resistance (n = 120)
Timed intercourse
Mean age was 26 years for all 3 groups

Informed decisions.

Maged 2015 (Continued)
Exclusion criteria: women with endocrinological abnormalities such as thyroid dysfunction or abnor-
mal prolactin levels, those with hypothalamic or pituitary dysfunctions evaluated by low gonadotropin
level, other causes of infertility such as tubal factor evaluated by HSG or laparoscopy, abnormal uterine
cavity evaluated by sonohystrography or hysteroscopy and male factor, evaluated by semen analysis.
Women with ovarian cysts and those with allergy to the study medications were also excluded from the
study. Women who had received any hormonal medications (except progesterone for withdrawal
bleeding) within the last 3e months before the study were also excluded
Interventions 1. Clomiphene citrate 100 mg orally in 2 divided doses a day. No treatment (n = 40)
2. NAC 1200 mg in 2 divided doses a day (in the form of powder inserted in small pockets to be diluted
into a standard glass of water from day 3 until day 7 of the menstrual cycle) (n = 40)
3. Metformin 500 mg: 1 tablet 3 times a day (n = 40)
Treatment period; from day 3 to day 7 of the menstrual cycle, treatment was repeated in non-pregnant
cases for 3 successive cycles
Outcomes Clinical pregnancy (defined as the presence of gestational sac containing fetal hearts on ultrasound
scan)
Occurrence and day of ovulation
Endometrial thickness and pattern
Number and size of follicles
Notes Conducted in Egypt
Trial period; September 2012 to March 2014.
Ahmed Mohamed Maged, Obstetrics and Gynecology Department, Kasr Aini Hospital Cairo Universi-
ty, 135 King Faisal Street Haram Giza, Cairo, Egypt. Tel: 0105227404. Fax:35873103. E-mail prof.ahmed-
maged@gmail.com. Email sent 13th October 2016 regarding live birth and any dropouts. No reply.
Risk of bias
Random sequence genera- Low risk Patients were randomised at the beginning of each cycle by sealed opaque en-
tion (selection bias) velopes containing randomly generated numbers into 3 groups
Allocation concealment Low risk Patients were randomized at the beginning of each cycle by sealed opaque en-
(selection bias) velopes containing randomly generated numbers into 3 groups
Blinding (performance High risk No blinding

All outcomes
Incomplete outcome data Unclear risk Numbers analysed in each group are not given
(attrition bias)
All outcomes
Selective reporting (re- Low risk No known selective reporting

porting bias)

Informed decisions.


Mier-Cabrera 2008
Participants Infertile women with peritoneal endometriosis stage 1 or 2 diagnosed by laparoscopy (n = 36). All par-
ticipants had fulguration of endometrial implants. Mean age: Treatment group 32.7 ± 2.36; Placebo
group 32.7 ± 2.36
Inclusion criteria: women between 25 and 35 years old who had been diagnosed as having peritoneal
endometriosis on exploratory laparoscopy, with fertile male partner
Exclusion criteria: women who reported having used nutritional supplements during the previous year;
who had pelvic inflammatory disease or autoimmune, endocrine or metabolic disorders; or who did
not agree to participate or missed a medical visit
Interventions 1. Vitamins C 343 mg + Vitamin E 84 mg: in a bar form, 1 bar a day (n = 18)
2. Placebo (n = 18)
Duration of trial was 6 months
Follow-up for up to 9 months after the trial
Outcomes Live birth (no data available)
Pregnancy (no explanation of whether pregnancies were biochemical, clinical or ongoing). "None of
the patients became pregnant during the trial. Once the trial ended, patients were followed up for 9
months for a possible pregnancy". The pregnancy rate was 19% (3 of 16) in the supplementation group
and 12% (2 of 18) in the placebo
MDA, oxidative stress markers obtained during the exploratory laparoscopy
Notes Consent signed
Ethics was approved
The study was conducted at the National Institute of Perinatology “Isidro Espinosa de los Reyes” in
Mexico City, study dates not reported
Funding given as a grant from Consejo Nacional de Ciencia Tecnologia Mexico.
Power calculation done.
Tried to contact author. Contacted author again 12th February 2013 to ask about clinical pregnancy
and live birth. No reply
Risk of bias
Random sequence genera- Low risk Reference was made to the use of 'randomisation codes', and investigators
tion (selection bias) stated, "Thirty-six participants were randomly assigned". Authors contacted
regarding this
Allocation concealment Unclear risk Not stated in the paper. Authors contacted regarding this. The response was,
(selection bias) "women were randomly allocated depending on the colour of a ball they took
out from a container"
Blinding (performance Low risk Women were blinded. The bars were "identical-looking and tasting bars". Au-
bias and detection bias) thors contacted regarding this and confirmed that investigators, outcome
All outcomes assessors and clinicians were blinded also. "Randomization codes were un-
locked at the end of the study".

Informed decisions.

Mier-Cabrera 2008 (Continued)
Incomplete outcome data Unclear risk 2 women in the treatment arm dropped out "for personal reasons". ITT not ap-
(attrition bias) plied
All outcomes
Selective reporting (re- High risk Investigators stated they would collect live birth rates but reported only preg-
porting bias) nancy rates

Mohammadbeigi 2012
Participants Infertile women with PCOS (n = 44). Natural or timed intercourse
Mean age: Treatment group: 26.5 yr (20 - 43); Control group: 29 yrs (23 - 26)
Inclusion criteria: primary or secondary infertility due to PCOS according to Rotterdam criteria includ-
ing oligomenorrhoea, amenorrhoea, clinical or laboratory evidence of increase androgen level or poly-
cystic ovaries in sonography
Exclusion criteria: any definite gland disorders such as kaohsiung hypothyroid, hypothyroidism, diabet-
ics and increase in blood prolactin levels
Interventions 1. Clomiphene 50 mg: 1 tablet a day + 400 units of Vitamin D + 1000 mg calcium: 1 tablet a day (n = 22)
2. Clomiphene 50 mg + placebo: 1 tablet a day (n = 22)
Duration: 3 menstruation cycles (3 months)
Outcomes Follicle size
Pregnancy (unknown whether this is clinical or biochemical - sonography had been done for all partici-
pants up to 3 months but this could be to assess follicle size)
Notes Conducted in Iran
Trial was run between 2010 and 2011.
Email was sent to author on the 30th November 2015 regarding data and risk of bias robab20@ya-
hoo.com - no reply. Dr Vahid Seyfoddin helped translate key points from the paper. New email found
nezhat79@gmail.com, email sent 27th September 2016 regarding block size, allocation concealment
and clinical pregnancy data
Risk of bias
Random sequence genera- Unclear risk "Patients were divided into two groups (22 Intervention and 22 controls) using
tion (selection bias) block randomization method". Unknown process of selection of blocks
Allocation concealment Unclear risk Unknown block number

(selection bias)

Informed decisions.

Mohammadbeigi 2012 (Continued)
Blinding (performance Low risk "Specialists did the randomisation only and the residents managed the study,
bias and detection bias) the radiologists was blinded while using the same instrument and only one
All outcomes practitioner" (placebo control)
Incomplete outcome data Low risk "All participants completed the study"
(attrition bias)
All outcomes
Selective reporting (re- Unclear risk Unknown whether the reported pregnancies were biochemical or clinical. Pro-
porting bias) tocol available

Nasr 2010
Methods Randomised, double-blind, placebo-controlled pilot study
Participants Women undergoing unilateral laparoscopic ovarian drilling (LOD) for clomiphene-resistant PCOS (n =
60)
Aged 18 - 38 years; mean age: treatment group 28.4 ± 4.2; placebo group 29.2 ± 3.7, with at least 2 years
of infertility due to anovulation, patent fallopian tubes, normal semen analysis
Exclusion criteria included no hormonal treatment for 3 months before enrolment and any contraindi-
cations to anaesthesia or laparoscopy
Interventions 1. NAC 1.2 grams: 1 sachet a day for 5 days, starting at day 3 of the cycle (immediately after LOD) for 12
consecutive cycles (n = 30)
2. Placebo (n = 30)
Both groups also had LOD
Follow-up by cycle monitoring and timed intercourse for a year. No women were lost to follow-up.
Outcomes Primary outcome: biochemical pregnancy
Secondary outcomes: ovulation, number of follicles, endometrial thickness, clinical pregnancy, miscar-
riage, multiple pregnancies, ongoing pregnancy, number of preterm deliveries, live birth
Notes Trial took place in Egypt between January 2005 and June 2007
Ethics obtained.
Informed written consent.
Endometrial thickness; significant difference in favour of the treatment group
Risk of bias
Random sequence genera- Low risk "Randomised double-blind placebo-controlled pilot study", "computer-gener-
tion (selection bias) ated random numbers".

Informed decisions.

Nasr 2010 (Continued)
Allocation concealment Unclear risk "Sealed envelopes".
(selection bias)
Blinding (performance Low risk Double-blind. "The placebo sachets were specially manufactured to look iden-
bias and detection bias) tical to the NAC sachets". "Throughout the study, access to the randomisation
All outcomes code was available only to the pharmacist and was not available to the treat-
ing gynaecologist or patients".
Incomplete outcome data Low risk No women lost to follow-up

(attrition bias)
All outcomes

porting bias)

Ozkaya 2011
Methods Randomised trial
Participants Women undergoing IVF aged 22 - 43 years. Mean age treatment group: 30.7 ± 4.5; placebo group: 28.8 ±
3.2) (n = 56)
Inclusion criteria: non-smokers, free from major illness including hypertension, all interested in becom-
ing pregnant
Exclusion criteria: myoma, adenomyosis, congenital abnormality, ovarian tumours, hormone or long-
term medication use
Interventions 1. Multi-vitamin/mineral (containing vitamins A, B, C, D, E and H, calcium, folic acid, nicotinic acid, iron,
magnesium, phosphor copper, manganese and zinc): 1 tablet a day (n = 26)
2. Placebo (candy) (n = 30).
for 45 days
Outcomes Follicular fluid
Notes Conducted in Turkey
3 groups were used in the study. The 1st group consisted of age-matched controls, so we did not use
these data in this review. The 2nd and 3rd groups were randomly assigned
Author emailed on 1st August 2012 to ask for any data on pregnancy, live birth or adverse events. Au-
thor replied on 13th August 2012. No outcomes appropriate to this review.
Risk of bias
Random sequence genera- Low risk Randomised by a computer-generated list

Allocation concealment Unclear risk Not mentioned

(selection bias)

Informed decisions.

Ozkaya 2011 (Continued)
Blinding (performance High risk Placebo used was candy
All outcomes
Incomplete outcome data Unclear risk None mentioned

(attrition bias)
All outcomes
Selective reporting (re- Low risk None known

porting bias)

Pacchiarotti 2016
Methods Randomised controlled double-blind trial
Participants Women with PCOS undergoing ICSI aged between 27 - 38 years (n = 569)
Inclusion criteria: absence of tubal, uterine, genetics and male causes of infertility; serum levels of FSH
on day 3 of the ovarian cycle 512 IU/L; Rotterdam criteria for PCOS; normal uterine cavity; BMI of 20 to
26 kg/m2; first IVF treatment. Only women undergoing 1st-time ICSI procedure fulfilling inclusion crite-
ria were enrolled in the study in order to limit their heterogeneity
Interventions 1. Myo-inositol 4000 mg + folic acid 400 mcg (Inofolic®): 1 tablet twice a day and Melatonin 3 mg: 1
tablet twice a day (n = 178)
2. Myo-inositol 4000 mg + folic acid 400 mcg (Inofolic®): 1 tablet twice a day (n = 180)
3. Folic acid 400 mcg: 1 tablet twice a day (n = 211)
Treatment was from the first day of the cycle until 14 days after embryo transfer
Outcomes Primary end points were: oocyte and embryo quality, clinical pregnancy (identified by the presence of a
gestational sac on ultrasonography 5 weeks after oocyte retrieval) and implantation rates.
Secondary outcomes were: gonadotropin IU administered, days of stimulation, serum estradiol(E2) lev-
els and endometrial thickness on the day of human chorionic gonadotropin (hCG) administration.
Notes Conducted in Italy
Trial ran from July 2009 to December 2011
43 women dropped out, 16 from the control, 13 from the intervention group A and 14 from group B;
reasons provided
Clinical Trial registration Number: NCT01540747 (ClinicalTrials.gov registry)
Has an author who was an employee of a pharmaceutical company
Emailed Dr Pacchiarotti 18th October 2016 to ask about allocation concealment and live birth data and
asked about trial details from included study Valeri 2015. Contact details; arypac@gmail.com. Dr Pac-
chiarotti replied 20th March 2017 saying that the clinical pregnancy was per woman as they have 80%
of the live birth data. We replied asking whether we could include these data. No reply yet. We will need
to follow up on this for next review update.

Informed decisions.

Pacchiarotti 2016 (Continued)
Risk of bias
Random sequence genera- Low risk "Randomization was performed using a computer based random assignment
tion (selection bias) schedule for each patient"

(selection bias)
Blinding (performance Unclear risk "double-blinded" but not placebo-controlled

All outcomes
Incomplete outcome data Low risk Dropout reasons were described and numbers given for each group
(attrition bias)
All outcomes
Selective reporting (re- Low risk Outcomes in the Methods were reported as per protocol
porting bias)

Panti Abubakar 2015
Participants Women with PCOS having clomiphene citrate for ovulation induction (timed intercourse) (n = 200)
Interventions 1. Combined antioxidant supplementation; vitacap which contains vitamin A (Palmitate) 5000 iu, vi-
tamin B1 (thiamine mononitrate) 5 mg, vitamin B6 (pyridoxine HCL) 2 mg, vitamin B12 (cyanocobal-
amin 5 mg, vitamin C 75 mg, vitamin D3 (cholecalciferol) 400 iu, Vitamin E (d-alpha tecopheryl acetate )
15 mg, nicotinamide 45 mg, folic acid 1000 mcg, ferrous fumerate 50 mg, dibasic calcium phosphate
70 mg, copper sulphate 0.1 mg, manganese sulphate 0.01 mg, zinc sulphate 50 mg, potassium iodide
0.025 mg and magnesium oxide 0.5 mg: 1 vitacap a day (n = 100)
2. Placebo; containing folic acid and fersolate. 1 tablet a day (n = 100)
Treatment given for 6 months
Outcomes Live birth
Clinical pregnancy
Menstrual regularisation
Notes Conducted in Nigeria, study dates not reported
Conference abstract
kapanti2002@yahoo.co.uk, email sent 18th October 2016. Author replied 20th October 201 with live
birth data. Emailed author re allocation concealment of odd and even envelopes 25th January 2017
Risk of bias

Informed decisions.

