FOGSI Focus Use of Adjuvants in Infertility Sunita Tandulwadkar, Madhuri Patil, Nandita Palshetkar
Page numbers followed by f refer to figure, and t refer to table
Acetylcholinesterase inhibitor 6
Acetylsalicylic acid 7
Acupressure 5, 11
Acupuncture 3, 5, 11, 26, 30, 32, 34
Adhesiolysis 62, 65f
Adjuvants therapy 14
Advanced sperm selection
procedures 6
techniques 2
Adverse pregnancy outcome 64
Alpha-lipoic acid 20
controlled-release 20
Amenorrhea 65
American Society for Reproductive Medicine 59
American Thyroid Association 59
Amino acids 40
excess, treatment of 8
pretreatment 6
Androstenedione 23
Anovulation 62
Antibiotics 40
prophylactic 65
Anti-Müllerian hormone 7, 22
Antioxidants 1, 5, 11, 40
scavenging 50, 51
therapy 50
Antithyroglobulin 56
antibodies 56
peroxidase 56, 59
Antral follicle count 22
Aromatase inhibitors 5, 53
Artificial oocyte activation 2, 41, 46
Asherman's syndrome 28, 63, 65, 65f
Aspirin 2, 3, 5, 7, 10, 26, 29, 32
Assisted hatching 3, 6, 43, 44, 46
Assisted reproductive technology 1, 5, 6, 13, 23, 29, 37, 56, 62
basis of 22
cycle 32
new technologies used in 12
outcome 10
culture 43
transfer 12, 43
trophectoderm cells, biopsy of 45
Bleeding, postoperative 63
Body mass index 8
Bologna criteria 22
Bone marrow-derived stem cells 35
Broad fundus, laparoscopic confirmation of 64f
ionophores 5
ions 41
Canadian Fertility and Andrology Society Clinical Practice Guidelines 33
Carnitine 51
Catalytic antioxidants 50
Chromium polynicotinate 5, 8, 9
Clinical pregnancy rate 1, 6, 32, 39, 41
Clomiphene citrate 8, 9, 19, 27, 52, 66
Coenzyme Q10 1, 5, 9
Colony-stimulating factor 8
Comet assay 39, 40f
Conception, natural 62
Connective tissue growth factor 29
Controlled ovarian
hyperstimulation 8, 58
stimulation 6
Corticosteroids 2, 3, 32, 34
Cryopreserved oocytes, fertilization of 2
Cumulus-oocyte complexes 6
Cyclic adenosine monophosphate 10
formation 6
Cyclic guanosine monophosphate 27
Cyst, large endometriotic 67f
Cystectomy, laparoscopic 67
Cytokines 2
Dehydroepiandrosterone 1, 3, 6, 23
administration 6
sulfate 8
Deoxyribonucleic acid 46
denaturation of 39
Dexamethasone 5, 8
Digital polymerase chain reaction 45
Distal tubal obstruction 62, 63
Dopamine agonist 5
Elective single embryo transfer 37
Electroacupuncture 34
Electrosurgical complications 63
biopsy 13
glue 3, 46
hydrogen peroxide induced damage prevention of 27
transfer 11, 18
treatment 64
Embryogenesis 59, 60
Endocrine Society 59
Endometrial receptivity
adjuvants for 32
amelioration of 27
Endometrial scratching 6, 13f, 32, 35, 68
Endometrial thickness 32
Endometrioma 66
cystectomy 62
Endometriosis 62, 66, 67
deep 66
minimal-mild 67
moderate 67
moderate-severe 67
severe 67
superficial 66
Endometrium 26, 27, 59, 60
thin 26
Energy substrates 40
Epidermal growth factor 28, 29, 33
Erectile dysfunction, treatment of 27
Estrogen pretreatment 5, 7
European Society of Human Reproduction and Embryology Classification 64
European Thyroid Association 59
Fatty liver disease, nonalcoholic 20
acupressure points for 12f
acupuncture points for 11f
Fertilization 59, 60
failure 41
rates 57
Fibroblast growth factor 29
Fibroids, multiple 63
Fluid intravasation syndrome 63
Fluorescence in situ hybridization 3, 14, 45
Follicle-stimulating hormone 1, 6, 19, 23, 52, 57
recombinant 50
Follicular-fluid testosterone 23
Folliculogenesis 57
Food and Drug Administration 34
Frozen embryo transfer 26
Frozen-thawed embryo transfer 33, 40
Genomic hybridization 45
Germ cells 53
Glucocorticoids 5, 8
