Medically assisted reproduction in the context of time
Scholten, I.
Publication date
2015
Document Version
Final published version
Link to publication
Citation for published version (APA):
Scholten, I. (2015). Medically assisted reproduction in the context of time.
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Reporting multiple cycles in
trials on medically assisted
reproduction
Submitted
Irma Scholten Miriam Braakhekke Jacqueline Limpens Peter G.A. Hompes Fulco van der Veen Ben W.J. Mol Judith Gianotten
ABSTRACT
Trials assessing effectiveness in medically assisted reproduction (MAR) should preferably be designed to study the desired effect over multiple cycles, as this reflects clinical practice and captures the relevant perspective for the couple. The aim of this study was to assess to what extent multiple cycles are reported in MAR trials and to identify any trial characteristics associated with reporting multiple cycles. We collected a sample of RCTs on MAR published in the periods 1999/2000, 2004/2005 and 2009/2010 in 11 pre-specified peer-reviewed journals. 223 trials -172 on in vitro fertilization (IVF), 32 on intrauterine insemination (IUI) and 19 on ovulation induction (OI)- were included. Of all 223 RCTs, 41 (18%) reported on multiple cycles. Reporting of multiple cycles was significantly more common in trials on IUI (n=18, 56%) and OI (n=12, 63%) compared to trials on IVF (n= 11, 7%, p<0.01).
Trials on IVF that used live birth as primary outcome reported significantly more often on multiple cycles (OR 11.7 (1.8-73)). Trials designed to compare protocol variations reported less often multiple cycles (OR 0.06 (0.005-0.65)). In trials on IUI and OI, characteristics influencing the reporting of multiple cycles could not be identified.
Our analysis shows that the majority of RCTs on MAR, especially those on IVF, do not report cumulative pregnancy rates over a longer time horizon. Since infertile couples usually undergo multiple cycles, the clinical significance of these trials is limited.
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INTRODUCTION
Approximately 10% of couples who wish to conceive fail to do so within one year of unprotected intercourse (1). These couples may choose to enter fertility care and, if indicated, receive Medically Assisted Reproduction (MAR). Decisions on adequate treatment for subfertile couples should be based on sound knowledge, which is ideally generated by randomized clinical trials (RCTs). RCTs are, in case of equipoise, widely accepted as the most robust method to evaluate effectiveness of an intervention (2,3).
Just as for natural conception, in medically assisted reproduction cumulative pregnancy rates rise with additional cycles (1,4). One treatment cycle can therefore not be seen as independent and effectiveness can only be assessed when multiple cycles and -in some instances- even multiple treatments are reported (5). In this respect, the cumulative live birth over a given period of time instead of per cycle success has been proposed as the primary outcome of trials (6). To capture overall chances on a live birth, RCTs on MAR should reflect this (1,4).
This issue has been emphasized by a recent editorial in the BMJ that advised studies on MAR with pregnancy or live birth rates as the outcome of interest to report cumulative rates with a follow-up period of at least one year (7). This would greatly enhance the clinical significance of trials.
It is unclear to what extent this approach is actually used in studies on MAR. Therefore, we systematically analysed a representative sample of RCTs published in the past decade, and assessed whether a multiple cycle approach was used in these RCTs, and which trial characteristics were associated with reporting multiple cycles.
METHODS
To create a representative database with RCTs on MAR, we conducted a systematic Medline search to RCTs published in the years 1999/2000, 2004/2005 or 2009/2010. By choosing five-year intervals, we were able to describe changes over time. We chose six journals in reproductive medicine and obstetrics and gynaecology with a high impact factor (Human Reproduction, Fertility and Sterility, Reproductive BioMedicine Online, British Journal of Obstetrics and Gynaecology, American Journal of Obstetrics and Gynecology, Obstetrics and Gynecology), and five high ranked general journals (New England Journal of Medicine, the Lancet, Journal of the American Medical Association, British Medical Journal and Plos Medicine).