Panti Abubakar 2015 (Continued)

Random sequence genera- Low risk "The women were randomized into two groups by picking one of the two
tion (selection bias) closed envelops. within the envelop is written odd or even number. The odd
number for intervention and even number for control. The selection of odd
and even number for intervention and control group was done by toss of coin"
Allocation concealment Low risk "The women were randomized into two groups by picking one of the two
(selection bias) closed envelopes, within the envelope is written odd or even number".
Blinding (performance Low risk "The trial was single blinded. The patient did not know" a placebo was used
All outcomes
Incomplete outcome data Low risk Dropouts accounted for

(attrition bias)
All outcomes

porting bias)

Papaleo 2009
Participants Infertile women with PCOS undergoing ovulation induction for ICSI (n = 60)
Mean age (years) treatment: 36.2 ± 2.4; non-treatment 35.4 ± 2.5
Inclusion criteria: women aged < 40 years with PCOS, indicated by oligomenorrhoea (6 or fewer men-
strual cycles during a period of 1 year), hyperandrogenism (hirsutism, acne or alopecia) or hyperan-
drogenaemia (elevated levels of total or free T) and typical features of ovaries on ultrasound scan. All
women had been treated at the IVF clinic for > 12 months.
Exclusion criteria: other medical conditions causing ovulatory disorders such as hyperinsulinaemia, hy-
perprolactinaemia, androgen excess such as adrenal hyperplasia or Cushing's syndrome
Duration of infertility (months) treatment: 46.1 ± 18.5, non-treatment: 37.7 ± 9.6
Interventions 1. Myo-inositol 2 g + folic acid 400 µg (Inofolic®): 2 tablets a day (n = 30)
2. Folic acid 400 µg (n = 30)
Duration: for 1 cycle of ICSI. Treatment starting on the day of GnRH administration
Outcomes Number of mature oocytes retrieved
Embryo quality
Pregnancy
Implantation rates
Total number of days of FSH stimulation
Total dose of gonadotropin administered

Informed decisions.

Papaleo 2009 (Continued)
Oestrogen levels
Fertilisation rate
Number of retrieved oocytes
Embryo cleavage rate
Live births
Miscarriage rates
Cancellation rate
Incidence of moderate or severe ovarian hyperstimulation syndrome
Notes The Institutional Review Board approved the protocol, and all participants gave written informed con-
sent before entering into the trial
Source of funding not stated
Authors contacted.
Trial conducted in Italy, start date March 2004 (unknown end date)
Authors could not supply live birth data
Risk of bias
Random sequence genera- Low risk Randomised according to "computerised allocation". Authors have since con-
tion (selection bias) firmed this
Allocation concealment Unclear risk "Computerised allocation"

(selection bias)
Blinding (performance High risk Authors confirmed in correspondence that participants and investigators were
bias and detection bias) not blinded; however, outcome assessors and clinicians were blinded. Not a
All outcomes placebo control

(attrition bias)
All outcomes
Selective reporting (re- High risk Data on live birth were not reported in the paper, even though it was listed as
porting bias) an outcome in the abstract of the paper

Polak de Fried 2013
Methods Prospective, randomized, double-blind placebo-controlled trial
Participants Infertile women undergoing IVF/ICSI, 34 women with ICSI cycles and 18 oocyte donation (n = 52)
Interventions 1. Vitamin D 100.000 IU: 1 tablet per month (n = 26)

Informed decisions.

Polak de Fried 2013 (Continued)

2. Placebo (n = 26)
Trial duration; 5 consecutive months
Outcomes Endometrial thickness
Cancellation rate
Number of embryos transferred
Implantation rate
Live birth
Notes Conducted in Argentina,study dates not reported
conference abstract
Author email; ester_polak@cermed.com. Author contacted on the 20th November 2015 regarding risk
of bias factors and live birth data. Author replied 14th December 2015 regarding dropouts, miscarriage,
adverse effects and live birth. Trial not yet published as a full text
Risk of bias
Random sequence genera- Low risk "Fifty two patients were computer randomized"

(selection bias)
Blinding (performance Low risk "Double blind" (placebo control)

All outcomes
Incomplete outcome data Low risk "no dropouts" email from author
(attrition bias)
All outcomes

porting bias)

Rashidi 2009
Methods Randomised clinical trial
Participants Infertile women with PCOS (n = 60). Mean age Treatment group: 24.95 ± 3.56, Control groups 25.8 ± 4.61
and 26.9 ± 4.44 respectively

Informed decisions.

Rashidi 2009 (Continued)
Inclusion criteria: oligomenorrhoea/amenorrhoea, hyperandrogenism, polycystic ovaries on transvagi-
nal ultrasound.
Exclusion criteria: women with systemic disease, coexisting male factor infertility or abnormal hys-
terosalpingography. Natural conception
Interventions 1. Calcium 1000 mg + vitamin D 400 IU (n = 20) This arm is not used in the analysis.
2. Calcium 1000 mg + vitamin D 400 IU + metformin 1500 mg: 1 tablet of each a day (n = 20)
3. Metformin 1500 mg: 1 tablet a day (n = 20)
Trial lasted 3 months with a 3-month follow-up.
Outcomes Follicular response
Frequency of menstrual cycle
Chemical pregnancy
Clinical pregnancy
No pregnancy occurred in any of the groups
Notes Trial held in Iran, study ran from February 2004 (unknown end date)
Tried to contact authors regarding allocation concealment and blinding 13th February 2013. No reply
Risk of bias
Random sequence genera- Low risk Participants were divided into 3 groups with the use of a random number table

(selection bias)
Blinding (performance Unclear risk No mention of blinding

All outcomes
Incomplete outcome data Low risk No dropouts from the trial

(attrition bias)
All outcomes
Selective reporting (re- Unclear risk Reported only chemical pregnancy

porting bias)

Razavi 2015
Methods Randomised double-blind placebo-controlled trial
Participants Infertile women with PCOS 18 - 40 years old (n = 64)

Informed decisions.

Razavi 2015 (Continued)
Mean age: 25.1 ± 4.5 vs 25.4 ± 4.9 years, P = 0.85
Inclusion criteria: age between 18 and 40 years with PCOS according to Rotterdam criteria
Exclusion criteria: elevated levels of prolactin, thyroid disorder, or Type 2 diabetes and congenital
adrenal hyperplasia. In addition, all PCOS women had normal baseline renal function tests, bilirubin,
and aminotransferases
Interventions 1. Selenium 200 ug: 1 tablet a day + metformin 500 mg: which was elevated in a stepwise manner dur-
ing the first 3 weeks to incorporate the side effects until the participants were taking a total of 1500 mg
a day (n = 32)
2. Placebo plus metformin: same dosage as above (n = 32)
Treatment was for 8 weeks
The trial ran from October 2014 to December 2014
Outcomes Pregnancy rates (biochemical)
Hormone levels
Notes Conducted in Iran
Trial was supported by an institutional grant.
Clinical trial number: IRCT201412295623N33
Contact details: Dr Z Asemi; asemi_r@yahoo.com. Email sent 18th October 2016 regarding clinical
pregnancy data and block size. No reply
Risk of bias
Random sequence genera- Low risk "patients with PCOS were randomly divided into 2 groups" "Patient allocation
tion (selection bias) and block size were obtained using random number tables".
Allocation concealment Low risk "At the time of randomization,sequentially numbered, sealed envelopes were
(selection bias) opened. Allocation to study group was concealed until the main analyses were
completed".
Blinding (performance Low risk Supplements and placebos were in the same form of package and the partic-
bias and detection bias) ipants and researcher were not conscious of the content of the pack until the
All outcomes end of trial
Incomplete outcome data Low risk Reasons and numbers for dropouts from each group were provided. ITT used
(attrition bias) in the analysis
All outcomes
Selective reporting (re- Low risk None noted

porting bias)

Rizk 2005
Methods Placebo-controlled, double-blind, randomised trial

Informed decisions.

Rizk 2005 (Continued)
Participants Women diagnosed with clomiphene citrate-resistant PCOS (n = 150) aged 18 - 39 years, undergoing
therapy for infertility. Timed intercourse. Mean age Treatment group: 28.9 ± 4.7, Placebo group 28.4 ±
5.7.
Inclusion criteria: clomiphene citrate-resistant, at least 1 patent tube, adequate semen analysis accord-
ing to WHO guidelines, no hormonal treatment
Exclusion criteria: hormonal treatment within 2 months of the study, no participants had taken med-
ication to affect carbohydrate metabolism, hyperprolactinaemia, hypercorticism or thyroid dysfunc-
tion
Interventions 1. NAC 1.2 g: 1 tablet a day + clomiphene citrate 100 mg: 1 tablet a day for 5 days, starting at day 3 of the
cycle for 1 cycle (n = 75)
2. Placebo + clomiphene citrate 100 mg: 1 tablet a day (n = 75)
Outcomes Ovulation rate
Ongoing pregnancy rate, however only pregnancy rate reported
Number of follicles of 18 mm
Hormone levels
Ovarian hyperstimulation syndrome (OHSS)
Multiple gestations
Notes Single-centre university-based hospital and private infertility practice in Eygpt
Trial conducted from March 2002 to November 2003.
Informed consent.
No mention of funding source
Data for miscarriage and multiple pregnancy not in meta-analysis, as they appear to skew data because
of the fact that there were no pregnancies or live birth events in the control group, so no miscarriages.
The intervention appears worse in terms of miscarriage when it is simply due to the intervention group
having pregnancy and live birth. Emailed author 7th September 2012 regarding the pregnancy rate in
the control group and asking for live birth data. Author replied on 10.09.12, confirming that there were
no pregnancies in the control group and no live birth data
Endometrial thickness; significant difference in favour of the treatment group vs control; see confer-
ence abstract
Risk of bias
Random sequence genera- Unclear risk "Patients were randomly assigned to receive CC and either NAC or placebo".
tion (selection bias) Method not described
Allocation concealment Low risk "Allocation was done by a third party (nurse)". "Using sealed envelopes".
(selection bias)
Blinding (performance Low risk "The NAC and placebo were supplied in identical sachets. The patients and the
bias and detection bias) physician monitoring the cycles were blinded to the identity of each medica-
All outcomes tion".

Informed decisions.

Rizk 2005 (Continued)
Incomplete outcome data Low risk No dropouts were reported
(attrition bias)
All outcomes

porting bias)

Rizzo 2010
Methods Prospective, randomised clinical trial
Participants Women with low oocyte quality detected in previous IVF cycles (n = 65). Aged 35 - 42 years. Mean age
Treatment group 37.81 ± 2.61, Placebo 38.09 ± 1.97
IVF
Interventions 1. Myo-inositol 2 g + folic acid 200 mg + melatonin 3 mg: each tablet twice a day (n = 32)
2. Myo-inositol 2 g + folic acid 200 mg: each tablet twice a day (n = 33)
Administered continuously from the day of GnRH administration
Outcomes Embryo quality
Pregnancy rate, biochemical and clinical
Total number of oocytes retrieved (immature and mature oocytes)
Fertilisation rate per number of retrieved oocytes and embryo cleavage rate
Spontaneous abortion defined as a pregnancy loss from 5 - 12 weeks pregnancy
Notes Setting: Messina, Italy, study dates not reported
All participants gave written informed consent for the procedure, and the study was approved by the
local ethics committee.
Source of funding unclear.
Risk of bias
Random sequence genera- Low risk Randomised: "According to a randomisation table, patients were assigned to
tion (selection bias) receive either 2 g..."

(selection bias)

All outcomes
Incomplete outcome data Low risk No losses to follow-up

(attrition bias)

Informed decisions.

Rizzo 2010 (Continued)
All outcomes
Selective reporting (re- Low risk Data given for all outcomes reported in the text
porting bias)

Rosalbino 2012
Methods Randomised controlled study
Participants Women aged < 40 years with PCOS undergoing ICSI (n = 54). Mean age Group 1: 36.8; Group 2: 36.9;
Group 3 36.7; Group 4: 37.0; Placebo: 36.9
Exclusion criteria: Women with insulin resistance and/or hyperglycaemia
Interventions 1. D-chiro-inositiol 300 mg: 1 tablet a day (n = 10)
2. D-chiro-inositol 600 mg: 1 tablet a day (n = 11)
5. Placebo (n = 11)
Treatment given 8 weeks before ICSI
Outcomes Number of oocytes retrieved
Total rFSH
17B-E2 levels on hCG administration
Stimulation days
Number of cycles cancelled
Risk of bias
Random sequence genera- Low risk "The randomization procedure was performed using a computer-based pro-
tion (selection bias) gram"
Allocation concealment Unclear risk Unknown allocation concealment

(selection bias)
Blinding (performance Unclear risk Not mentioned

All outcomes
Incomplete outcome data Low risk No attrition

(attrition bias)

Informed decisions.

