Comprehensive evidence on assisted reproductive technologies

  • By: Annika Strandell
  • On: January 14, 2014, 16:00
thumbnail image: Comprehensive evidence on assisted reproductive technologies

Last year saw the publication of an overview of Cochrane Reviews on the topic of assisted reproductive technology (ART).[1] There are currently 14 overviews and 24 overview protocols published in the Cochrane Database of Systematic Reviews (CDSR). As the number of published systematic reviews increases, it is likely that the number of overviews will also increase. Overviews are important to facilitate decision-making for patients and doctors, as well as for guideline panels, policy-makers, and caregivers. The ART overview is by far the largest overview to date, with 54 Cochrane Reviews, and presents a narrative description of each stage of the ART pathway.

Infertility is defined as failure to conceive after one year of trying. At least 10% of couples will experience infertility at some point,[2] and many will seek treatment in the form of in vitro fertilisation (IVF) or another type of ART. If you do need fertility treatment such as IVF then you would hope that you are getting the best available care. Fertility treatments are complex and costly, and the stakes are high.

A cycle of assisted reproduction includes several steps: down-regulation; ovulation induction; triggering of ovulation; oocyte retrieval; fertilisation; embryo transfer; and luteal phase support.

Each step should be supported by good evidence from well-designed studies. In the ART overview, the Cochrane Menstrual Disorders and Subfertility Group ( considered the evidence from all Cochrane Reviews of ART published in CDSR. A total of 54 systematic reviews relating to all stages of the ART cycle were included. In addition, 15 protocols and two suggested titles were identified for possible future inclusion. All 54 reviews were assessed for quality using the AMSTAR tool,[3] and all were found to be of high methodological quality. However, the quality of the evidence depends on the quality of the included studies, which vary in their limitations and risk of bias. Another quality aspect is how often the reviews are updated. In this overview, 32 of the 54 reviews had conducted a literature search within the past three years.

The objective of the overview was to summarise the evidence from Cochrane Reviews on procedures and treatment options available to couples with infertility undergoing ART. Reviews of IVF and intracytoplasmic sperm injection (ICSI) were included, but reviews of intrauterine insemination and ovulation induction as a sole procedure were not. The primary outcome for the overview was live birth, and the most important complications to consider were ovarian hyperstimulation syndrome (OHSS) and multiple births.

The quality of evidence was assessed for each outcome in the separate reviews according to the GRADE system.[4] In this overview the quality of evidence varied widely by review and by outcome, ranging from very low quality (the estimate of effect is very uncertain) to high quality (future studies are very unlikely to change the confidence in the estimate of effect).

Thirty of the reviews identified interventions that were effective (n=18) or promising (n=12), 13 reviews identified interventions that were ineffective (n=3) or possibly ineffective (n=10), and 11 reviews found insufficient evidence to draw conclusions. Thus, 21 reviews support us with firm conclusions on how to perform several steps in the IVF/ICSI procedures and 33 identify knowledge gaps and implications for research. This should be interesting reading for everyone who is involved in ART. It is certainly a source that could be used for possible improvements in IVF or ICSI programmes.

Among those 18 reviews identifying effective interventions, some examples from the different steps in ART are:

  • Metformin in polycystic ovary syndrome reduces the risk of OHSS.[5]
  • Laparoscopic tubal occlusion is an alternative to salpingectomy for improving IVF pregnancy rates in women with hydrosalpinges.[6]
  • Recombinant follicle-stimulating hormone (FSH) is equally effective as urinary FSH.[7]
  • Urinary human chorionic gonadotropin (hCG) is favoured over recombinant hCG for triggering ovulation.[8]
  • Low oxygen concentrations for embryo culture is associated with increased live birth rates.[9]
  • Cumulative live birth rates after single embryo transfer followed by a frozen/thawed transfer are comparable with that after a double embryo transfer.[10]
  • Using ultrasound guided transfer increases clinical pregnancy rates compared with 'clinical touch'.[11]

These conclusions have to be considered in relation to the quality of the evidence, which varies from low to high in these examples.

Another aspect of effective interventions is that the effect might be positive for one outcome and negative for another. An example is the review on gonadotropin-releasing hormone agonist versus hCG for oocyte triggering in antagonist ART cycles.[12] The intervention results in a reduced risk of OHSS but also in a reduced rate of live birth. Most patients would favour an increased chance of a live birth, but for others it might be important to avoid OHSS. Thus, the recommendation may vary, depending on individual values and preferences.

Two ineffective interventions based on moderate quality of evidence were follicular flushing during oocyte retrieval and pre-implantation genetic screening for abnormal numbers of chromosomes in women with advanced age.[13,14] Time to discard those procedures where they are still in use! Coasting to prevent OHSS is also classified as an ineffective intervention,[15] but the quality of evidence is very low, so our confidence in the estimate of effect is very low. This conclusion, based on a single conference abstract, calls for more research.