Glyceryl trinitrate 27
Gonadotropin-releasing hormone 1, 8, 18, 23, 53, 63
agonist 32, 33
Granulocyte colony stimulating factor 6, 29, 32, 34
intrauterine perfusion of 26
Granulocyte-macrophage colony-stimulating factor 40
Granulosa cells 6
Growth hormone 1, 3, 5, 6, 23, 32, 35, 50, 52
factor 6
hormones 23
Heparin 2, 3, 5, 10, 28, 32, 33
mechanism of action of 28f
Homeostatic model assessment 19
Human chorionic gonadotropin 5, 23, 29, 32, 33, 50, 52, 56
low-dose 26, 29
Human fertilization and embryology authority 40, 46
Human menopausal gonadotropin 8
Human oocytes activation 41
Human serum albumin 40
Hyaluronan-enriched transfer medium 40
Hyaluronic acid 39
Hyaluronic binding assay score 39
Hydrosalpinx 68
bilateral 68f
disconnection of 6
removal of 6
Hydroxyvitamin D 19
Hyperinsulinemia 8
Hyperthyroid 53
Hypnosis 5, 11
Hypomenorrhea 65
Hypothesis 45
Hypothyroid 53
Hypothyroidism, subclinical 56, 59
Hysterosalpingography, abnormal 11
Hysteroscopic myomectomy 62, 63
complications of 63
Hysteroscopic surgeries, postoperative management in 65
Immune therapy 2, 5
Immunoglobulin 10
A 10
G 10
Implantation 59, 60
failure, recurrent 10, 63
rate 32
In vitro fertilization 3, 5, 32
additional therapy in 1
outcome 6, 11
program 5
treatment 1, 5, 18, 23, 28, 37, 59, 62, 64, 67
Infertility 62, 65
globally, prevalence of 37
history of 64
severe male factor 38
Injury, endometrial 3
Inositol 8, 9, 18
growth factor 1 18, 23, 28, 29, 41
resistance 8
sensitizing agents 18
International Committee for Monitoring Assisted Reproductive Technology 37
International Federation of Gynecology and Obstetrics Classification 63
International Societies, guidelines of 59t
Intracytoplasmic morphologically selected sperm injection 12, 13, 37, 38f, 46
Intracytoplasmic sperm injection 1, 2, 7, 23, 29, 32, 37, 58
Intralipid 10
Intramural fibroids 63
Intrauterine granulocyte-colony stimulating factor instillation 29
Intrauterine insemination 67
cycles 27
Ions 40
Ketoconazole 8
L-arginine 5, 7, 26, 28, 32, 33
Laser-assisted zona hatching technology 44
Letrozole 8, 53
Leukemia inhibiting factor 59
Levothyroxine 58, 59
Leydig cells 52, 53
Lipids 40
Lipoic acid 20
Live birth rate 6, 32, 37
L-methylfolate 8, 9
Low molecular weight heparin 26, 28
inhibits 2
Luteal phase
adjuvants for 32
estradiol in 24
Luteinizing hormone 6, 18, 23, 27, 57, 66
recombinant 23
therapy 52
Lycopene 52
Magnesium 19
Massage therapy 11
Matrix metalloproteinase 59
Meiotic spindle 42f
Melatonin 3, 5, 8, 9
Methylprednisolone 5, 8
Methylxanthine 33
Metroplasty, hysteroscopic lateral 64
Micronutrients 5, 11
Mid-tubal block 62
idiopathic recurrent 2
recurrent 45
Mitochondrial deoxyribonucleic acid 41
load measurement 41
Mitochondrial function 41
Morcellator, hysteroscopic 63
Müllerian anomalies 64
Myoinositol 5
Myomas 63
Myomectomy, laparoscopic 62, 63
Myometrium 27
N-acetylcysteine 5, 8, 9, 19, 50
Natural killer cell 2, 10, 27, 34
Neuromuscular electric stimulation 34
Nimodipine 27
Nitric oxide donor 33
Nonpharmacological adjuvants 5, 11
Obesity 53
Omega-3 fatty acids 20
Oocyte 42f, 59, 60
matured in vitro, fertilization of 2
meiotic stage, assessment of 42f
drilling, laparoscopic 6, 62, 66
endometrioma, management of 6
follicle 57
function 58
syndrome 7, 10, 66
response 22
stimulation 14, 59
Ovulation 59, 60
Ovum pick-up 29
Oxidative stress 11
Pelvic floor neuromuscular electrical stimulation 30, 34
Pentoxifylline 26, 28, 32, 33, 51
Phosphodiesterase type 5 27