Rosalbino 2012 (Continued)
All outcomes

porting bias)

Salehpour 2009
Methods Randomised, controlled, double-blind trial
Participants Women with PCOS attending IVF clinic (n = 46); Mean age Treatment group: 27; Control group 28
Exclusion criteria: infertility factors apart from anovulation, other pathologies, hormone consumption
for less than 2 months before enrolment.
Interventions 1. NAC 200 mg: 1 tablet 3 times a day (n = 23)
2. Placebo (n = 23)
7 women lost to follow-up. Reasons described were intolerance to the smell of medications and blood
samples inappropriate for the study
Treatment 6 weeks' duration
Follow-up 6 weeks
Outcomes Ovulation
Weight
Endocrine
Metabolic and hormonal factors
Notes Trial carried out in Teheran, Iran, from February 2007 and February 2008
Informed consent.
Power calculation.
Ethics approved.
Funding source stated, "research is supported by Shahid Beheshti Medical University"
Risk of bias
Random sequence genera- Unclear risk "In order to minimise the effects of confounding factors through a randomised
tion (selection bias) method". Method not stated

(selection bias)
Blinding (performance Low risk "Medication was provided to patients by a midwife. Both patient and physician
bias and detection bias) were blinded to the type of treatment regimen".
All outcomes

Informed decisions.

Salehpour 2009 (Continued)
Incomplete outcome data Unclear risk 14 dropouts; 7 from each arm, reasons generally described but not for each
(attrition bias) woman
All outcomes
Selective reporting (re- Low risk All outcomes described in the text were reported
porting bias)

Salehpour 2012
Methods Randomised placebo-controlled double-blind trial
Participants Infertile women with PCOS undergoing timed intercourse (n = 180)
Women were aged 20 – 35 years
Inclusion criteria: infertility duration < 10 years, BMI < 35 kg/m2, both participant tubes confirmed by
hysterosalpingography or laparoscopy and with partner’s normal semen analysis results
(total volume > 2 cc, concentration > 20 million/ml, total motility > 50%, normal morphology > 14%)
Exclusion criteria: thyroid dysfunction, hyperprolactinaemia, hypercorticism, history of large ovarian

cyst formation (> 6 cm), history of visual disturbance caused by clomiphene citrate and finally histo-
ry of asthma and or allergy to medications. Women who had received any hormonal medications (ex-
cept progesterone for withdrawal bleeding) or medications affecting glucose metabolism for at least 3
months before the study were also excluded; also no sexual dysfunction
Interventions 1. NAC 1.2 g: 1 sachet a day (divided into 2 doses per day) + clomiphene citrate 100 mg: 1 tablet a day (n
= 90)
2. Placebo + clomiphene citrate 100 mg/day divided and given in 2 doses a day given for 5 days starting
at day 3 of the cycle. Timed intercourse occurred after an hCG trigger (n = 90)
8 women in the 1st group and 4 in the 2nd group left the study due to inappropriate drug intake or dis-
continued cycle; also 1 woman dropped out of the placebo group due to developing an ovarian cyst
Outcomes Number of follicles > 18 mm
Ovulation rates
Pregnancy rates
Adverse effects including multiple pregnancy
Ovarian hyperstimulation syndrome
Notes Trial carried out in the Shahid Beheshti University of Medical Sciences IVF Center, Taleghani Hospital,
Iran between January 2008 and December 2009
Informed consent
Power calculation
Ethics approved

Informed decisions.

Salehpour 2012 (Continued)
Reprint request to: Dr Azadeh Akbari Sene, IVF Center, Infertility and Reproductive Health Research
Center, Taleghani Hospital, Velenjak st, Tehran, Iran. Email: doctor_asturias@yahoo.com. RM-P sent an
email 12th December 2015. No reply
Risk of bias
Random sequence genera- Unclear risk "Then patients were randomly divided into two groups".

(selection bias)
Blinding (performance Low risk Double-blind. In the 2nd group in addition to 100 mg daily CC, participants re-
bias and detection bias) ceived a placebo (oral rehydration solution powder) from day 3 until day 7.
All outcomes ORS powder was given to the participants in the same packets as NAC
Incomplete outcome data Low risk Dropouts were explained

(attrition bias)
All outcomes
Selective reporting (re- Low risk All outcomes described in the text were reported
porting bias)

Schachter 2007
Methods Randomised trial
Participants Infertile women diagnosed with insulin-resistant PCOS (n = 102)
18 women were scheduled for ovulation induction and 84 for IVF/ICSI
Mean age: 28.8 ± 0.4 years
Interventions 1. Folic acid 0.4 mg a day (n = 23)
2. Metformin 1700 mg a day (2 divided doses of 850 mg tablets) + folic acid 0.4 mg: 1 tablet a day (n = 28)
3. Vitamin B complex (50 mg B6, 400 ug folic acid, 500 ug B12, 1 g trimethylglycine and 6 mg pyridox-
al-5-phosphate): 1 tablet a day (n = 24)
4. Metformin 1700 mg a day (2 divided doses of 850 mg tablets) + vitamin B complex: 1 tablet a day (n =
27)
Women were recruited over 14 months and outcomes were measured over 3 cycles
All groups were given folic acid
Outcomes Homocysteine levels
Cumulative clinical pregnancy rate over 3 cycles
Ongoing pregnancy rate
Notes Israel Tel Aviv, study dates not reported

Informed decisions.

Schachter 2007 (Continued)
Dr Morey Schachter ivfdoc@asaf.health.gov.il. Email sent 8th December 2015, no reply
Laboratory costs were partially funded by a company producing vitamins and supplements
Risk of bias
Random sequence genera- Low risk "These 102 patients were randomized before treatment, and after giving in-
tion (selection bias) formed consent, assigned to one of four groups by opening sealed envelopes
containing computer generated random assignation numbers"
Allocation concealment Low risk Sealed envelopes containing computer-generated random assignation num-
(selection bias) bers"
Blinding (performance Unclear risk Unknown

All outcomes
Incomplete outcome data Low risk No attrition

(attrition bias)
All outcomes

porting bias)

Unfer 2011
Methods Prospective randomised trial
Participants Euglycemic (normal levels of serum glucose) women with PCOS undergoing ovulation induction for
ICSI (n = 84). Mean age Treatment group: 35.5 ± 3.2; D-chiro-inositol group: 36.5 ± 2.5
Inclusion criteria: women who have attended IVF department for > 12 months, younger than 40 years,
diagnosed with PCOS according to the Rotterdam criteria
Exclusion criteria: women with hyperglycaemia or insulin resistance, or both
Interventions 1. Myo-inositol 2 g: 1 tablet twice a day (n = 43)
2. D-chiro-inositol (member of vitamin B family) 0.6 g: 1 tablet twice a day (n = 41)
Twice a day for 8 weeks
Outcomes Total number of oocytes
Number of mature oocytes
Embryo quality
Pregnancy, divided into biochemical and clinical pregnancies
Miscarriage
Notes Trial held in Messina, Italy, study dates not reported
Funding source not mentioned.

Informed decisions.

Unfer 2011 (Continued)
Emailed and posted letter to Dr Unfer 28th November 2011, requesting information on risk of bias. A
colleague of the author, Gianfranco Carlomagno (gianfranco.carlomagno@agunco.it), replied 5th De-
cember 2011 with risk of bias information and offering to find data on live birth. Emailed back asking
for live birth data 12th December 2011. Emailed again 10th August 2012 asking about live birth data.
Author replied 16th August 2012. Live birth data added to the analysis
Risk of bias
Random sequence genera- Low risk "Patients were randomly assigned to receive..." In email correspondence, au-
tion (selection bias) thor replied "The randomisation was computer based".
Allocation concealment Unclear risk In email correspondence, author replied, "the treatments were provided in
(selection bias) opaque envelopes identified by A or B".
Blinding (performance Unclear risk In email correspondence, author replied, "both patients and clinicians were
bias and detection bias) blinded". However not placebo-controlled
All outcomes
Incomplete outcome data Low risk All losses were accounted for: 4 women in the control group had cancelled cy-
(attrition bias) cles and nil in the treatment group
All outcomes
Selective reporting (re- Low risk Key outcomes reported, including live birth. Protocol available
porting bias)

Valeri 2015
Methods Double-blind randomised controlled trial
Participants Infertile women aged > 40 years undergoing IVF (n = 358)
Interventions 1. Melatonin 5 mg: 1 tablet a day (n = 178)
Trial ran from July 2009 to December 2013
Outcomes Oocyte maturity
Oxidative stress
Antioxidative capacity
Progesterone concentration in follicular fluid
Embryo grade
Notes Conducted in Italy, trial ran from July 2009 to Decenber 2013
Trial funded by pharmaceutical company
Trial registration no: NCT01540747

Informed decisions.

Valeri 2015 (Continued)
Email sent to Dr Pacchiarotti regarding the methods of this trial. Dr Pacchiarotti replied 20th March
2017 giving some methods information
Risk of bias
Random sequence genera- Low risk Computer-generated


(selection bias)
Blinding (performance Unclear risk Double-blind but control is no treatment

All outcomes

(attrition bias)
All outcomes

porting bias)

Westphal 2006
Methods Randomised, double-blind, placebo-controlled trial
Participants Infertile women (n = 93). Mean age Treatment group: 35.4; Placebo group 34.8
Inclusion criteria: women aged 24 - 42 years, unsuccessfully trying to conceive for 6 to 36 months
Exclusion criteria: any woman taking any pharmacological treatment for infertility for 2 months before
start of the trial.
Interventions 1. Fertility blend: capsules containing chaste berry, green tea amino acid, L-arginine, vitamins E, B6 and
B12 and folate, iron, magnesium, zinc and selenium. 3 capsules a day for 3 menstrual cycles (n = 53)
2. Placebo (n = 40)
Duration of treatment: 3 menstrual cycles, then women received an additional 3 months of open-label
fertility blend after completion of the study, with monitoring only of pregnancy and side effects
Duration of trial: 4 months
Outcomes Basal body temperature changes
Length of menstrual cycle
Pregnancy rates
Side effects
Mid-luteal phase progesterone levels
Miscarriage

Informed decisions.

Westphal 2006 (Continued)
Notes No power calculation performed
Institutional review board approval was obtained for the trial
Conducted in the USA, study dates not reported
Funding stated: David Sen Lin Foundation
No loss to follow-up.
14 pregnant in treatment group in first 3 months, then 17 in 6 months, but the second 3 months was
unblinded; therefore, only first 3 months' data used. Not all women in the trial received the extra 3
months of treatment or placebo
Miscarriage and side effect data cannot be used as they include data from the later 3 months when not
all women received treatment or placebo in this phase.
Tried to contact author 25th November 2009 with email, mail and fax, with no reply. Tried to contact
author again regarding live birth, no reply
Risk of bias
Random sequence genera- Unclear risk Described as randomised; mechanism not stated. "Fertilty Blend5 (FB), admin-
tion (selection bias) istered in a randomised, double-blind, placebo-controlled fashion".
Allocation concealment Unclear risk Mechanism not stated. Authors contacted May 2010 regarding this
(selection bias)
Blinding (performance Low risk Stated as being double-blinded, no clear explanation. Authors contacted re-
bias and detection bias) garding this. Placebo control
All outcomes

(attrition bias)
All outcomes
Selective reporting (re- High risk Data on miscarriage and side effects cannot be used in analysis, as these da-
porting bias) ta were combined with the extra open-label 3-month data. Not all women re-
ceived treatment or placebo in this phase

Youssef 2015
Participants Infertile couples with unexplained infertility seeking ICSI/IVF treatment following at least 3 failed previ-
ous IUI cycles (n = 218). Mean age Treatment group: 30.9 years; Control group: 30.6
Inclusion criteria: women aged < 40 years with normal ovulatory cycles, normal baseline; FSH 12 IU/l,
thyroid-stimulating hormone, prolactin levels, tubal patency at hysterosalpingography, normal trans-
vaginal ultrasound scan, presence of both ovaries and normal findings at laparoscopy. All male part-
ners had a normal semen analysis by WHO criteria
Exclusion criteria: Couples who had received any form of vitamin supplementation for a period of 3
months before start of treatment

Informed decisions.

Youssef 2015 (Continued)
Interventions Women in both groups received a daily dose of 2.5 mg of folic acid.
1. OCTATRON ® NERHADOU INTERNATIONAL (composition; vitamin A 3000 IU; d-alpha tocopheryl

acid; (vitamin E) 15 IU; ascorbic acid (vitamin C) 90 mg; Zinc (amino acid-chelated) 11 mg; molyb-
denum (amino acid chelated) 45 μg; selenium (amino acid chelated) 55 μg, biotin 10 μg and mixed
bioflavonoid 100 mg): 1 capsule a day (n= 112)
2. Folic acid 2.5 mg: 1 tablet a day (n = 106)
Treatment was for 2½ months
7 women lost from each arm with explanation
Outcomes The primary outcome was the number of mature oocytes
Secondary outcomes were clinical pregnancy rate, defined as appearance of intrauterine gestational
sac with fetal heart pulsation at 7 weeks
Fertilisation rate
Number of embryos transferred and cryopreserved
Multiple pregnancy rate

Early miscarriage rate
Duration of stimulation
Amount of FSH
Notes Cairo Egypt
Trial ran from February 2011 to March 2013
"On pregnancy confirmation, both groups received antioxidant and folic acid supplementation during
the first trimester with follow-up in accordance with this canter ’s policy. Participants ’ compliance with
treatment, that is, the intake of supplements was confirmed and recorded on each visit by the caring
physicians".
This paper is the published version of Aboulfoutouh 2011 in first version of the review
Email and letter sent to authors 9th August 2012asking about types of antioxidants used and ITT in the
pregnancy outcome. Authors replied with data information. Participants were followed up only to clini-
cal pregnancy, so no live birth data are provided
Risk of bias
Random sequence genera- Low risk "We developed computer generated list for randomization" from an email re-
tion (selection bias) ceived 12th December 2015
Allocation concealment Low risk "used closed opaque envelops for concealment by third party nurse" from an
(selection bias) email received 12th December 2015
Blinding (performance High risk No blinding, control is no treatment

All outcomes
Incomplete outcome data Low risk Attrition explained

(attrition bias)
All outcomes

Informed decisions.