Search methods
An information specialist (JL) identified RCTs on MAR by electronically searching OVID MEDLINE for the selected journals and the chosen publication years in combination with two broad search filters:
one for RCTs and one for fertility treatments. In the filter fertility treatment MAR was included, as well as the separate treatments IVF, IUI, ovulation induction and their synonyms. The RCT filter was adapted from the sensitivity- and precision-maximizing version of the Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE (8,9). The search filter for fertility treatments was subjectively derived, using a reference set of six random publication years of the above-mentioned reproductive medicine journals combined with the broad RCT-filter. (Appendix 1 for search filters) Selection of RCTs
We selected RCTs by first screening title and abstract on eligibility and then by reading the remaining RCTs full text.We included studies if they performed an RCT on effectiveness of MAR with pregnancy as an outcome. For this study, we considered In Vitro Fertilisation (IVF), intrauterine insemination (IUI) and ovulation induction (OI) as MAR (10). Pragmatic trials, which are designed to evaluate the effectiveness of interventions in real-world settings, were included. Explanatory trials, which aim to test whether an intervention works under optimal situations were excluded (11). We also excluded studies with a cross-over design as there is empirical evidence that they produce biased results (12). For the current study, two researchers (IS and MB) selected the appropriate studies. Data extraction
For all included RCTs, we extracted general data on journal and year of publication. Single cycle was defined as reporting one treatment cycle. Multiple cycles were defined as reporting two or more consecutive treatment cycles. In addition to our main outcome, i.e. reporting multiple cycles, we extracted data on whether the study was single- or multicentre, on sample size, type of funding, , type of comparison and primary outcome . We hypothesized that these characteristics were associated to the reporting of multiple cycles. For type of comparison we distinguished comparisons between various treatment regimes, -defined as trials in which different treatment protocols within one treatment modality were tested, like different forms of stimulation or different types of progesterone in the luteal phase in trials on IVF-, comparisons between two separate treatments, -defined as trials in which two different treatment modalities were tested, for example IVF versus IUI within a certain patient category- and comparisons with no treatment. For primary outcome we distinguished number of oocytes/follicles, fertilization, biochemical pregnancies, clinical pregnancies, ongoing pregnancies, live birth and other outcomes, not directly related to pregnancy.. All data were analysed separately for IVF, IUI and OI studies. For type of funding, we distinguished commercial funding, non-commercial funding, both commercial and non-commercial funding and funding not reported.
Statistical analysis
We described numbers and percentages of trials using single and multiple cycles per type of MAR. A linear-by-linear association was performed to test for trend in the duration of treatment in the five-year intervals. Chi-square test for trend was used to test differences between the use of multiple cycles for
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the studied trial characteristics. When a significant difference was found in a characteristic, in depth analysis with chi-square test using dummy variables was performed to identify which characteristic caused the difference. Calculations were performed with SPSS® (SPSS Inc., Chicago, IL).
RESULTS
By combining a broad search filter for RCTs and for studies on MAR we found 989 records in the selected publication years in the 11 pre-selected peer reviewed papers. After screening for eligibility on title and abstract, 370 articles were judged full text, of which 223 full-text articles were identified that met the inclusion criteria (Figure 1). 214 of the 223 studies (96%) were published in Human Reproduction, Fertility and Sterility and RBM Online.
989 records
370 records
Screening title and abstract
300 records
27 no RCT 7 RCT with cross-over design
22 not on IVF, IUI or OI 12 pregnancy not an outcome 1 not concerning subfertile couples
1 fulltext not available
223 records
19 explanatory RCT 58 not immediately pregnancy related
Fertility and Sterility 1999-2000: N=20 2004-2005: N=29 2009-2010: N=49 Human Reproduction 1999-2000: N=32 2004-2005: N=37 2009-2010: N=15 RBM online 1999-2000: N=0 2004-2005: N=16 2009-2010: N=16 Other Journals 1999-2000: N=2 2004-2005: N=5 2009-2010: N=2
Data on the number of cycles reported per type of MAR is summarized in table 1. Of the 223 trials included, 172 studied IVF (77%), 32 studied IUI (14%) and 19 (9%) studied OI. Multiple cycles were used in 18% of all RCTs and was significantly more common in trials on IUI (n=18, 56%) and OI (n=12, 63%) than in those on IVF (n= 11, 7%) (p<0.01). A trend over time in reporting multiple cycle follow up could not be identified (p=0.59).