Physiological intracytoplasmic sperm injection 12, 13, 37, 39, 46
Pituitary downregulation 14
Placentation 59, 60
derived growth factor 29
rich plasma 26, 29, 32, 35
Polar body 42f
Polycystic ovary
disease 66
laparoscopic drilling of 66, 66f
syndrome 6, 8, 18, 66
treatment of 5
endometrial 65
hysteroscopic removal of 6
treatment of 66
Poor ovarian
reserve 7, 22
response 22
Poor responders
in vitro fertilization outcome in 6
treatment of 5
Poseidon classification 22, 22t
Prednisone 5, 8
multiple 66
rate 27, 32
Preimplantation genetic
diagnosis 2
screening 3, 6, 13, 44, 46
cycles 2
testing 13, 44
Prolactin 53
Proximal tubal occlusion 62
Pyridostigmine 5, 6
addition of 6
Randomized controlled trial 1, 7, 24, 27, 32, 39, 50, 66
Reactive oxygen species 9, 32, 50
Recombinant human growth hormone, low dose of 35
Reproductive surgery 12f
Resectoscope 63
Resistance index 27, 32
Routine hysteroscopy 6, 11
laparoscopy 13f
Salpingitis isthmica nodosa 62
Selective estrogen receptor modulator 52
Selenium 51
Semen parameters, abnormal 2
Septal resection, methods for 64
Septate uterus 64
Septoplasty, hysteroscopic 64
Septum 6
Sertoli cells 53
Sex hormone binding globulin 53
Sildenafil 2, 5, 27, 32, 34
additional actions of 27
citrate 10, 26, 27, 34
mechanism of action of 27f
Single-nucleotide polymorphism 45
Smooth muscle relaxation 27
Somatostatin analogs 18
Sperm 59, 60
dispersion test 40, 40f
structure assay 39, 40f
deoxyribonucleic acid fragmentation 37, 39
fertility 37
Spermatogenesis 57
Spermatozoa 39f
classification of 38, 39f
heads 38f
normal 38f
vacuolated 38f
Spindle imaging 42
Stem cell 26, 32
therapy 30, 35
Steroidogenesis, gonadotropin-induced 6
Steroids 10, 24
Subfertility, male 50
Submucous myoma 6, 63
hysteroscopic resection of 63f
Surgeries, fertility-enhancing 62, 68
Terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate-nick-end labeling assay 39, 40f
Testis, Sertoli cells of 53
Testosterone 3, 5, 23
autoimmunity 56, 58, 60
effect of 60
impact of 56
on fertilization, effect of 57
on implantation, effect of 58
on ovarian reserve, effect of 57
function 58
hormone 53, 59, 59t
receptor alpha 59
receptor beta 59
peroxidase autoantibodies 60t
stimulating hormone 59, 60
Thyroxine 59
Time-lapse embryo monitoring 2, 6
Tocopherol 33
Total failed fertilization with standard insemination 2
Transcutaneous electrical acupuncture point stimulation 34
Transdermal testosterone 6
Transforming growth factor 29
Triiodothyronine 59
uterine cavity 64
uterus 64
cannulation 62
factor 62
reconstruction 62
sterilization reversal 62
Tumor necrosis factor alpha 2, 28
Ultrasonography 66
pulsatility index 32
vasodilators 2
blood flow 26
cavity 63
factors 64
myomas 62
polyp 62, 65, 65f
radial artery 30
septum 64, 64f
volumetric flow 27
Varicocelectomy 53
Vascular endothelial growth factor 10, 27
Vasodilators 5, 10, 26
functions of 27
Vitamin 40
C 51
D 5, 8, 9
deficiency 19
E 26-28, 32, 33, 50
Zinc 51
deficiency 51
Zona pellucida 43
Chapter Notes

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Rational for Additional Therapy in In Vitro FertilizationCHAPTER 1

Bhavana Mittal
The problem of infertility is at a rise. The treatments for infertility are, however, bound by a limited success rate. Since “necessity is the mother of invention”, assisted reproductive technology (ART) is a rapidly evolving field of medicine. Newer drugs and technologies are being tried to improve the result of the procedure. But only a few of them are actually beneficial, safe, and cost effective.