Youssef 2015 (Continued)
Selective reporting (re- Low risk Outcomes reported. Protocol available
porting bias)
17B-E2: 17B estradiol

ASRM: American Society for Reproductive Medicine
BMI: body mass index
CC: clomiphene citrate
ESHRE: European Society for Human Reproduction and Embryology
FSH: follicle stimulating hormone
GnRH: gonadotropin releasing hormone
hCG: human chorionic gonadotropin
HSG: hysterosalpingography
ICSI: intracytoplasmic sperm injection
ITT: intention-to-treat
IVF: in vitro fertilisation
MDA: malondialdehyde
NAC: N-acetylcysteine
OC: oral contraceptive
OHSS: ovarian hyperstimulation syndrome
PCOS: poly cystic ovarian syndrome
rFSH: recombinant follicle stimulating hormone
SD: standard deviation
WHO: World Health Organization

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion
Aflatoonian 2014 Population were vitamin D-deficient
Aksoy 2010 Not a randomised study
Al-Omari 2003 Non-randomised trial. "Forty-two infertile PCOS were divided into three groups".
Ardabili 2012 This trial included women with PCOS, but they were not intending to become pregnant. Therefore,
the population is inappropriate for inclusion in this review.
Asadi 2014 Vitamin D not given orally but by injection into the muscle
Baillargeon 2004 This trial included women with PCOS, but they were not intending to become pregnant. Therefore,
the population is inappropriate for inclusion in this review
Benelli 2016 This trial included women with PCOS, but they were not intending to become pregnant. Therefore,
Bonakdaran 2012 This trial included women with PCOS, but they were not intending to become pregnant. Therefore,
Cheang 2008 This trial included women with PCOS, but they were not intending to become pregnant. Therefore,
Ciotta 2012 This trial included women with PCOS, but they were not intending to become pregnant. Therefore,

Informed decisions.

Costantino 2009 This trial included women with PCOS, but they were not intending to become pregnant. Therefore,
Crha 2003 Not an RCT. "patients for the supplemented and control sets were selected by the case-control
method according to their age and smoking or non-smoking habits."
Elgindy 2010 Participants were fertile women with infertile male partners.
Elnashar 2007 Interventions N-acetyl-cysteine versus metformin
Farzadi 2006 The intervention versus control used in this trial was metformin versus placebo
Firouzabadi 2012 83% of the women enrolled were vitamin D-deficient
Genazzani 2008 This trial included women with PCOS, but they were not intending to become pregnant. Therefore,
Hashim 2010 Interventions N-acetyl-cysteine plus clomiphene citrate versus metformin plus clomiphene citrate
Hebisha 2016 Enrolled women who attended infertility clinic due to male factor issues
Henmi 2003 Described as randomised, but authors confirmed the process of allocation as "alternative treat-
ments". Additionally, 28/46 in the placebo arm withdrew because of travel difficulties and move-
ment out of the study area. No withdrawals from the treatment arm were reported. There was no
Intention-to-treat.
Hernández-Yero 2012 This trial included women with PCOS, but they were not intending to become pregnant. Therefore,
the population is not suitable for inclusion in this review
Immediata 2014 Wrong comparison; Inositol vs metformin
Iuorno 2002 This trial included women with PCOS, but they were not intending to become pregnant. Therefore,
Jamilian 2016 This trial included women with PCOS, but they were not intending to become pregnant. Therefore,
the population is not suitable for inclusion in this review.
Jamilian 2016a This trial included women with PCOS, but they were not intending to become pregnant. Therefore,
Kamencic 2008 This trial included women with endometriosis, but they were not intending to become pregnant.
Therefore, the population is not suitable for inclusion in this review
Kilicdag 2005 This trial included women with PCOS, but they were not intending to become pregnant. Therefore,
Le Donne 2012 This trial included women with PCOS, but they were not intending to become pregnant. Therefore,
Li 2013 This trial included women with PCOS, but they were not intending to become pregnant. Therefore,
Moosavifar 2010 Participants were not subfertile women; they were partners of subfertile men
Nazzaro 2011 Not randomised. Attempted to contact authors regarding sequence allocation via email 10 Novem-
ber 2011

Informed decisions.

Nestler 1999 This trial included women with PCOS, but they were not intending to become pregnant. Therefore,
Nestler 2001 This trial included women with PCOS, but they were not intending to become pregnant. Therefore,
Nichols 2010 Lead investigator confirmed (May 2010). Stated that the trial was abandoned before recruitment
because of lack of funding
Nordio 2012 This trial included women with PCOS, but they were not intending to become pregnant. Therefore,
Oner 2011 This trial included women with PCOS, but they were not intending to become pregnant. Therefore,
Pal 2016 A secondary analysis of an RCT measuring ovulation induction (OI) outcomes in women with poly-
cystic ovary syndrome (PCOS).
Papaleo 2007 Not a randomised controlled trial
Papaleo 2008 Interventions myo-inositol plus folic acid versus clomiphene citrate
Pasha 2011 Inappropriate population
Pizzo 2014 This trial included women with PCOS, but they were not intending to become pregnant. Therefore,
Raffone 2010 Interventions myo-inositol plus folic acid versus metformin
Ruder 2014 A secondary analysis of an RCT on the cost-effectiveness of fast track to IVF
Salem 2012 Different doses of clomiphene in each arm, i.e. L-carnitine 3 gm plus clomiphene 100 mg (n = 85)
versus clomiphene 150 mg (n = 85)
Santanam 2003 The population included here were women with endometriosis, and the trial aimed to show differ-
ences in inflammatory markers. These women were not attending a fertility clinic
Taheri 2015 Population is Vitamin D-deficient
Tamura 2008 A quasi-randomised trial. "Patients were divided into two groups". Email sent asking about ran-
domisation but undeliverable. Letter sent to University of Texas 12 January 2012. Letter returned to
sender 17 February 2012.
Twigt 2011 Participants were randomly assigned to different stimulation protocols and not to folic acid. All
participants took folic acid
Vargas 2011 This trial included women with PCOS, but they were not intending to become pregnant. Therefore,
Yoon 2010 This trial included women with PCOS, but they were not intending to become pregnant. Therefore,
PCOS: poly cystic ovarian syndrome

RCT: random controlled trial


Informed decisions.

Characteristics of ongoing studies [ordered by study ID]

CTRI/2012/08/002943
Trial name or title Nutritional supplement for women With polycystic ovary syndrome or subfertilty
Methods Randomised, parallel-group, placebo-controlled trial

Method of generating randomisation sequence: computer-generated randomisation
Method of allocation concealment: pre-numbered or coded identical
Containers blinding and masking: participant- and investigator-blinded
Participants Inclusion criteria: Women between 18 and 38 years of age with PCOS
Presence of any 2 of the following parameters: (Roterdam criteria 2003)
• Oligomenorrhoea and/or anovulation;

• Hyperandrogenism (clinical and/or biochemical) (Ferriman-Gallwey score > 8); biological (lutein-
ising hormone (LH)/FSH ratio > 2).
OR
• Subfertile women;
• Sexually active and male partner with potential to produce a child;
• Polycystic ovaries with exclusion of other aetiologies;
• Women with normal uterine cavity;
• Participants with impaired glucose tolerance or insulin resistance;
• Normal physical activity confirmed by physical and clinical examination, and routine laboratory
tests, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), haematology,
routine urinalysis and measurement of oral temperature and vital signs.
Interventions Intervention 1: multiple micronutrients supplementation: 1 Formula A tablet + 1 Formula B tablet

together after main meal twice a day for 4 months
Ingredients Formula A: N-acetyl L-cysteine, elemental magnesium, zinc, iron, manganese, copper,
selenium, iodine, chromium.
Ingredients Formula B: inositol, vitamin C, para-amino-benzoic acid, vitamin E acetate, L-arginine,
D-chiro-inositol, vitamin B complex
Control intervention 1: placebo tablets for Formula A: 1 tablet after main meal twice a day for 4
months
Control intervention 2: placebo tablets for Formula B: 1 tablet after main meal twice a day for 4
months
Outcomes Improvement in overall status of PCOS or infertility.
• Timepoint: days 30, 60, 90 and 120.
Improvement in different parameters defining the status of PCOS or infertility-like hormonal levels,
insulin resistance, weight and safety of the therapy
• Timepoint: days 30, 60, 90 and 120
Starting date 31 August 2012
Contact information Dr Yashwant Mane
Dr Yashwant Mane Atharva Infertilty and Test Tube Baby
Center Jagir Complex Dwarka, Nasik, India
422011

Informed decisions.

CTRI/2012/08/002943 (Continued)
Nashik,
MAHARASHTRA
India
ph 02532598953
email drysmane7473@yahoo.co.in
Notes

Fernando 2014
Trial name or title A pilot double-blind randomised placebo-controlled dose–response trial assessing the effects of
melatonin on infertility treatment (MIART): study protocol
Methods Pilot phase II cross-over double-blinded randomised placebo-controlled dose–response trial
Each treatment arm will be randomly allocated a letter (A, B, C or D) by way of opaque sealed enve-
lope Randomisation will be computerised and participants will be randomised at a ratio of 1:1:1:1
to 1 of
the groups, A–D, using the minimisation method.
Participants We plan to recruit a total of 160 infertile women undergoing IVF/ICSI
INCLUSION CRITERIA;
1. Undergoing first cycle of IVF or ICSI;

2. Age between 18 and 45;
3. Body mass index between 18 and 35;
4. Undergoing a gonadotrophin releasing hormone (GnRH) antagonist cycle (without oral contra-
ceptive
pill (OCP) scheduling).
EXCLUSION CRITERIA
1. Current untreated pelvic pathology: moderate-to-severe endometriosis, submucosal uterine
fibroids/polyps assessed by the treating specialist to affect fertility, pelvic inflammatory disease
uterine malformations, Asherman’s syndrome and hydrosalpinx
2. Currently enrolled in another interventional clinical trial
3. Concurrent use of other adjuvant therapies (e.g. Chinese herbs, acupuncture)
4. Current pregnancy
5. Malignancy or other contraindication to IVF
6. Autoimmune disorders
7. Undergoing preimplantation genetic diagnosis
8. Hypersensitivity to melatonin or its metabolites
9. Concurrent use of any of the following medications:
A. Fluvoxamine (e.g. luvox, movox, voxam);
B. Cimetidine (e.g. magicul, tagamet);
C. Quinolones and other CYP1A2 inhibitors (ciprofloxacin, avalox);
D. Carbamazepine (e.g. tegretol), rifampicin (e.g. rifadin) and other CYP1A2 inducers;
E. Zolpidem (e.g. stilnox), zopiclone (e.g. imovane) and other non-benzodiazepine hypnotics.
10. Inability to comply with trial protocol
Interventions 1. Placebo capsule taken twice a day;

2. 2 mg melatonin capsule twice a day (4 mg/day total);
3. 4 mg melatonin capsule twice per day (8 mg/day total);
4. 8 mg melatonin capsule twice per day (16 mg/day total).

Informed decisions.

Fernando 2014 (Continued)
Outcomes Primary outcome: Clinical pregnancy rate, defined as the presence of a live pregnancy in the uter-
ine cavity at a transvaginal ultrasound at 6 – 8 weeks’ gestation
Secondary outcomes: Live birth, miscarriage, adverse events, melatonin serum levels
Starting date Recruitment will start in July 2014. This will occur over 2 years. Analysis and dissemination will oc-
cur after this period of time. The study is expected to be completed by February 2017.
Contact information Dr Shavi Fernando; shavif@hotmail.com
Notes Participants will be recruited from Monash IVF infertility clinics in Melbourne, Australia over a peri-
od of 2 years
Ethics and dissemination: Ethical approval has been obtained from Monash Health HREC (Re-
f:13402B), Monash University HREC (Ref: CF14/523-2014000181) and Monash Surgical Private Hos-
pital HREC (Ref: 14107). Data analysis, interpretation and conclusions will be presented at national
and international conferences and published in peer reviewed journals.
Trial registration number: ACTRN12613001317785

IRCT201112148408N1
Trial name or title Evaluation of the effects of Calcium- Vitamine D supplementary on ovulation and fertility outcomes
of patients with poly cystic ovary syndrome referring to Infertility Clinic of Imam Khomeini Hospital
in 2011 and 2012 for in vitro fertilization
Methods Randomisation: randomised. Blinding: double-blind. Placebo: used
Participants Abnormal menstrual cycles (oligomenorrhoea or amenorrhoea); sonographically-confirmed poly-

cystic ovary; hyperandrogenism
Interventions Intervention 1: In control group, participants do not receive routine administration of calcium-D
combinations
Intervention 2: In intervention group, supplementary tablets of 1000 mg calcium combined with

400 IU vitamin D are administered (orally) twice a day for 3 months
Outcomes Pregnancy. Timepoint: 2 and 12 weeks. Method of measurement: sonography and biochemistry
Starting date 21 January 2012
Contact information Azadeh Mahdian
Department of Obstetrics and Gynecology, Vali-e- Asr Hospital, Imam Khomeini Hospital Complex,
Keshavarz Blv
Tehran
Iran, Islamic Republic of
mahdian@razi.tums.ac.ir
Notes


Informed decisions.