Table 1. Single and multiple cycle follow up in RCTs on MAR
Number of cycles included in analysis
1 cycle 2-6 cycles 7-12 cycles >12 cycles
n= 182 n= 34 n= 5 n= 2
IVF/ICSI (n= 172) 161 (94) 10 (6) 0 1 (1)
IUI (n= 32) 14 (44) 17 (53) 0 1 (3)
OI (n= 19) 7 (37) 7 (37) 5 (26) 0
NB Cells are counts (percentages within treatment module) Percentage do not add up to 100 due to rounding
The trial characteristics and their association with single or multiple cycles of treatment are listed in table 2. Trials comparing protocol variations reported less often on multiple cycles as trials studying other comparisons (OR 0.06 (0.005-0.65)). IVF trials using live birth as primary outcome reported
Table 2. Trial characteristics and the association with single and multiple cycle follow up
IVF/ICSI IUI OI
Single Multiple p-value Single Multiple p-value Single Multiple p-value n= 161 n= 11 n= 14 n= 18 n= 7 n= 12 Year of publication 0.19 0.84 0.71 1999-2000 41 4 3 5 0 1 2004-2005 62 6 5 7 3 4 2009-2010 58 1 6 6 4 7 Journal of Publication <0.01# 0.65 0.53 NEJM 0 1 0 1 0 0 the Lancet 0 0 0 1 0 0 BMJ 0 0 0 1 0 1 Human Reproduction 62 7 6 4 1 4
Fertility and Sterility 70 3 7 9 4 5
RBM online 27 0 1 1 1 2
AJOG 0 0 0 1 1 0
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IVF/ICSI IUI OI
Single Multiple p-value Single Multiple p-value Single Multiple p-value n= 161 n= 11 n= 14 n= 18 n= 7 n= 12 Multicenter study 0.05 0.68 0.31 Yes 32 5 4 4 4 4 No 129 6 10 14 3 8 Sample size 0.93 0.51 0.12 <100 50 3 5 5 1 6 100-500 97 7 8 12 6 6 500-1000 10 1 0 1 0 0 >1000 4 0 1 0 0 0
Type of comparison under study <0.01* 0.7 0.23
Protocol variations 159 9 13 16 7 8 Comparison of two separate treatments 2 1 1 2 0 1 Comparison with no treatment 0 1 0 0 0 0 Other 0 0 0 0 0 3
Primary outcome under study 0.02^ 0.35 0.27
Number of oocytes/
follicles 30 2 3 0 0 0
Fertilization 12 0 n.a n.a n.a n.a
Biochemical pregnancy 6 0 1 2 1 1
Clinical pregnancy 68 4 6 12 0 4
Ongoing pregnancy 17 0 2 1 0 1
Livebirth 5 3 1 1 0 0
Other eg not direct
pregnancy related 23 2 1 2 6 6
Funding 0.22 0.45 0.46
Yes, commercial 25 1 1 0 1 0
Yes, non-commercial 14 2 0 2 0 2
Yes, both commercial and
non-commercial 2 1 0 1 0 1
No 11 0 1 1 1 1
Not reported 109 7 12 14 5 8 # In depth analysis; Multiple cycle analysis is significantly more seen in IVF/ICSI studie published in NEJM (OR 29.5 (1.9-898))
* In depth analysis: Multiple cycle analysis is signifcantly less seen in IVF/ICSI studies that study protocol variations (OR 11.7 (1.8-73))
^ In depth analysis: Multiple cycle analysis is signficantly more seen in IVF/ICSI studies with livebirth as primary outcome (OR 0.06 (0.005-0.65))
more often on multiple cycles of treatment compared to trials with another primary outcome (OR 11.7 (1.8-73)). Year of publication, multi-or single center trial, sample size and the type of funding were not significantly associated with the use of either single or multiple cycles of treatment (P-values 0.19, 0.05, 0.93, and 0.22 respectively). For trials on IUI and OI, no significant associations could be identified.
DISCUSSION
This systematic analysis of RCTs on MAR shows that the majority of trials do not report multiple treatment cycles. This is especially true for trials on IVF, where only 7% of trials studied multiple cycles. In IUI and OI trials multiple cycles were significantly more used, in 56% and 63% respectively. In IVF trials, studies on protocol variations were identified as studies that were associated with not reporting multiple cycles, while live birth as primary outcome was associated with reporting multiple cycles. In IUI and OI trials, such characteristics could not be identified, presumably because of the small number of trials on these treatments. The majority of RCTs in MAR, especially those on IVF, do not report on cumulative pregnancy chances and therefore do no capture the full chance on a live birth. Generalisability of the data generated by these studies is therefore problematic.