Dehydroepiandrosterone (DHEA) is a food supplement in many countries. Its mechanism of action in women with decreased ovarian reserve is:
  • To increase the production of insulin-like growth factor 1 and estradiol in granulose cells
  • To act as a precursor of androstenedione and testosterone in theca cells.
Thereby it improves the follicular function.
In women with normal ovarian reserve, DHEA has not demonstrated any benefit.1
In women with diminished ovarian reserve, one meta-analysis has shown improvement in clinical pregnancy rate.2 A Cochrane review on the same subject, showed a higher pregnancy rate and live birth rate but the benefit was not obvious when studies with high risk of performance bias were excluded.3
Side-effects noted with use of long-term DHEA are minor androgenic effects but no long-term risks are seen.
At present, routine DHEA supplementation cannot be recommended in absence of good quality evidence.
Antioxidants Including CoenzymeQ10
Coenzyme Q10 (CoQ10) has been proposed to rejuvenate mitochondrial energy stores in granulosa cells.4 CoQ10 supplementation has been proposed to defer ovarian aging.5
There are only few clinical trials on the application of CoQ10 in assisted reproduction. One randomized controlled trial (RCT) found no improvement in clinical pregnancy rate on use of CoQ10 in a dose of 600 mg daily in in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) patients between the age of 35 years and 43 years.6
Serious side effects are noted with the use of CoQ10.
CoQ10 cannot be recommended for all poor responders without further evidence.
Growth Hormone
Growth hormone (GH) increases the insulin-like growth factor 1 (IGF-1) level in follicles which potentiates follicle-stimulating hormone (FSH) action on granulosa cells, increases estradiol production and oocyte maturation.
Growth hormone used in a dose of 8–24 IU/day and given daily or alternate day has found to improve live birth rate in poor responders.7 Low dose (0.5 IU/day) of GH is also sufficient to improve live birth rate in poor responders.8 A Cochrane review of 10 RCTs showed higher clinical pregnancy rate (CPR) and live birth rate (LBR) when GH was added in women suspected of having low ovarian reserve.9
No benefit has been found in the use of GH in normal responders. Also, use of GH is seen in gonadotropin-releasing hormone (GnRH) agonist and not antagonist cycle.10,11
Overall, the use of GH as an adjuvant remains inconclusive.2
Immune Therapy
The rationale behind immune therapy is maternal immunomodulation around implantation window. Natural killer cells, cytokines, tumor necrosis factor alpha (TNFα), growth factors, and balance between Th1 and Th2 cells are important factors at this time.
However, there are no RCTs on the subject. Also, this treatment can result in some serious side effects and is expensive. At present, immune therapy cannot be offered due to lack of proper evidence, cost, and potential side effects.
Artificial Oocyte Activation
Calcium ionophore releases calcium ions around ooplasm after sperm–oocyte fusion. This can enhance fertilization rate and has been proposed to be beneficial in women with previous ICSI cycle with total failed fertilization.
RCTs in women with reduced ovarian reserve12 and male infertility13 did not find any advantage of this intervention. Another systemic review 14 also could not prove any benefit of this treatment.
There is insufficient safety data. At present, this intervention cannot be recommended.
Drugs like prednisolone and dexamethasone have been used for immunomodulation at the time of implantation by suppressing natural killer (NK) cells and maintaining cytokines and growth factors.
Use of prednisolone in women with increased NK cells has shown to improve IVF outcome.15 A significant benefit of prednisolone and heparin has been found in women with unexplained recurrent implantation failure (RIF).16,17
Dan et al.18 found benefit of prednisolone in idiopathic recurrent miscarriage (RM) in terms of increased LBR and reduced miscarriage rate. Short-term use of corticosteroids is not associated with many risks. Currently, prednisolone can be offered in selected patients.
Low molecular weight heparin inhibits clotting factor Xa and has been used to prevent microthrombi at implantation site. This promotes trophoblast invasion. Significant improvement in LBR has been shown in women with more than 3 recurrent implantation failure19 and first IVF cycle.20 A third RCT, however, failed to show such benefit.21 Risks associated with heparin are bleeding and thrombocytopenia. Heparin treatment is acceptable in women with thrombophilia. In women without thrombophilia, it should be prescribed in selected cases with proper counseling.
