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 (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
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.
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
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.
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 (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.
- 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.
- 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.
- Nagels HE, Rishworth JR, Siristatidis CS, et al. Androgens (dehydroepiandrosterone or testosterone) for women undergoing assisted reproduction. Cochrane Database Syst Rev. 2015;(11):CD009749.
- 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.
- 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.
- 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.
- 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.
- Duffy JM, Ahmad G, Mohiyiddeen L, et al. Growth hormone for in vitro fertilization. Cochrane Database Syst Rev. 2010;(1):CD000099.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Seshadri S, Sunkara SK. Low-molecular-weight-heparin in recurrent implantation failure. Fertil Steril. 2011;95.
- 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.
- 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.
- 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.
- 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.
- Arce JC, Ziebe S, Lundin K, et al. Interobserver agreement and intraobserver reproducibility of embryo quality assessments. Hum Reprod. 2006;21(8):2141–8.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.