The current study is by our knowledge the first to assess to what extent multiple cycles are studied in trials on MAR. Although we did not include all published RCTs on the selected treatments, we provide a representative overview as we collected a systematic sample of RCTs in high impact journals in general and reproductive medicine. The number of trials on IUI and OI was quite small in the selected journals, which makes it difficult to draw firm conclusions for these treatments. The trials included in the current study all aimed to study the effectiveness of MAR. For these pragmatic trials, it is imperative to report multiple cycles of treatment.
It has already been acknowledged ten years ago that randomization should be performed at the first cycle and the allocation should be continued thereafter, since a per cycle analysis or a cross-over design in RCTs on MAR may lead to an overestimation of treatment success (13). Multiple cycle analysis reflects how a treatment works in daily practice. Couples might switch treatments between cycles, natural conception can occur or couples can drop out of treatment as is illustrated in cohort studies on patient flow over a certain treatment period (14).
There may be several reasons why investigators continue to design and execute single cycle trials. First, investigators might consider multiple cycles not relevant for their topic and assume -erroneously - that data derived from a single cycle provide enough information to implement a treatment. This is especially the case for IVF trials comparing variations of a protocol within a treatment regimen.
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Indeed, our study showed that single cycles are significantly more common in this type of trials. Second, single cycle studies might include faster, thus facilitating swift completion of trials for a low price. Recruitment for clinical trials often takes longer than expected and therewith, trials are at risk of not reaching the required sample size, thus lacking precision in estimating the magnitude of the effect of a treatment (15). Third, as overestimation of treatment success may lead to performing more treatments, companies making money on these treatments might benefit from single cycle trials and thus may be prone to perform these. Finally, patients may be more willing to participate in a single cycle trial, as they are only bound to the trials’ rules for one cycle.
The solution is to perform multicenter trials, in which a high number of participants can be gathered and followed for a longer time, thereby providing more useful information within the same time span. Participation in multicenter trials is also associated with a better knowledge of trial results and an improvement in the implementation of the results (16). Indeed, a multicenter trial with multiple cycles of treatment might be more difficult to conduct, but a single center trial, the results of which cannot be implemented in daily practice is a waste of effort and resources.
In conclusion, although acknowledged as an important feature for RCTs on MAR treatments, multiple cycle treatment is reported in a minority of pragmatic trials on IVF and half of all pragmatic trials on IUI and OI which were designed to improve patient care. This is important information for clinicians, as the results of the single cycle trials they implement in daily practice might not represent the best estimate of the truth.
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APPENDIx
Database(s): Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) 1946 to Present Search Strategy:
# Searches Results
1 (randomized controlled trial or controlled clinical trial).pt. or random allocation/ or trial.ti,ot. or (randomi?ed or placebo* or randomly or ((singl* or doubl* or treb* or tripl*) adj (blind*3 or mask*3)) or (random adj2 allocated)).tw,ot.
783950
2 animals/ not humans/ 3693569
3 ((comment or editorial or historical-article or review or practice guideline or meta-analysis) not (randomized controlled trial or controlled clinical trial)).pt.
2784485
4 1 not (2 or 3) 619195
5 (human reproduction or “fertility and sterility” or (“bjog an international journal of obstetrics & gynaecology” or “british journal of obstetrics & gynaecology”) or “american journal of obstetrics & gynecology” or obstetrics & gynecology).jn.
102780
6 (“new england journal of medicine” or lancet or jama or bmj or “plos medicine public library of science”).jn.