Low dose aspirin is an antiplatelet agent, it improves trophoblast invasion and has been used for implantation failure. A Cochrane review did not find benefit of use of aspirin in RMs.22 In a review on women with congenital thrombophilia, no benefit of addition of aspirin was seen in terms of LBR or miscarriage rate.23 Therefore, aspirin should be used in selected cases at present.
Uterine Artery Vasodilators
Sildenafil has been used as a nitric oxide donor. This cause vasodilation and improves endometrial blood flow and thickness. Currently, there is not enough evidence to justify the use of vasodilators to improve implantation.
Intracytoplasmic Sperm Injection
Intracytoplasmic sperm injection has been accepted in cases of:
  • Abnormal semen parameters
  • Total failed fertilization with standard insemination
  • Fertilization of cryopreserved oocytes
  • Fertilization of oocytes matured in vitro
  • Preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS) cycles
There is not much evidence in support of the same.
Advanced Sperm Selection Techniques
Embryos with good morphology may not be genetically competent.24
Morphology has limited value in predicting implantation potential.25 It is affected by timing and is observer dependent.26 There is an effort to select the most competent embryos to increase the success of IVF.
Time Lapse Monitoring
Time lapse monitoring (TLM) has the advantage of continuous monitoring, avoids exposure of embryos, reproducibility, and flexibility of laboratory work. Currently, there is not enough evidence in favor of TLM over conventional morphological assessment.27 Also, there are concerns over UV rays exposure while taking images and cost of procedure. It can be offered in situations like repeated implantation failure.3
TABLE 1   Potential role of various adjuvant therapies in IVF practice.
Therapy or medication
Proposed use in IVF
Safety and possible side effects
Increases pregnancy rates
Limited evidence
Meta-analysis shows possible benefit with pregnancy in IVF patients
Low dose aspirin
To improve implantation and decrease miscarriage rate
No/low risk/mild side-effects
Limited evidence
Insufficient evidence of the benefit in pregnancy rates in IVF patients
To improve implantation and decrease miscarriage rate
No/low risk/mild side-effects
Limited evidence
Studies show inconsistent results
Overall, no benefit shown in the pregnancy rate of IVF patients
To improve egg and embryo quality
No/low risk/mild side-effects
No evidence
Antioxidant effect on egg and embryo quality being evaluated
To increase egg numbers and quality in poor responders
Moderate risk/moderate side effects
No/limited evidence
Currently being trialed
To increase egg numbers and quality in poor responder
Moderate risk/moderate side-effects
No/limited evidence
Limited small trials with variable results
Growth hormone
To increase egg numbers and quality in poor responders
Moderate risk/moderate side- effects
No evidence
Limited small trials with variable results
To improve the implantation rate in patients experiencing repeated IVF failure due to immune dysfunction
High risk/serious side-effects
No evidence
Currently no evidence Still under research
Endometrial injury
To improve embryo implantation
No/low risk Mild side-effects
Limited evidence
To date, studies have been too small to draw any conclusion
(IVF: in vitro fertilization; DHEA: dehydroepiandrosterone)
Preimplantation Genetic Screening
Use of PGS by fluorescence in situ hybridization (FISH) technique has shown lower success rates in RCTs.28 No effect was seen in good prognosis women.29 Next generation sequencing (NGS) in PGS is very accurate, reliable and shows 63.8 % CPR per embryo transfer following NGS.30,31
Endometrial Injury
Moderate quality of evidence in favor of endometrial scratching has been found in different RCTs.32-34 However, these studies have been found to be very heterogeneous in methodology.35 Endometrial scratching can only be recommended in RIF at present.
Embryo Glue
A Cochrane review on the subject demonstrated increased LBR but increased multiple pregnancy rate also.36 Embryo glue can be used at present only after proper counseling.
Assisted Hatching
Assisted hatching (AH) has not been found beneficial in good prognosis patients.37 Another Cochrane review found significant improvement in CPR but no difference in LBR with AH.38 In women with decreased ovarian reserve, AH showed decreased LBR (Butts, 2014).39 In absence of corroborative evidence, AH cannot be routinely offered.
Improvement in the result of ART is the need of the hour. However, any new treatment or “adjuvant” should be judged in terms of theoretical basis of benefit, evidence and favor of its use, potential side-effects, and use (Table 1). There should be proper counseling of the patient before the use of such treatment.