NCT01019785
Trial name or title Vitamin D during In Vitro Fertilization (IVF) - a prospective randomised trial delivery
Methods Randomised double-blind trial
Participants Target sample size: 1000 women older than 18 years of age initiating IVF treatment in Sweden
Interventions Dietary supplementation: ergocalciferol (vitamin D), either high 100,000 U once or low-dose 500 U
once
Outcomes Biochemical pregnancy, live birth, take-home baby rate, OHSS and pregnancy complication rate
(pregnancy, hypertension, SGA, diabetes)
Starting date November 2009
Contact information Pelle G. Lindqvist
Karolinska University Hospital
Huddinge
ClinicalTrials.gov identifier NCT01019785.
Notes clinicaltrials.gov/ct2/show/NCT01019785?term=NCT01019785&rank=1

NCT01267604
Trial name or title Improving oocyte retrieval using a combined therapy of recombinant follicle-stimulating hormone
(rFSH) and inositol and melatonin
Methods Randomised double-blinded (participant, investigator) controlled trial.
Participants Women 18 - 39 years undergoing assisted reproductive techniques (ART) because of male infertility
BMI 18 - 30 kg/m2
Fewer than 3 prior oocyte retrievals
No fertility problems
Interventions Recombinant FSH: 225 IU rFSH
Drug: recombinant FSH (rFSH) 225 IU
Experimental: recombinant FSH inositol melatonin
225 IU rFSH, 4 g inositol and 3 mg melatonin dietary supplement: rFSH + inositol + melatonin
225 IU rFSH, 4 g inositol, 3 mg melatonin
Outcomes Primary: total number of oocytes, number of clinical pregnancies, live birth rate
Starting date December 2010
Contact information Vittorio Unfer, MD
+39 0640500835
vunfer@gmail.com

Informed decisions.

NCT01267604 (Continued)
Gianfranco Carlomagno, PhD
gianfranco.carlomagno@gmail.com
University of Modena and Reggio Emilia Recruiting
Reggio Emilia, Italy, 42100
Contact: Giovanni Battista La Sala, MD
+39 0522 296464
giovanni.lasala@asmn.re.it
Principal investigator: Giovanni Battista La Sala, MD
Research Center for Reproductive Medicine Villa Mafalda Recruiting
Roma, Italy, 00199
Notes May not become an included study because all women are fertile, but they have subfertile male
partners
ClinicalTrials.gov Identifier: NCT01267604.
Recruiting.
Trial found on clinicaltrials.gov on 7th August 2012

NCT01782911
Trial name or title Effect of resveratrol on metabolic parameters and oocyte quality in PCOS patients (RES-IVF)
Methods Randomised
Participants Women with PCOS
Interventions Resveratrol versus placebo
Outcomes Implantation
Pregnancy rates
Starting date February 2013
Contact information Israel Ortega, Medical doctor
91 180 2900
israel.ortega@ivi.es
Notes Not yet recruiting. Madrid

NCT02058212
Trial name or title Use of antioxidant in endometriotic women to improve intracytoplasmic sperm injection (ICSI)
(ROS)

Informed decisions.

NCT02058212 (Continued)
Official title: Does antioxidant supplementation to endometriotic women undergoing ICSI alter re-
active oxygen species (ROS) levels and affect pregnancy outcome
Methods Randomised, parallel-assignment, single-blind (participant)
Participants Women with endometriosis undergoing IVF, 20 - 40 years
Interventions Drug: ascorbate 1000 mg, vitamin E 400, zinc and selenium
Outcomes Pregnancy
Starting date March 2013
Contact information Olfat Nouh Riad, Assisstant Professor, Cairo University
Egyption centre for IVF
Maadi, Egypt, 11451
Notes ClinicalTrials.gov Identifier: NCT02058212

NCT03023514
Trial name or title Lipoic acid supplementation in IVF
Methods Allocation: randomised
Participants Women infertility - 30 to 50 years
Interventions Dietary supplement: oral lipoic acid|drug: vaginal progesterone
Outcomes Number of implants per cycle
Number of biochemical pregnancies per group
Number of clinical pregnancies per group
Number of live birth per group
Number of miscarriage per group
Starting date 2015
Contact information Lo.Li.Pharma s.r.l
Notes ClinicalTrials.gov/show/NCT03023514

DATA AND ANALYSES


Informed decisions.

Comparison 1. Antioxidant(s) versus placebo or no treatment/standard treatment
Outcome or subgroup title No. of No. of Statistical method Effect size

studies partici-
pants
1 Live birth; antioxidants vs placebo or no 8 651 Odds Ratio (M-H, Fixed, 95% 2.13 [1.45, 3.12]
treatment/standard treatment (natural CI)
conceptions and undergoing fertility treat-
ments)
1.1 Placebo 5 388 Odds Ratio (M-H, Fixed, 95% 2.01 [1.17, 3.44]
CI)
1.2 No treatment 3 263 Odds Ratio (M-H, Fixed, 95% 2.26 [1.31, 3.91]
CI)
2 Live birth; type of antioxidant 8 Odds Ratio (M-H, Fixed, 95% Subtotals only
CI)
2.1 N-acetyl-cysteine 1 60 Odds Ratio (M-H, Fixed, 95% 3.0 [1.05, 8.60]
CI)
2.2 L-arginine 1 37 Odds Ratio (M-H, Fixed, 95% 0.43 [0.09, 2.09]
CI)
2.3 CoQ10 1 39 Odds Ratio (M-H, Fixed, 95% 0.82 [0.19, 3.54]
CI)
2.4 Vitamin D 1 52 Odds Ratio (M-H, Fixed, 95% 0.79 [0.21, 3.02]
CI)
2.5 Vitamin B complex 1 102 Odds Ratio (M-H, Fixed, 95% 2.07 [0.93, 4.57]
CI)
2.6 Combined antioxidants 2 258 Odds Ratio (M-H, Fixed, 95% 6.76 [2.79, 16.41]
CI)
2.7 Vitamin E 1 103 Odds Ratio (M-H, Fixed, 95% 1.43 [0.50, 4.10]
CI)
3 Live birth; indications for subfertility 6 Odds Ratio (M-H, Fixed, 95% Subtotals only
CI)
3.1 Polycystic ovary syndrome 3 362 Odds Ratio (M-H, Fixed, 95% 3.34 [1.90, 5.86]
CI)
3.2 Tubal subfertility 1 37 Odds Ratio (M-H, Fixed, 95% 0.43 [0.09, 2.09]
CI)
3.3 Varying indications 1 58 Odds Ratio (M-H, Fixed, 95% 4.5 [1.46, 13.86]
CI)
3.4 Unexplained subfertility 1 103 Odds Ratio (M-H, Fixed, 95% 1.43 [0.50, 4.10]
CI)
4 Live birth; IVF/ICSI 4 230 Odds Ratio (M-H, Fixed, 95% 1.21 [0.69, 2.11]
CI)

Informed decisions.


studies partici-
pants
5 Clinical pregnancy; antioxidants vs place- 26 4271 Odds Ratio (M-H, Fixed, 95% 1.52 [1.31, 1.76]
bo or no treatment/standard treatment CI)
(natural conceptions and undergoing fertil-
ity treatments)
5.1 Placebo 12 2444 Odds Ratio (M-H, Fixed, 95% 1.47 [1.20, 1.82]
CI)
5.2 No treatment/standard treatment 15 1827 Odds Ratio (M-H, Fixed, 95% 1.57 [1.27, 1.93]
CI)
6 Clinical pregnancy; type of antioxidant 26 Odds Ratio (M-H, Fixed, 95% Subtotals only
CI)
6.1 N-acetyl-cysteine 6 1354 Odds Ratio (M-H, Fixed, 95% 1.22 [0.92, 1.63]
CI)
6.2 Combined antioxidants 4 569 Odds Ratio (M-H, Fixed, 95% 2.28 [1.51, 3.43]
CI)
6.3 Melatonin 4 568 Odds Ratio (M-H, Fixed, 95% 1.29 [0.91, 1.83]
CI)
6.4 Vitamin E 1 103 Odds Ratio (M-H, Fixed, 95% 1.43 [0.50, 4.10]
CI)
6.5 Ascorbic acid 1 619 Odds Ratio (M-H, Fixed, 95% 0.75 [0.50, 1.14]
CI)
6.6 L-arginine 2 71 Odds Ratio (M-H, Fixed, 95% 1.05 [0.32, 3.46]
CI)
6.7 Myo-inositol plus folic acid 4 694 Odds Ratio (M-H, Fixed, 95% 1.35 [0.98, 1.86]
CI)
6.8 CoQ10 2 149 Odds Ratio (M-H, Fixed, 95% 4.28 [1.79, 10.26]
CI)
6.9 L-carnitine 1 170 Odds Ratio (M-H, Fixed, 95% 82.05 [10.92, 616.59]
CI)
6.10 Vitamin D 1 52 Odds Ratio (M-H, Fixed, 95% 0.83 [0.25, 2.76]
CI)
6.11 Vitamin B complex 1 102 Odds Ratio (M-H, Fixed, 95% 1.94 [0.82, 4.58]
CI)
6.12 Myo-inositol plus melatonin plus folic 1 389 Odds Ratio (M-H, Fixed, 95% 1.38 [0.90, 2.12]
acid CI)
7 Clinical pregnancy; indications for sub- 22 Odds Ratio (M-H, Fixed, 95% Subtotals only
fertility CI)

Informed decisions.


studies partici-
pants
7.1 Polycystic ovary syndrome 11 1721 Odds Ratio (M-H, Fixed, 95% 2.63 [2.06, 3.36]
CI)
7.2 Unexplained 3 967 Odds Ratio (M-H, Fixed, 95% 0.82 [0.59, 1.14]
CI)
7.3 Tubal subfertility 2 71 Odds Ratio (M-H, Fixed, 95% 1.05 [0.32, 3.46]
CI)
7.4 Varying indications 5 1004 Odds Ratio (M-H, Fixed, 95% 1.27 [0.94, 1.71]
CI)
7.5 Poor responders 1 65 Odds Ratio (M-H, Fixed, 95% 1.88 [0.64, 5.47]
CI)
8 Clinical pregnancy; IVF/ICSI 15 2263 Odds Ratio (M-H, Fixed, 95% 1.19 [0.98, 1.43]
CI)
9 Adverse events 20 Odds Ratio (M-H, Fixed, 95% Subtotals only

CI)
9.1 Miscarriage 18 2834 Odds Ratio (M-H, Fixed, 95% 0.79 [0.58, 1.08]
CI)
9.2 Multiple pregnancy 8 2163 Odds Ratio (M-H, Fixed, 95% 1.00 [0.73, 1.38]
CI)
9.3 Gastrointestinal disturbances 3 343 Odds Ratio (M-H, Fixed, 95% 1.55 [0.47, 5.10]
CI)
9.4 Ectopic pregnancy 1 58 Odds Ratio (M-H, Fixed, 95% 2.90 [0.11, 74.13]
CI)
9.5 Headache 1 170 Odds Ratio (M-H, Fixed, 95% 2.02 [0.18, 22.75]
CI)

Analysis 1.1. Comparison 1 Antioxidant(s) versus placebo or no treatment/
standard treatment, Outcome 1 Live birth; antioxidants vs placebo or no treatment/
standard treatment (natural conceptions and undergoing fertility treatments).
Study or subgroup Antioxidant Placebo/No Odds Ratio Weight Odds Ratio
treatment
n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI
1.1.1 Placebo
Battaglia 2002 3/18 6/19 13.3% 0.43[0.09,2.09]
Bentov 2014 4/17 6/22 10.94% 0.82[0.19,3.54]
Nasr 2010 20/30 12/30 10.94% 3[1.05,8.6]
Panti Abubakar 2015 18/100 2/100 4.48% 10.76[2.42,47.73]
Polak de Fried 2013 5/26 6/26 13.25% 0.79[0.21,3.02]
Subtotal (95% CI) 191 197 52.92% 2.01[1.17,3.44]
Favours placebo/no treat 0.005 0.1 1 10 200 Favours antioxidant

Informed decisions.

Study or subgroup Antioxidant Placebo/No Odds Ratio Weight Odds Ratio

treatment
Total events: 50 (Antioxidant), 32 (Placebo/No treatment)
Heterogeneity: Tau2=0; Chi2=12.38, df=4(P=0.01); I2=67.7%
Test for overall effect: Z=2.55(P=0.01)

1.1.2 No treatment
Agrawal 2012 18/30 7/28 7.92% 4.5[1.46,13.86]
Cicek 2012 10/53 7/50 15.98% 1.43[0.5,4.1]
Schachter 2007 13/24 7/23 8.96% 2.7[0.82,8.94]
Schachter 2007 14/27 11/28 14.22% 1.66[0.57,4.85]
Subtotal (95% CI) 134 129 47.08% 2.26[1.31,3.91]
Heterogeneity: Tau2=0; Chi2=2.57, df=3(P=0.46); I2=0%
Test for overall effect: Z=2.92(P=0)

Total (95% CI) 325 326 100% 2.13[1.45,3.12]
Test for subgroup differences: Chi2=0.09, df=1 (P=0.76), I2=0%

Analysis 1.2. Comparison 1 Antioxidant(s) versus placebo or no
treatment/standard treatment, Outcome 2 Live birth; type of antioxidant.
Study or subgroup Antioxidant(s) Placebo/No Odds Ratio Weight Odds Ratio
treatment
1.2.1 N-acetyl-cysteine
Nasr 2010 20/30 12/30 100% 3[1.05,8.6]
Subtotal (95% CI) 30 30 100% 3[1.05,8.6]
Total events: 20 (Antioxidant(s)), 12 (Placebo/No treatment)
Heterogeneity: Not applicable

1.2.2 L-arginine
Battaglia 2002 3/18 6/19 100% 0.43[0.09,2.09]
Subtotal (95% CI) 18 19 100% 0.43[0.09,2.09]
Heterogeneity: Tau2=0; Chi2=0, df=0(P<0.0001); I2=100%

1.2.3 CoQ10
Bentov 2014 4/17 6/22 100% 0.82[0.19,3.54]
Subtotal (95% CI) 17 22 100% 0.82[0.19,3.54]

1.2.4 Vitamin D
Favours placebo/no treat 0.01 0.1 1 10 100 Favours antioxidant(s)

Informed decisions.


treatment
Polak de Fried 2013 5/26 6/26 100% 0.79[0.21,3.02]
Subtotal (95% CI) 26 26 100% 0.79[0.21,3.02]