High-quality evidence was found in seven reviews for three outcomes (Table 1). The largest studies are those including comparisons between different drugs, reflecting the involvement and interest of pharmaceutical companies. For example, the review of recombinant versus urinary gonadotrophin for ovarian stimulation in ART cycles included more than 9000 couples.[7] It is interesting to study the subgroup analyses by sponsor: there is a favourable result for the gonadotrophin produced and marketed by the sponsor. The total effect is negative, indicating equal efficacy. There is no need for further trials to address this research question, but the subgroup analyses do raise concern about the risk of publication bias.

Table 1. Reviews and outcomes with high-quality evidence from an overview of Cochrane Reviews of ART[1]

Reviews and outcomes with high-quality evidence from an overview of Cochrane reviews of ART

This overview provides the most up-to-date evidence from randomised controlled trials for ART cycles. The use of the evidence from this overview to guide clinical practice should help to improve live birth rates and reduce rates of multiple pregnancy, cycle cancellation, and OHSS. Let us hope that medical societies and guideline groups use this overview to guide their clinical practice. The European Society of Human Reproduction and Embryology (ESHRE; is one such group that is working with Cochrane on developing guidance.

Annika Strandell

Associate professor, Sahlgrenska Academy, University of Gothenburg, Sweden

How to cite: Strandell A. Comprehensive evidence on assisted reproductive technologies [editorial]. Cochrane Database of Systematic Reviews 2014;(1):ED000077.


1. Farquhar C, Rishworth JR, Brown J, Nelen WLDM, Marjoribanks J. Assisted reproductive technology: an overview of Cochrane Reviews. Cochrane Database of Systematic Reviews 2013;8:CD010537.

2. Snick HK, Snick TS, Evers JL, Collins JA. The spontaneous pregnancy prognosis in untreated subfertile couples: the Walcheren primary care study. Human Reproduction 1997;12(7):1582-8.

3. Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Medical Research Methodology 2007;7:10.

4. Guyatt GH, Oxman AD, Vist G, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schünemann HJ, for the GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336:924-6.

5. Tso LO, Costello MF, Andriolo RB, Freitas V. Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. Cochrane Database of Systematic Reviews 2009;2:CD006105.

6. Johnson N, van Voorst S, Sowter MC, Strandell A, Mol BWJ. Surgical treatment for tubal disease in women due to undergo in vitro fertilisation. Cochrane Database of Systematic Reviews 2010;1:CD002125.

7. van Wely M, Kwan I, Burt AL, Thomas J, Vail A, Van der Veen F, et al. Recombinant versus urinary gonadotrophin for ovarian stimulation in assisted reproductive technology cycles. Cochrane Database of Systematic Reviews 2011;2:CD005354

8. Youssef MAFM, Al-Inany HG, Aboulghar M, Mansour R, Abou-Setta AM. Recombinant versus urinary human chorionic gonadotrophin for final oocyte maturation triggering in IVF and ICSI cycles. Cochrane Database of Systematic Reviews 2011;4:CD003719

9. Bontekoe S, Mantikou E, van Wely M, Seshadri S, Repping S, Mastenbroek S. Low oxygen concentrations for embryo culture in assisted reproductive technologies. Cochrane Database of Systematic Reviews 2012;7:CD008950.

10. Pandian Z, Marjoribanks J, Ozturk O, Serour G, Bhattacharya S. Number of embryos for transfer following in-vitro fertilisation or intra-cytoplasmic sperm injection. Cochrane Database of Systematic Reviews 2013;(7):CD003416.

11. Brown J, Buckingham K, Abou-Setta AM, Buckett W. Ultrasound versus 'clinical touch' for catheter guidance during embryo transfer in women. Cochrane Database of Systematic Reviews 2010;1:CD006107.

12. Youssef MAFM, Van der Veen F, Al-Inany HG, Griesinger G, Mochtar MH, Aboulfoutouh I, et al. Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist assisted reproductive technology cycles. Cochrane Database of Systematic Reviews 2011;1:CD008046

13. Wongtrangan S, Vutyavanich T, Brown J. Follicular flushing during oocyte retrieval in assisted reproductive techniques. Cochrane Database of Systematic Reviews 2010;9:CD004634 dx.doi.org10.1002/14651858.CD004634.pub2

14. Twisk M, Mastenbroek S, van Wely M, Heineman MJ, Van der Veen F, Repping S. Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection. Cochrane Database of Systematic Reviews 2006;1:CD005291.

15. D'Angelo A, Brown J, Amso NN. Coasting (withholding gonadotrophins) for preventing ovarian hyperstimulation syndrome. Cochrane Database of Systematic Reviews 2011;6:CD002811.

16. Duffy JMN, Ahmad G, Mohiyiddeen L, Nardo LG, Watson A. Growth hormone for in vitro fertilization. Cochrane Database of Systematic Reviews 2010;1.CD000099.

17. Kwan I, Bhattacharya S, McNeil A. Monitoring of stimulated cycles in assisted reproduction (IVF and ICSI). Cochrane Database of Systematic Reviews 2008;2:CD005289.

18. Kroon B, Hart RJ, Wong BMS, Ford E, Yazdani A. Antibiotics prior to embryo transfer in ART. Cochrane Database of Systematic Reviews 2012;3:CD008995.

Competing interests: The author has completed the Unified Competing Interest form at (available on request) and declares no conflicts of interest.

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