  1. Yeung T, Chai J, Li R, et al. A double-blind randomised controlled trial on the effect of dehydroepiandrosterone on ovarian reserve markers, ovarian response and number of oocytes in anticipated normal ovarian responders. BJOG. 2016;123(7):1097–105.
  1. Li J, Yuan H, Chen Y, et al. A meta-analysis of dehydroepiandrosterone supplementation among women with diminished ovarian reserve undergoing in vitro fertilization or intracytoplasmic sperm injection. Int J Gynaecol Obstet. 2015;131(3):240–5.
  1. Nagels HE, Rishworth JR, Siristatidis CS, et al. Androgens (dehydroepiandrosterone or testosterone) for women undergoing assisted reproduction. Cochrane Database Syst Rev. 2015;(11):CD009749.

  1. 4 Bentov Y, Casper RF. The aging oocyte—can mitochondrial function be improved? Fertil Steril. 2013;99(1):18–22.
  1. Ben-Meir A, Burstein E, Borrego-Alvarez A, et al. Coenzyme Q10 restores oocyte mitochondrial function and fertility during reproductive aging. Aging Cell. 2015;14(5):887–95.
  1. Bentov Y, Hannam T, Jurisicova A, et al. Coenzyme Q10 supplementation and oocyte aneuploidy in women undergoing IVF-ICSI treatment. Clin Med Insights Reprod Health. 2014;8:31–6.
  1. Kyrou D, Kolibianakis EM, Venetis CA, et al. How to improve the probability of pregnancy in poor responders undergoing in vitro fertilization: a systematic review and meta-analysis. Fertil Steril. 2009;91(3):749–66.
  1. Lattes K, Brassesco M, Gomez M, et al. Low-dose growth hormone supplementation increases clinical pregnancy rate in poor responders undergoing in vitro fertilisation. Gynecol Endocrinol. 2015;31(7):565–8.
  1. Duffy JM, Ahmad G, Mohiyiddeen L, et al. Growth hormone for in vitro fertilization. Cochrane Database Syst Rev. 2010;(1):CD000099.
  1. Eftekhar M, Aflatoonian A, Mohammadian F, et al. Adjuvant growth hormone therapy in antagonist protocol in poor responders undergoing assisted reproductive technology. Arch Gynecol Obstet. 2013;287(5):1017–21.
  1. Dakhly DM, Bayoumi YA, Gad Allah SH. Which is the best IVF/ICSI protocol to be used in poor responders receiving growth hormone as an adjuvant treatment? A prospective randomized trial. Gynecol Endocrinol. 2015;32(2):116–9.
  1. Caglar Aytac P, Kilicdag EB, Haydardedeoglu B, et al. Can calcium ionophore “use” in patients with diminished ovarian reserve increase fertilization and pregnancy rates? A randomized, controlled study. Fertil Steril. 2015;104(5):1168–74.
  1. Eftekhar M, Janati S, Rahsepar M, et al. Effect of oocyte activation with calcium ionophore on ICSI outcomes in teratospermia: A randomized clinical trial. Iran J Reprod Med. 2013;11(11):875–82.
  1. Sfontouris IA, Nastri CO, Lima ML, et al. Artificial oocyte activation to improve reproductive outcomes in women with previous fertilization failure: a systematic review and meta-analysis of RCTs. Hum Reprod. 2015;30(8):1831–41.
  1. Gomaa MF, Elkholy AG, El-Said MM, et al. Combined oral prednisolone and heparin versus heparin: the effect on peripheral NK cells and clinical outcome in patients with unexplained recurrent miscarriage. A double-blind placebo randomized controlled trial. Arch Gynecol Obstet. 2014;290(4):757–62.
  1. Siristatidis C, Chrelias C, Creatsa M, et al. Addition of prednisolone and heparin in patients with failed IVF/ICSI cycles: a preliminary report of a clinical trial. Hum Fertil (Camb). 2013;16(3):207–10.
  1. Fawzy M, El-Refaeey AA. Does combined prednisolone and low molecular weight heparin have a role in unexplained implantation failure? Arch Gynecol Obstet. 2014;289(3):677–80.
  1. Dan S, Wei W, Yichao S, et al. Effect of prednisolone administration on patients with unexplained recurrent miscarriage and in routine intracytoplasmic sperm injection: A meta-analysis. Am J Reprod Immunol. 2015;74(1):89–97.