1.2.5 Vitamin B complex
Schachter 2007 13/24 7/23 38.65% 2.7[0.82,8.94]
Schachter 2007 14/27 11/28 61.35% 1.66[0.57,4.85]
Subtotal (95% CI) 51 51 100% 2.07[0.93,4.57]

1.2.6 Combined antioxidants
Agrawal 2012 18/30 7/28 63.85% 4.5[1.46,13.86]
Panti Abubakar 2015 18/100 2/100 36.15% 10.76[2.42,47.73]
Subtotal (95% CI) 130 128 100% 6.76[2.79,16.41]
Test for overall effect: Z=4.23(P<0.0001)

1.2.7 Vitamin E
Cicek 2012 10/53 7/50 100% 1.43[0.5,4.1]
Subtotal (95% CI) 53 50 100% 1.43[0.5,4.1]

standard treatment, Outcome 3 Live birth; indications for subfertility.
treatment
1.3.1 Polycystic ovary syndrome
Nasr 2010 20/30 12/30 28.34% 3[1.05,8.6]
Panti Abubakar 2015 18/100 2/100 11.62% 10.76[2.42,47.73]
Schachter 2007 14/27 11/28 36.84% 1.66[0.57,4.85]
Schachter 2007 13/24 7/23 23.21% 2.7[0.82,8.94]
Subtotal (95% CI) 181 181 100% 3.34[1.9,5.86]

1.3.2 Tubal subfertility
Battaglia 2002 3/18 6/19 100% 0.43[0.09,2.09]
Subtotal (95% CI) 18 19 100% 0.43[0.09,2.09]

Informed decisions.


treatment
Heterogeneity: Tau2=0; Chi2=0, df=0(P<0.0001); I2=100%

Agrawal 2012 18/30 7/28 100% 4.5[1.46,13.86]
Subtotal (95% CI) 30 28 100% 4.5[1.46,13.86]

1.3.4 Unexplained subfertility
Cicek 2012 10/53 7/50 100% 1.43[0.5,4.1]
Subtotal (95% CI) 53 50 100% 1.43[0.5,4.1]

treatment/standard treatment, Outcome 4 Live birth; IVF/ICSI.
treatment
Battaglia 2002 3/18 6/19 21.93% 0.43[0.09,2.09]
Bentov 2014 4/17 6/22 18.03% 0.82[0.19,3.54]
Polak de Fried 2013 5/26 6/26 21.84% 0.79[0.21,3.02]
Schachter 2007 13/24 7/23 14.77% 2.7[0.82,8.94]
Schachter 2007 14/27 11/28 23.44% 1.66[0.57,4.85]

Total (95% CI) 112 118 100% 1.21[0.69,2.11]
Favours placebo/no treat 0.01 0.1 1 10 100 Favours antioxidants

Analysis 1.5. Comparison 1 Antioxidant(s) versus placebo or no treatment/standard
treatment, Outcome 5 Clinical pregnancy; antioxidants vs placebo or no treatment/
treatment
1.5.1 Placebo
Badawy 2006 63/404 79/400 22.8% 0.75[0.52,1.08]

Informed decisions.


treatment
Battaglia 2002 3/18 6/19 1.66% 0.43[0.09,2.09]
Bentov 2014 6/17 6/22 1.15% 1.45[0.37,5.71]
Cheraghi 2016 3/20 2/20 0.58% 1.59[0.24,10.7]
Griesinger 2002 104/461 44/158 17.27% 0.75[0.5,1.14]
Ismail 2014 42/85 1/85 0.17% 82.05[10.92,616.59]
Nasr 2010 21/30 13/30 1.33% 3.05[1.05,8.84]
Panti Abubakar 2015 22/100 2/100 0.53% 13.82[3.15,60.58]
Polak de Fried 2013 7/26 8/26 1.99% 0.83[0.25,2.76]
Rizk 2005 16/75 0/75 0.13% 41.87[2.46,712.37]
Salehpour 2012 17/90 8/90 2.21% 2.39[0.97,5.86]
Westphal 2006 14/53 4/40 1.14% 3.23[0.97,10.73]
Subtotal (95% CI) 1379 1065 50.96% 1.47[1.2,1.82]
Heterogeneity: Tau2=0; Chi2=60.58, df=11(P<0.0001); I2=81.84%

1.5.2 No treatment/standard treatment
Agrawal 2012 20/30 11/28 1.29% 3.09[1.06,9.04]
Batioglu 2012 20/40 18/45 2.88% 1.5[0.63,3.55]
Battaglia 1999 3/17 0/17 0.14% 8.45[0.4,177.29]
Brusco 2013 36/58 39/91 3.92% 2.18[1.11,4.28]
Cheraghi 2016 2/20 4/20 1.22% 0.44[0.07,2.76]
Cicek 2012 10/53 7/50 1.99% 1.43[0.5,4.1]
El Refaeey 2014 19/55 3/55 0.67% 9.15[2.52,33.22]
Eryilmaz 2011 7/30 7/30 1.83% 1[0.3,3.31]
Lisi 2012 14/47 12/47 2.87% 1.24[0.5,3.06]
Maged 2015 8/40 4/40 1.09% 2.25[0.62,8.18]
Pacchiarotti 2016 123/358 62/211 17.42% 1.26[0.87,1.82]
Papaleo 2009 8/30 7/30 1.75% 1.19[0.37,3.85]
Rizzo 2010 12/32 8/33 1.68% 1.88[0.64,5.47]
Schachter 2007 18/24 14/23 1.22% 1.93[0.55,6.71]
Schachter 2007 21/27 18/28 1.34% 1.94[0.59,6.4]
Youssef 2015 43/112 36/106 7.75% 1.21[0.7,2.11]
Subtotal (95% CI) 973 854 49.04% 1.57[1.27,1.93]

Total (95% CI) 2352 1919 100% 1.52[1.31,1.76]
Test for subgroup differences: Chi2=0.16, df=1 (P=0.69), I2=0%


Informed decisions.


standard treatment, Outcome 6 Clinical pregnancy; type of antioxidant.
treatment
1.6.1 N-acetyl-cysteine
Badawy 2006 63/404 79/400 77.7% 0.75[0.52,1.08]
Cheraghi 2016 5/40 6/40 6.09% 0.81[0.23,2.9]
Maged 2015 8/40 4/40 3.71% 2.25[0.62,8.18]
Nasr 2010 21/30 13/30 4.52% 3.05[1.05,8.84]
Rizk 2005 16/75 0/75 0.45% 41.87[2.46,712.37]
Salehpour 2012 17/90 8/90 7.52% 2.39[0.97,5.86]
Subtotal (95% CI) 679 675 100% 1.22[0.92,1.63]
Heterogeneity: Tau2=0; Chi2=19.09, df=5(P=0); I2=73.82%

1.6.2 Combined antioxidants
Agrawal 2012 20/30 11/28 12.04% 3.09[1.06,9.04]
Panti Abubakar 2015 22/100 2/100 4.95% 13.82[3.15,60.58]
Westphal 2006 14/53 4/40 10.65% 3.23[0.97,10.73]
Youssef 2015 43/112 36/106 72.35% 1.21[0.7,2.11]
Subtotal (95% CI) 295 274 100% 2.28[1.51,3.43]

1.6.3 Melatonin
Batioglu 2012 20/40 18/45 15.3% 1.5[0.63,3.55]
Eryilmaz 2011 7/30 7/30 9.69% 1[0.3,3.31]
Pacchiarotti 2016 65/178 58/180 66.12% 1.21[0.78,1.87]
Rizzo 2010 12/32 8/33 8.89% 1.88[0.64,5.47]
Subtotal (95% CI) 280 288 100% 1.29[0.91,1.83]

1.6.4 Vitamin E
Cicek 2012 10/53 7/50 100% 1.43[0.5,4.1]
Subtotal (95% CI) 53 50 100% 1.43[0.5,4.1]

1.6.5 Ascorbic acid
Griesinger 2002 104/461 44/158 100% 0.75[0.5,1.14]
Subtotal (95% CI) 461 158 100% 0.75[0.5,1.14]

1.6.6 L-arginine
Battaglia 1999 3/17 0/17 7.65% 8.45[0.4,177.29]

Informed decisions.


treatment
Battaglia 2002 3/18 6/19 92.35% 0.43[0.09,2.09]
Subtotal (95% CI) 35 36 100% 1.05[0.32,3.46]

1.6.7 Myo-inositol plus folic acid
Brusco 2013 36/58 39/91 18.06% 2.18[1.11,4.28]
Lisi 2012 14/47 12/47 13.21% 1.24[0.5,3.06]
Pacchiarotti 2016 58/180 62/211 60.68% 1.14[0.74,1.76]
Papaleo 2009 8/30 7/30 8.05% 1.19[0.37,3.85]
Subtotal (95% CI) 315 379 100% 1.35[0.98,1.86]

1.6.8 CoQ10
Bentov 2014 6/17 6/22 63.28% 1.45[0.37,5.71]
El Refaeey 2014 19/55 3/55 36.72% 9.15[2.52,33.22]
Subtotal (95% CI) 72 77 100% 4.28[1.79,10.26]

1.6.9 L-carnitine
Ismail 2014 42/85 1/85 100% 82.05[10.92,616.59]
Subtotal (95% CI) 85 85 100% 82.05[10.92,616.59]

1.6.10 Vitamin D
Polak de Fried 2013 7/26 8/26 100% 0.83[0.25,2.76]
Subtotal (95% CI) 26 26 100% 0.83[0.25,2.76]

1.6.11 Vitamin B complex
Schachter 2007 18/24 14/23 47.65% 1.93[0.55,6.71]
Schachter 2007 21/27 18/28 52.35% 1.94[0.59,6.4]
Subtotal (95% CI) 51 51 100% 1.94[0.82,4.58]
Heterogeneity: Tau2=0; Chi2=0, df=1(P=0.99); I2=0%

1.6.12 Myo-inositol plus melatonin plus folic acid
Pacchiarotti 2016 65/178 62/211 100% 1.38[0.9,2.12]
Subtotal (95% CI) 178 211 100% 1.38[0.9,2.12]

Informed decisions.


treatment

standard treatment, Outcome 7 Clinical pregnancy; indications for subfertility.
treatment
1.7.1 Polycystic ovary syndrome
Cheraghi 2016 3/20 2/20 2.03% 1.59[0.24,10.7]
El Refaeey 2014 19/55 3/55 2.35% 9.15[2.52,33.22]
Ismail 2014 42/85 1/85 0.61% 82.05[10.92,616.59]
Maged 2015 8/40 4/40 3.83% 2.25[0.62,8.18]
Nasr 2010 21/30 13/30 4.67% 3.05[1.05,8.84]
Pacchiarotti 2016 123/358 62/211 61.29% 1.26[0.87,1.82]
Panti Abubakar 2015 22/100 2/100 1.87% 13.82[3.15,60.58]
Papaleo 2009 8/30 7/30 6.14% 1.19[0.37,3.85]
Rizk 2005 16/75 0/75 0.47% 41.87[2.46,712.37]
Salehpour 2012 17/90 8/90 7.77% 2.39[0.97,5.86]
Schachter 2007 18/24 14/23 4.28% 1.93[0.55,6.71]
Schachter 2007 21/27 18/28 4.7% 1.94[0.59,6.4]
Subtotal (95% CI) 934 787 100% 2.63[2.06,3.36]

1.7.2 Unexplained
Badawy 2006 63/404 79/400 85.67% 0.75[0.52,1.08]
Cicek 2012 10/53 7/50 7.47% 1.43[0.5,4.1]
Eryilmaz 2011 7/30 7/30 6.86% 1[0.3,3.31]
Subtotal (95% CI) 487 480 100% 0.82[0.59,1.14]

1.7.3 Tubal subfertility
Battaglia 1999 3/17 0/17 7.65% 8.45[0.4,177.29]
Battaglia 2002 3/18 6/19 92.35% 0.43[0.09,2.09]
Subtotal (95% CI) 35 36 100% 1.05[0.32,3.46]

Agrawal 2012 20/30 11/28 4.87% 3.09[1.06,9.04]
Batioglu 2012 20/40 18/45 10.88% 1.5[0.63,3.55]
Brusco 2013 36/58 39/91 14.79% 2.18[1.11,4.28]
Griesinger 2002 104/461 44/158 65.16% 0.75[0.5,1.14]

Informed decisions.


treatment
Westphal 2006 14/53 4/40 4.31% 3.23[0.97,10.73]
Subtotal (95% CI) 642 362 100% 1.27[0.94,1.71]

1.7.5 Poor responders
Rizzo 2010 12/32 8/33 100% 1.88[0.64,5.47]
Subtotal (95% CI) 32 33 100% 1.88[0.64,5.47]

treatment/standard treatment, Outcome 8 Clinical pregnancy; IVF/ICSI.
Study or subgroup Favours place- Placebo/No Odds Ratio Weight Odds Ratio
bo/no treat treatment
Batioglu 2012 20/40 18/45 4.3% 1.5[0.63,3.55]
Battaglia 1999 3/17 0/17 0.2% 8.45[0.4,177.29]
Battaglia 2002 3/18 6/19 2.47% 0.43[0.09,2.09]
Bentov 2014 6/17 6/22 1.72% 1.45[0.37,5.71]
Brusco 2013 36/58 39/91 5.85% 2.18[1.11,4.28]
Cheraghi 2016 5/40 6/40 2.67% 0.81[0.23,2.9]
Eryilmaz 2011 7/30 7/30 2.73% 1[0.3,3.31]
Griesinger 2002 104/461 44/158 25.77% 0.75[0.5,1.14]
Lisi 2012 14/47 12/47 4.28% 1.24[0.5,3.06]
Pacchiarotti 2016 123/358 62/211 26.01% 1.26[0.87,1.82]
Papaleo 2009 8/30 7/30 2.61% 1.19[0.37,3.85]
Polak de Fried 2013 8/26 10/26 3.52% 0.71[0.23,2.24]
Rizzo 2010 12/32 8/33 2.5% 1.88[0.64,5.47]
Schachter 2007 18/24 14/23 1.82% 1.93[0.55,6.71]
Schachter 2007 21/27 18/28 1.99% 1.94[0.59,6.4]
Youssef 2015 43/112 36/106 11.57% 1.21[0.7,2.11]

Total (95% CI) 1337 926 100% 1.19[0.98,1.43]
Total events: 431 (Favours placebo/no treat), 293 (Placebo/No treatment)


Informed decisions.

