No common denominator: a review of outcome measures in IVF RCTs.
Which outcome measures are reported in RCTs for IVF?



Many combinations of numerator and denominator are in use, and are often employed in a manner that compromises the validity of the study.



The choice of numerator and denominator governs the meaning, relevance and statistical integrity of a study's results. RCTs only provide reliable evidence when outcomes are assessed in the cohort of randomised participants, rather than in the subgroup of patients who completed treatment.



Review of outcome measures reported in 142 IVF RCTs published in 2013 or 2014.



Trials were identified by searching the Cochrane Gynaecology and Fertility Specialised Register. English-language publications of RCTs reporting clinical or preclinical outcomes in peer-reviewed journals in the period 1 January 2013 to 31 December 2014 were eligible. Reported numerators and denominators were extracted. Where they were reported, we checked to see if live birth rates were calculated correctly using the entire randomised cohort or a later denominator.



Over 800 combinations of numerator and denominator were identified (613 in no more than one study). No single outcome measure appeared in the majority of trials. Only 22 (43%) studies reporting live birth presented a calculation including all randomised participants or only excluding protocol violators. A variety of definitions were used for key clinical numerators: for example, a consensus regarding what should constitute an ongoing pregnancy does not appear to exist at present.



Several of the included articles may have been secondary publications. Our categorisation scheme was essentially arbitrary, so the frequencies we present should be interpreted with this in mind. The analysis of live birth denominators was post hoc.



There is massive diversity in numerator and denominator selection in IVF trials due to its multistage nature, and this causes methodological frailty in the evidence base. The twin spectres of outcome reporting bias and analysis of non-randomised comparisons do not appear to be widely recognised. Initiatives to standardise outcome reporting, such as requiring all effectiveness studies to report live birth or cumulative live birth, are welcome. However, there is a need to recognise that early outcomes of treatment, such as stimulation response or embryo quality, may be appropriate choices of primary outcome for early phase studies.



J.W. is funded by a Doctoral Research Fellowship from the National Institute for Health Research. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. J.W. also declares that publishing research is beneficial to his career. J.W. and A.V. are statistical editors, and M.S. is Information Specialist, for the Cochrane Gynaecology and Fertility Group, although the views expressed here are not necessarily those of the group. D.R.B. is funded by the NHS as Scientific Director of a clinical IVF service. The authors declare no other conflicts of interest.
Centre for Biostatistics, Institute of Population Health, Manchester Academic Health Science Centre (MAHSC), University of Manchester, Manchester M13 9PL, UK jack.wilkinson@manchester.ac.uk.|Research & Development, Salford Royal NHS Foundation Trust , Salford M6 8HD, UK.
Jack
J
Wilkinson
Centre for Biostatistics, Institute of Population Health, Manchester Academic Health Science Centre (MAHSC), University of Manchester, Manchester M13 9PL, UK.
Stephen A
SA
Roberts
Cochrane Gynaecology and Fertility, The University of Auckland, Auckland City Hospital , Auckland 1142, New Zealand.
Marian
M
Showell
Department of Reproductive Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre (MAHSC) , Manchester M13 9WL, UK.
Daniel R
DR
Brison
Centre for Biostatistics, Institute of Population Health, Manchester Academic Health Science Centre (MAHSC), University of Manchester, Manchester M13 9PL, UK.|Research & Development, Salford Royal NHS Foundation Trust , Salford M6 8HD, UK.
Andy
A
Vail
D001723:Birth Rate; D005260:Female; D005307:Fertilization in Vitro / Q000379:methods*; D006801:Humans; D050498:Live Birth; D017063:Outcome Assessment, Health Care; D010062:Ovulation Induction / Q000379:methods*; D011247:Pregnancy; D018873:Pregnancy Rate; D012107:Research Design; D016896:Treatment Outcome
CROWN; IMPRINT; IVF; assisted reproduction; core outcomes; infertility trial; live birth; ongoing pregnancy; outcome measures; reporting guidelines
Hum Reprod. 2004 Sep;19(9):1936-8
15217998
Hum Reprod. 2003 May;18(5):1000-4
12721176
Hum Reprod. 2014 Oct 10;29(10):2075-82
25217611
Hum Reprod. 2016 Feb;31(2):249-51
26724801
Hum Reprod. 2010 Jan;25(1):9-13
19819894
CMAJ. 2004 Sep 28;171(7):735-40
15451835
N Engl J Med. 2007 Jan 25;356(4):379-86
17251534
Hum Reprod. 2004 Nov;19(11):2442-4
15358719
Trials. 2009 May 20;10:33
19454041
Fertil Steril. 2011 Jun 30;95(8):2527-30
21435640
JAMA. 1991 Jul 3;266(1):93-8
2046134
Hum Reprod. 2004 Jan;19(1):3-7
14688149
Hum Reprod. 2014 Sep;29(9):1846-50
25006207
Fertil Steril. 2011 Jul;96(1):40-6
21621770
Hum Reprod. 2005 Aug;20(8):2362-3; author reply 2364-5
16024540
Fertil Steril. 2013 Mar 15;99(4):963-9
23312225
BJOG. 2014 Sep;121(10):1181-2
24889142
Hum Reprod. 2014 Jun;29(6):1211-7
24713124
Fertil Steril. 2014 May;101(5):1203-4
24786739
Hum Reprod Update. 2014 May-Jun;20(3):370-85
24430863
Hum Reprod Update. 2014 Jan-Feb;20(1):124-40
24077980
CMAJ. 2001 Nov 13;165(10):1339-41
11760981
Syst Rev. 2016 Jan 20;5:11
26792080