  1. Potdar N, Gelbaya TA, Konje JC, et al. Adjunct low-molecular weight heparin to improve live birth rate after recurrent implantation failure: a systematic review and meta-analysis. Hum Reprod Update. 2013;19(6):674–84.
  1. Akhtar MA, Sur S, Raine-Fenning N, et al. Heparin for assisted reproduction: summary of a Cochrane review. Fertil Steril. 2015;103(1):33–4.
  1. Seshadri S, Sunkara SK. Low-molecular-weight-heparin in recurrent implantation failure. Fertil Steril. 2011;95.
  1. de Jong PG, Kaandorp S, Di Nisio M, et al. Aspirin and/or heparin for women with unexplained recurrent miscarriage with or without inherited thrombophilia. Cochrane Database Syst Rev. 2014;(7):CD004734.
  1. Areia AL, Fonseca E, Areia M, et al. Low-molecular-weight heparin plus aspirin versus aspirin alone in pregnant women with hereditary thrombophilia to improve live birth rate: meta-analysis of randomized controlled trials. Arch Gynecol Obstet. 2015;293(1):81–6.
  1. Alfarawati S, Fragouli E, Colls P, et al. The relationship between blastocyst morphology, chromosomal abnormality, and embryo gender. Fertil Steril. 2011;95(2):520–4.
  1. Alpha Scientists in Reproductive Medicine and ESHRE Special Interest Group of Embryology. The Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting. Hum Reprod. 2011;26(6):1270–83.
  1. Arce JC, Ziebe S, Lundin K, et al. Interobserver agreement and intraobserver reproducibility of embryo quality assessments. Hum Reprod. 2006;21(8):2141–8.
  1. Armstrong S, Arroll N, Cree LM, et al. Time-lapse systems for embryo incubation and assessment in assisted reproduction. Cochrane Database Syst Rev. 2015;(2):CD011320.
  1. Mastenbroek S, Twisk M, van der Veen F, et al. Preimplantation genetic screening: a systematic review and meta-analysis of RCTs. Hum Reprod Update. 2011;17(4):454–66.
  1. Twisk M, Mastenbroek S, van Wely M, et al. Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection. Cochrane Database Syst Rev. 2006;(1):CD005291.
  1. Fiorentino F, Biricik A, Bono S, et al. Development and validation of a next-generation sequencing-based protocol for 24-chromosome aneuploidy screening of embryos. Fertil Steril. 2014;101(5):1375–82.
  1. Fiorentino F, Bono S, Biricik A, et al. Application of next-generation sequencing technology for comprehensive aneuploidy screening of blastocysts in clinical preimplantation genetic screening cycles. Hum Reprod. 2014;29(12):2802–13.
  1. El-Toukhy T, Sunkara S, Khalaf Y, et al. Local endometrial injury and IVF outcome: a systematic review and meta-analysis. Reprod Biomed Online. 2012;25(4):345–54.
  1. Nastri CO, Lensen S, Polanski L, et al. Endometrial injury and reproductive outcomes: there's more to this story than meets the horse's blind eye. Hum Reprod. 2015;30(3):749.
  1. Potdar N, Gelbaya T, Nardo LG, et al. Endometrial injury to overcome recurrent embryo implantation failure: a systematic review and meta-analysis. Reprod Biomed Online. 2012;25(6):561–71.
  1. Simon C, Bellver J. Scratching beneath ‘The Scratching Case’: systematic reviews and meta-analyses, the back door for evidence-based medicine. Hum Reprod. 2014;29(8):1618–21.
  1. Bontekoe S, Heineman MJ, Johnson N, et al. Adherence compounds in embryo transfer media for assisted reproductive technologies. Cochrane Database Syst Rev. 2014;(2):CD007421.
  1. Martins WP, Rocha IA, Ferriani RA, et al. Assisted hatching of human embryos: a systematic review and meta-analysis of randomized controlled trials. Hum Reprod Update. 2011;17(4):438–53.
  1. Carney SK, Das S, Blake D, et al. Assisted hatching on assisted conception in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI). Cochrane Database Syst Rev. 2012;12:CD001894.
  1. Butts SF, Owen C, Mainigi M, et al. Assisted hatching and intracytoplasmic sperm injection are not associated with improved outcomes in assisted reproduction cycles for diminished ovarian reserve: an analysis of cycles in the United States from 2004 to 2011. Fertil Steril. 2014;102(4):1041–7.