Analysis 1.9. Comparison 1 Antioxidant(s) versus placebo or

no treatment/standard treatment, Outcome 9 Adverse events.
treatment
1.9.1 Miscarriage
Agrawal 2012 1/30 4/28 4.32% 0.21[0.02,1.98]
Badawy 2006 27/404 29/400 29.37% 0.92[0.53,1.58]
Battaglia 1999 3/17 0/17 0.44% 8.45[0.4,177.29]
Battaglia 2002 0/18 0/19 Not estimable
Bentov 2014 2/17 0/22 0.41% 7.26[0.33,161.84]
Cicek 2012 0/53 1/50 1.65% 0.31[0.01,7.75]
El Refaeey 2014 2/55 0/55 0.52% 5.19[0.24,110.57]
Eryilmaz 2011 1/30 1/30 1.04% 1[0.06,16.76]
Ismail 2014 2/85 4/85 4.22% 0.49[0.09,2.74]
Nasr 2010 2/30 4/30 4.03% 0.46[0.08,2.75]
Pacchiarotti 2016 12/358 24/211 31.53% 0.27[0.13,0.55]
Panti Abubakar 2015 4/100 0/100 0.52% 9.37[0.5,176.43]
Papaleo 2009 2/30 2/30 2.02% 1[0.13,7.6]
Polak de Fried 2013 2/26 2/26 1.99% 1[0.13,7.69]
Rizzo 2010 2/32 2/33 1.99% 1.03[0.14,7.81]
Schachter 2007 7/27 7/28 5.5% 1.05[0.31,3.53]
Schachter 2007 5/24 7/23 6.11% 0.6[0.16,2.27]
Westphal 2006 3/53 1/40 1.16% 2.34[0.23,23.38]
Youssef 2015 5/112 3/106 3.18% 1.6[0.37,6.89]
Subtotal (95% CI) 1501 1333 100% 0.79[0.58,1.08]

1.9.2 Multiple pregnancy
Badawy 2006 8/404 12/400 15.62% 0.65[0.26,1.62]
El Refaeey 2014 1/55 0/55 0.64% 3.06[0.12,76.64]
Ismail 2014 5/85 0/85 0.62% 11.68[0.64,214.68]
Nasr 2010 0/30 0/30 Not estimable
Pacchiarotti 2016 73/358 41/211 54.27% 1.06[0.69,1.63]
Polak de Fried 2013 3/26 1/26 1.17% 3.26[0.32,33.61]
Salehpour 2012 1/90 2/90 2.61% 0.49[0.04,5.55]
Youssef 2015 18/112 22/106 25.07% 0.73[0.37,1.46]
Subtotal (95% CI) 1160 1003 100% 1[0.73,1.38]

1.9.3 Gastrointestinal disturbances
Ismail 2014 4/85 2/85 42.71% 2.05[0.37,11.5]
Maged 2015 0/40 1/40 33.2% 0.33[0.01,8.22]
Westphal 2006 3/53 1/40 24.09% 2.34[0.23,23.38]
Subtotal (95% CI) 178 165 100% 1.55[0.47,5.1]

Favours antioxidant(s) 0.002 0.1 1 10 500 Favours placebo/no treat

Informed decisions.


treatment
1.9.4 Ectopic pregnancy
Agrawal 2012 1/30 0/28 100% 2.9[0.11,74.13]
Subtotal (95% CI) 30 28 100% 2.9[0.11,74.13]

1.9.5 Headache
Ismail 2014 2/85 1/85 100% 2.02[0.18,22.75]
Subtotal (95% CI) 85 85 100% 2.02[0.18,22.75]
Favours antioxidant(s) 0.002 0.1 1 10 500 Favours placebo/no treat

Comparison 2. Head-to-head antioxidants

studies partici-
pants
1 Live birth; type of antioxidant (natural 1 Odds Ratio (M-H, Fixed, 95% CI) Totals not select-
conceptions and undergoing fertility treated
ments)
1.1 Myo-Inositol versus d-chiro-inositol 1 Odds Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
2 Clinical pregnancy; type of antioxidant 1 Odds Ratio (M-H, Fixed, 95% CI) Totals not select-
(natural conceptions and undergoing fertil- ed
ity treatments)
2.1 Myo-Inositol versus d-chiro-inositol 1 Odds Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
3 Adverse events 1 Odds Ratio (M-H, Fixed, 95% CI) Totals not select-
ed
3.1 Miscarriage 1 Odds Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]

Analysis 2.1. Comparison 2 Head-to-head antioxidants, Outcome 1 Live birth;
type of antioxidant (natural conceptions and undergoing fertility treatments).
Study or subgroup Antioxidant a Antioxidant b Odds Ratio Odds Ratio
2.1.1 Myo-Inositol versus d-chiro-inositol
Unfer 2011 15/43 5/41 3.86[1.25,11.89]
Favours antioxidant b 0.01 0.1 1 10 100 Favours antioxidant a

Informed decisions.


Analysis 2.2. Comparison 2 Head-to-head antioxidants, Outcome 2 Clinical pregnancy;
type of antioxidant (natural conceptions and undergoing fertility treatments).
2.2.1 Myo-Inositol versus d-chiro-inositol
Unfer 2011 15/43 5/41 3.86[1.25,11.89]
Favours antioxidant b 0.01 0.1 1 10 100 Favours antioxidant a

Analysis 2.3. Comparison 2 Head-to-head antioxidants, Outcome 3 Adverse events.
2.3.1 Miscarriage
Unfer 2011 4/43 3/41 1.3[0.27,6.2]
Favours antioxidant a 0.01 0.1 1 10 100 Favours antioxidant b

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

studies partici-
pants
1 Live birth; pentoxifylline vs 1 112 Odds Ratio (M-H, Fixed, 95% CI) 1.54 [0.68, 3.50]
placebo or no treatment/standard
treatment (natural conceptions
and undergoing fertility treat-
ments)
2 Clinical pregnancy; pentoxifylline 3 276 Odds Ratio (M-H, Fixed, 95% CI) 2.07 [1.20, 3.56]
vs placebo or no treatment/stan-
dard treatment (natural concep-
tions and undergoing fertility
treatments)
2.1 Placebo 2 164 Odds Ratio (M-H, Fixed, 95% CI) 2.07 [0.94, 4.56]
2.2 No treatment 1 112 Odds Ratio (M-H, Fixed, 95% CI) 2.06 [0.97, 4.38]
3 Clinical pregnancy; type of an- 3 Odds Ratio (M-H, Fixed, 95% CI) Subtotals only
tioxidant
3.1 Pentoxifylline 2 164 Odds Ratio (M-H, Fixed, 95% CI) 2.07 [0.94, 4.56]
3.2 Pentoxifylline plus vitamin E 1 112 Odds Ratio (M-H, Fixed, 95% CI) 2.06 [0.97, 4.38]
4 Clinical pregnancy; indications 3 Odds Ratio (M-H, Fixed, 95% CI) Subtotals only
for subfertility
4.1 Endometriosis 2 164 Odds Ratio (M-H, Fixed, 95% CI) 2.07 [0.94, 4.56]

Informed decisions.


studies partici-
pants
4.2 Varying indications 1 112 Odds Ratio (M-H, Fixed, 95% CI) 2.06 [0.97, 4.38]
5 Clinical pregnancy; IVF/ICSI 1 112 Odds Ratio (M-H, Fixed, 95% CI) 2.06 [0.97, 4.38]
6 Adverse events 3 Odds Ratio (M-H, Fixed, 95% CI) Subtotals only
6.1 Miscarriage 3 276 Odds Ratio (M-H, Fixed, 95% CI) 1.34 [0.46, 3.90]
6.2 Multiple pregnancy 1 112 Odds Ratio (M-H, Fixed, 95% CI) 0.78 [0.20, 3.09]
6.3 Ectopic pregnancy 1 112 Odds Ratio (M-H, Fixed, 95% CI) 2.04 [0.18, 23.13]

Analysis 3.1. Comparison 3 Pentoxifylline versus placebo or no treatment/
standard care, Outcome 1 Live birth; pentoxifylline vs placebo or no treatment/
Study or subgroup Pentoxifylline Placebo or Odds Ratio Weight Odds Ratio
no treatment
Aleyasin 2009 19/56 14/56 100% 1.54[0.68,3.5]

Total (95% CI) 56 56 100% 1.54[0.68,3.5]
Total events: 19 (Pentoxifylline), 14 (Placebo or no treatment)
Favours placebo/not treat 0.01 0.1 1 10 100 Favours pentoxifylline

Analysis 3.2. Comparison 3 Pentoxifylline versus placebo or no treatment/standard
care, Outcome 2 Clinical pregnancy; pentoxifylline vs placebo or no treatment/
no treatment
3.2.1 Placebo
Balasch 1997 9/30 5/30 19.25% 2.14[0.62,7.39]
Creus 2008 12/51 7/53 28.88% 2.02[0.73,5.64]
Subtotal (95% CI) 81 83 48.13% 2.07[0.94,4.56]

3.2.2 No treatment
Aleyasin 2009 32/56 22/56 51.87% 2.06[0.97,4.38]
Subtotal (95% CI) 56 56 51.87% 2.06[0.97,4.38]
Favours placebo/no treat 0.01 0.1 1 10 100 Favours pentoxifylline

Informed decisions.


no treatment

Total (95% CI) 137 139 100% 2.07[1.2,3.56]
Heterogeneity: Tau2=0; Chi2=0.01, df=2(P=1); I2=0%
Test for subgroup differences: Chi2=0, df=1 (P=0.99), I2=0%

standard care, Outcome 3 Clinical pregnancy; type of antioxidant.
no treatment
3.3.1 Pentoxifylline
Balasch 1997 9/30 5/30 40% 2.14[0.62,7.39]
Creus 2008 12/51 7/53 60% 2.02[0.73,5.64]
Subtotal (95% CI) 81 83 100% 2.07[0.94,4.56]

3.3.2 Pentoxifylline plus vitamin E
Aleyasin 2009 32/56 22/56 100% 2.06[0.97,4.38]
Subtotal (95% CI) 56 56 100% 2.06[0.97,4.38]

standard care, Outcome 4 Clinical pregnancy; indications for subfertility.
no treatment
3.4.1 Endometriosis
Balasch 1997 9/30 5/30 40% 2.14[0.62,7.39]
Creus 2008 12/51 7/53 60% 2.02[0.73,5.64]
Subtotal (95% CI) 81 83 100% 2.07[0.94,4.56]


Informed decisions.


no treatment
Aleyasin 2009 32/56 22/56 100% 2.06[0.97,4.38]
Subtotal (95% CI) 56 56 100% 2.06[0.97,4.38]

Analysis 3.5. Comparison 3 Pentoxifylline versus placebo or no
treatment/standard care, Outcome 5 Clinical pregnancy; IVF/ICSI.
no treatment
Aleyasin 2009 32/56 22/56 100% 2.06[0.97,4.38]

Total (95% CI) 56 56 100% 2.06[0.97,4.38]

Analysis 3.6. Comparison 3 Pentoxifylline versus placebo
or no treatment/standard care, Outcome 6 Adverse events.
no treatment
3.6.1 Miscarriage
Aleyasin 2009 6/56 5/56 75.57% 1.22[0.35,4.27]
Balasch 1997 1/30 1/30 16.36% 1[0.06,16.76]
Creus 2008 1/51 0/53 8.06% 3.18[0.13,79.83]
Subtotal (95% CI) 137 139 100% 1.34[0.46,3.9]

3.6.2 Multiple pregnancy
Aleyasin 2009 4/56 5/56 100% 0.78[0.2,3.09]
Subtotal (95% CI) 56 56 100% 0.78[0.2,3.09]

3.6.3 Ectopic pregnancy
Aleyasin 2009 2/56 1/56 100% 2.04[0.18,23.13]
Favours pentoxifylline 0.01 0.1 1 10 100 Favours placebo/no treat

Informed decisions.


no treatment
Subtotal (95% CI) 56 56 100% 2.04[0.18,23.13]
Favours pentoxifylline 0.01 0.1 1 10 100 Favours placebo/no treat

ADDITIONAL TABLES

Table 1. Gerli 2007- data not included in meta-analysis
Outcome Data Notes
Clinical pregnancy rate; myo-inositol + folic acid 4/23 Only 42 of the 92 women enrolled in this trial de-
clared a desire to become pregnant
Clinical pregnancy rate; folic acid + placebo 1/19 -
Miscarriage rate; myo-inositol + folic acid Miscarriage reported, 1 miscarriage occurred in the first trimester, but it
but unknown whether is unknown from which group
from treatment or con-
trol
Miscarriage rate; folic acid + placebo Unknown -

Table 2. 'Biochemical' and 'pregnancy' data for those trials that did not specifically report 'clinical pregnancy'
Trial Pregnancy in antioxidant group Pregnancy in control group
Ciotta 2011 4/16 (myo-inositol + folic acid) 5/18 (folic acid)
Alborzi 2007 17/43 (pentoxifylline) 16/45 (placebo)
Mier-Cabrera 2008 0/16 (vitamins C + E), at follow-up over 9 months 3/16 0/18 (placebo), at follow-up over 9 months
2/18
Mohammadbeigi 2012 9/22 (vitamin D) 7/22 (placebo)
Razavi 2015 6/32 (selenium) 1/32 (placebo)

APPENDICES
Appendix 1. Cochrane Gynaecology and Fertility specialised register search strategy

PROCITE platform
Inception to 27 September 2016

Informed decisions.

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"
441 records found
Appendix 2. CENTRAL CRSO search strategy

Web platform
Inception to 27 September 2016
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)

Informed decisions.

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 search strategy

Ovid platform
From 1946 to 27 September 2016

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$.tw. (139453)
5 exp Zinc/ (46748)
20 exp Acetylcysteine/ (9543)
25 omega$.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)
Informed decisions.

33 lutein$.tw. (31314)
35 exp Inositol/ (20428)
39 n acetyl cysteine.tw. (1956)
42 or/1-41 (1239820)
49 (in vitro fertilisation or intracytoplasmic sperm injection$).tw. (5857)
53 ART.tw. (42946)
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 search strategy

Ovid platform

3 vitamin$.tw. (166429)
4 exp vitamin/ or exp ascorbic acid/ or exp carotenoid/ or exp tocopherol/ (432169)
5 exp Zinc/ (75273)
20 exp acetylcysteine/ (22243)
Informed decisions.

21 n-acetyl-cysteine.tw. (2448)
26 omega$.tw. (14166)
28 exp edible oil/ or exp castor oil/ or exp cod liver oil/ or exp fish oil/ or exp lyprinol/ or exp olive oil/ or exp safflower oil/ or exp fatty
acid/ or exp essential fatty acid/ or exp arachidonic acid/ or exp linoleic acid/ or exp linolenic acid/ or exp gamma linolenic acid/ or exp
unsaturated fatty acid/ or exp omega 3 fatty acid/ or exp omega 6 fatty acid/ or exp polyunsaturated fatty acid/ (425301)
35 exp inositol/ (8444)
41 or/1-40 (1344153)
43 (female$ 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)
51 vitro fertilization.tw. (17633)
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)
Informed decisions.

80 75 not 79 (1283559)
81 41 and 56 and 80 (785)
Appendix 5. PsycINFO search strategy

Ovid platform
1 exp Antioxidants/ (1289)

3 exp Vitamins/ (2994)
5 exp Zinc/ (472)
18 omega$.tw. (909)
19 exp Fatty Acids/ (2614)
22 or/1-21 (15067)
23 exp Infertility/ (1531)
32 vitro fertilization.tw. (435)
34 or/23-33 (2032)
35 22 and 34 (12)
Appendix 6. AMED search strategy

Ovid platform
1 exp Antioxidants/ or exp Free radicals/ (1454)

3 exp Vitamins/ or exp Dietary supplements/ (2999)
4 exp Ascorbic acid/ (252)
6 exp Zinc/ (100)
Informed decisions.

17 Acetylcysteine.tw. (27)
21 omega$.tw. (211)
22 exp Fatty acids/ (432)
23 exp Fish oils/ (86)
31 or/1-30 (7934)
32 exp Infertility female/ (150)
43 or/32-42 (186)
44 31 and 43 (4)
Appendix 7. CINAHL search strategy

Ovid platform

# Query Results
S63 S50 AND S62 46
S62 S51 OR S52 OR S53 OR S54 OR S55 OR S56 OR S57 OR S58 OR S59 OR S60 OR S61 973,529
S61 TX allocat* random* 4,373
S60 (MH "Quantitative Studies") 13,575
S59 (MH "Placebos") 9,311
S58 TX placebo* 34,242
S57 TX random* allocat* 4,373
S56 (MH "Random Assignment") 39,396
S55 TX randomi* control* trial* 89,855

Informed decisions.

(Continued)
S54 TX ( (singl* n1 blind*) or (singl* n1 mask*) ) or TX ( (doubl* n1 blind*) or (doubl* n1 777,926
mask*) ) or TX ( (tripl* n1 blind*) or (tripl* n1 mask*) ) or TX ( (trebl* n1 blind*) or (trebl* n1
mask*) )
S53 TX clinic* n1 trial* 173,348
S52 PT Clinical trial 78,187
S51 (MH "Clinical Trials+") 189,346
S50 S26 AND S49 125
S49 S27 OR S28 OR S29 OR S30 OR S31 OR S32 OR S33 OR S34 OR S35 OR S36 OR S37 OR S38 6,349
OR S39 OR S40 OR S41 OR S42 OR S43 OR S44 OR S45 OR S46 OR S47 OR S48
S48 TX intra-uterine insemination 10
S47 TX natural cycle* 119
S46 TX timed intercourse 22
S45 TX (ovari* N2 induction) 12
S44 TX COH 68
S43 TX ovarian hyperstimulation 345
S42 TX superovulat* 24
S41 TX ovulation induc* 588
S40 TX intrauterine insemination 152
S39 TX IUI 83
S38 TX artificial insemination 459
S37 TX assisted reproduct* 1,331
S36 (MM "Insemination, Artificial") 244
S35 (MM "Reproduction Techniques+") 4,061
S34 TX intracytoplasmic sperm injection* 246
S33 TX embryo* N3 transfer* 809
S32 TX ovar* N3 hyperstimulat* 348
S31 TX ovari* N3 stimulat* 253
S30 TX IVF or TX ICSI 1,289
S29 (MM "Fertilization in Vitro") 1,487
S28 TX vitro fertilization 2,919

Informed decisions.

(Continued)
S27 TX vitro fertilisation 276
S26 S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR 106,012

S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22 OR S23 OR S24 OR S25
S25 TX Nutraceutical* 738
S24 TX micronutrient* 3,381
S23 TX nutritional supplement* 1,710
S22 TX dietary supplement* 28,026
S21 TX melatonin 1,919
S20 TX n acetyl cysteine 203
S19 TX l-arginine 938
S18 TX (fish N2 oil*) 2,915
S17 (MH "Acetylcysteine") 1,042
S16 TX n-acetylcysteine 691
S15 TX ascorbic acid 4,277
S14 TX multivitamin* 946
S13 TX(astaxanthin* or lycopene*) 850
S12 TX (carnitine* or carotenoid*) 2,960
S11 (MM "Carnitine") 494
S10 TX coenzyme q10 415
S9 TX (ubiquin* or folic acid) 6,007
S8 TX (zinc or selenium) 6,881
S7 TX omega$ 7,321
S6 TX fatty acid* 17,157
S5 (MH "Fatty Acids, Omega 3") OR (MH "Fatty Acids, Unsaturated+") 17,162
S4 TX vitamin* 35,451
S3 (MH "Vitamins+") 34,733
S2 TX antioxidant* 16,804
S1 (MM "Antioxidants+") 6,858

Informed decisions.

Appendix 8. Search strategies for The WHO portal (ICTRP), clinicaltrials.gov, Google, DARE, Web of Knowledge and
OpenGrey
From inception to 27 September 2016
Web platforms
'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';
WHAT'S NEW

Date Event Description
16 October 2017 Amended Some references updated and corrected

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

Date Event Description
28 June 2017 New search has been performed Updated. Twenty-three new trials added, making a total of
50 trials now included in this updated review. New studies
added:Battaglia 1999; Bentov 2014; Brusco 2013; Carlomagno
2012; Cheraghi 2016; Choi 2012; Colazingari 2013; Daneshbo-
di 2013; Deeba 2015; El Refaeey 2014; Ismail 2014; Keikha 2010;
Lesoine 2016; Maged 2015; Mohammadbeigi 2012; Pacchiarot-
ti 2016; Panti Abubakar 2015; Polak de Fried 2013; Razavi 2015;
Rosalbino 2012; Salehpour 2012; Schachter 2007; Valeri 2015.
28 June 2017 New citation required and conclusions With the addition of new studies data now show an association
have changed between the use of antioxidants and live birth and clinical preg-
nancy.
22 April 2008 Amended Converted to new review format.
9 August 2007 New citation required and major Substantive amendment

changes

CONTRIBUTIONS OF AUTHORS
Marian Showell conducted the searches, assessed studies for inclusion, extracted data, analysed the data and wrote the review.
Rebecca Mackenzie-Proctor assisted with assessing the trials for inclusion, extracted the data, assisted with the data analysis and helped
with writing of the updated review.
Vanessa Jordan assisted with the methodology in the updated review and commented on the drafts.
Roger Hart helped with the writing of the review and provided clinical advice.

Informed decisions.

DECLARATIONS OF INTEREST
Roger Hart is the Medical Director of Fertility Specialists of WA and a shareholder in Western IVF. He has received educational sponsorship
from Merck Serono and Ferring pharmaceuticals, and is on the medical advisory board of MSD and Ferring Pharmaceuticals.
Rebecca Mackenzie-Proctor: no conflict of interest to declare
Vanessa Jordan: no conflict of interest to declare
Marian Showell: no conflict of interest to declare
SOURCES OF SUPPORT
Internal sources
• NZ GOVT MOH, New Zealand.
External sources
• None, Other.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
After publication of the protocol:
• two of the five protocol authors (Agarwal A, Gupta S) withdrew from involvement in the review.
• we have removed the secondary outcome of stillbirth rate per woman.
• we have removed the exclusion criterion 'Trials that exclusively reported on women who have previously had chemotherapy' as not
clinically relevant to this review.
• we have expanded the inclusion criteria for participants to include women undergoing ART. Exclusion criteria now cover trials that enrol
exclusively fertile women attending a fertility clinic because of male partner infertility, and women who are Vitamin D-deficient.
• exclusion criteria for interventions now cover 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.
• we have created a separate comparison for pentoxifylline, as we had concerns that this medicine does not have purely antioxidant
capabilities.
• we have updated the search strategy.
• we have added two 'Summary of findings' tables.
• where we had data from multi-armed trials, we have pooled the intervention arms versus the control arm. This differs from the protocol,
where we said that we would divide the intervention arms. This was done on the advice of a statistician.
• we decided, with clinical advice, that we would treat trials using folic acid (< 1 mg) as a control as assessing standard treatment and
would include them in the 'no treatment' subgroup.
For the 2017 update:
• we have analysed trials that used an antioxidant plus an antioxidant versus the same antioxidants plus placebo/no treatment or
standard treatment in the 'Antioxidants versus no treatment' comparison, whereas in the original review they were considered as head-
to-head.
• prior to the 2017 update, the effect estimate used was the Peto odds ratio. As this is not recommended as a default approach for meta-
analysis unless intervention effects are small (odds ratios close to one) and events are not particularly common (Higgins 2011), we have
used the Mantel-Haenszel odds ratio for the 2017 update.
INDEX TERMS
Medical Subject Headings (MeSH)

Abortion, Spontaneous [epidemiology]; Administration, Oral; Antioxidants [*administration & dosage] [adverse effects]; Infertility,
Female [*drug therapy]; Live Birth [epidemiology]; Oxidative Stress; Pentoxifylline [adverse effects] [therapeutic use]; Pregnancy
Rate; Pregnancy, Multiple; Randomized Controlled Trials as Topic
MeSH check words

Female; Humans; Pregnancy


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Showell MG, Mackenzie-Proctor R, Jordan V, Hart RJ

Showell MG, Mackenzie-Proctor R, Jordan V, Hart RJ.

Antioxidants for female subfertility (Review) i

Antioxidants for female subfertility (Review) ii

Antioxidants for female subfertility

Marian G Showell1, Rebecca Mackenzie-Proctor2, Vanessa Jordan1, Roger J Hart3

Editorial group: Cochrane Gynaecology and Fertility Group

Data collection and analysis

Vitamins and minerals for subfertility in women

Antioxidants for female subfertility (Review) 2

Quality of the evidence:

Antioxidants for female subfertility (Review) 3

Cochrane Database of Systematic Reviews

CI: Confidence interval; OR: Odds ratio

GRADE Working Group grades of evidence

Pentoxifylline compared to placebo or no treatment/standard care for female subfertility

Cochrane Database of Systematic Reviews

CI: Confidence interval; OR: Odds ratio;

GRADE Working Group grades of evidence

Cochrane Database of Systematic Reviews

Antioxidants for female subfertility (Review) 7

The local development of oxidative stress will have significant METHODS

Antioxidants for female subfertility (Review) 8

Antioxidants for female subfertility (Review) 9

Antioxidants for female subfertility (Review) 10

Antioxidants for female subfertility (Review) 11

Figure 1. Study flow diagram.

Antioxidants for female subfertility (Review) 12

Antioxidants for female subfertility (Review) 13

Thirty-six trials reported on clinical pregnancy rates in the text of

Excluded studies Risk of bias in included studies

Antioxidants for female subfertility (Review) 15

Antioxidants for female subfertility (Review) 16

Antioxidants for female subfertility (Review) 17

Antioxidants for female subfertility (Review) 18

Antioxidants for female subfertility (Review) 19

Antioxidants for female subfertility (Review) 20

Figure 4. Funnel plot of comparison: 1 Antioxidant(s) versus placebo or no treatment/standard treatment,

Antioxidants for female subfertility (Review) 21

One trial (Cicek 2012) enrolled women with unexplained subfertility

Antioxidants for female subfertility (Review) 23

Antioxidants for female subfertility (Review) 24

Antioxidants for female subfertility (Review) 25

Antioxidants for female subfertility (Review) 26

Antioxidants for female subfertility (Review) 27

Antioxidants for female subfertility (Review) 28

Antioxidants for female subfertility (Review) 29

1.7.1 Polycystic ovary syndrome 1.8 Clinical pregnancy rate; IVF/ICSI

Antioxidants for female subfertility (Review) 30

Antioxidants for female subfertility (Review) 31

1.9.2 Multiple pregnancy 2.2 Clinical pregnancy; type of antioxidant

1.9.3 Gastrointestinal disturbances 2.3.1 Miscarriage

Secondary outcome: Clinical pregnancy

Antioxidants for female subfertility (Review) 32

3.3 Clinical pregnancy; type of antioxidant See Analysis 3.5.

See Analysis 3.6

Antioxidants for female subfertility (Review) 33

Antioxidants for female subfertility (Review) 36

Antioxidants for female subfertility (Review) 37