310337 7 (“2010” or “2009” or “2005” or “2004” or “2000” or “1999”).yr. 3833379
8 (5 or 6) and 7 57339
9 4 and 8 4307
10 exp Pregnancy Rate/ 13532
11 ((implantation or fertil* or delivery) adj2 rate*).tw. 13609
12 (achieve adj3 pregnancy).tw,ot. 697
13 ((succesful or clinical or ongoing or spontaneous) adj (pregnan* or conception*)).tw. 5793
14 (pregnanc* adj3 (rate* or outcome*)).tw. 33845
15 ((childbirth* or birth or births or reproductive) adj2 (rate* or outcome*)).tw. 12589
16 live birth*.tw. 13303
17 ((fertil* or infert*) adj3 (treat* or therap* or success*)).tw. 10903
18 (subfertil* or sub-fertil*).tw. 3435
19 ((unexplained or idiopathic or primary) adj3 infertil*).tw. 3530 20 (Time Factors/ or time*.tw,ot.) and (Coitus/ or (coital or coitus or intercourse).tw,ot.) 4914
21 exp Infertility/dt, su, th 17056
22 exp Reproductive Techniques, Assisted/ 50502
23 assisted reproduc*.tw,ot,kw. 8212
24 (reproduct* techni* or reproduct* technolog*).tw,ot,kw. 6704
25 insemin*.tw,ot. 14170
26 (IUI or siui or (iui* and (ferti* or infertil*))).tw,ot. 1123
27 (husband adj5 (sperm or semen)).tw,ot. 117
28 (sperm adj5 donation).tw,ot. 173
29 ((sperm or sperm) adj1 donor).tw,ot. 500
30 ICSI.tw,ot. 5205
# Searches Results
32 IVF.tw,ot. 15413
33 ((in vitro or test-tube) adj2 fertil*).tw. 17695
34 test tube bab*.tw. 152
35 embryo implantation/ 8738
36 ((gamete* or zygote* or blastocyst* or oocyt* or embryo*) adj4 (transfer* or implant* or injection*)).tw. 22417
37 Varicocele/dt, su, th 1959
38 (varicoc?ele* adj5 surg*).tw. 596
39 varicoc?electom*.tw,ot,kw. 778
40 exp Sterilization Reversal/ 1354
41 (sterili?at* adj3 revers*).tw,ot. 416
42 (refertili* or refertil*).tw. 108
43 vasovasostom*.tw,ot. 524
44 (vasectomy adj3 revers*).tw,ot. 398
45 ((fallopian tube* or tubal or cornual or vas) adj5 (reanastomos?s or anastomos?s)).tw,ot. 465 46 ((tubal or fallopian tube* or tubo or tubo-periton*) adj2 (infertil* or patency or factor or flushing or
perfusion* or catheter* or cannulat*)).tw.
2251
47 hydrotubation.tw. 158
48 ((tubal or fallopian tube* or uterine) adj transfer*).tw. 139 49 ((intrafallopian or intra-fallopian) adj4 transfer*).tw. 762 50 ((transabdominal or transvaginal) adj2 GIFT).tw. 5
51 sperm perfusion*.tw. 31
52 (ZIFT or MIFT).tw,ot. 107
53 ((ovarian or ovary or ovaries or ovulat*) adj3 (stimula* or induc*)).tw. 14031 54 (OHSS or ovarian hyperstimul*).tw. or Ovarian Hyperstimulation Syndrome/ 3963
55 assisted hatching.tw. 265
56 fertility agents/ or exp fertility agents, female/ or fertility agents, male/ 18173 57 exp gonadotropins/ or exp gonadotropin-releasing hormone/ 129954 58 ((recombinant or rec) adj3 (HCG or Chorionic Gonadotropin* or FSH or follicle stimulating
hormone* or LH or luteinizing hormone*)).tw,ot.
1625 59 (rFSH or r-FSH or rHCG or r-HCG or rLH or r-LH).tw,ot,kw. 840 60 (GNRH or LHFSHRH or GN-RH or LHRH or LH-RH or LFRH or gonadorelin or dirigestran
or luliberin or kryptocur or cystorelin or factrel or gonadoliberin).tw.
26100 61 ((luteini?ing hormone or lhfsh or LH or FSH or gonadotropin or GN) adj2 releasing hormone*).tw. 16647 62 (clomiphen* or clomifen* or clomide or clomid or klostilbegit or chloramiphene or serophene
or zuclomiphene or zuclomifene or dyneric or enclomiphen* or enclomifen* or clostilbegit or gravosan).tw.
4540
63 (Buserelin or Goserelin or Leuprolide or Nafarelin or Triptorelin).tw. 3960
64 polycystic ovary syndrome/dt, th 2397
3
# Searches Results
66 (polycystic ovary syndrome/ or exp ovary/ or exp Infertility/ or (pcos or polycystic ovar* syndrome*).tw.) and (endoscopy/ or hysteroscopy/ or exp laparoscopy/ or Electrocoagulation/ or (laparoscop* or electrocoagul* or electrocaut*).tw.)
4832
67 (Endometriosis/ or polycystic ovary syndrome/ or Fallopian Tubes/su or Salpingectomy/ or (pcos or polycystic ovar* syndrome* or endometrios* or fallopian tube disease* or tubectom* or salpingectom*).tw.) and (exp infertility/ or exp fertility/ or exp pregnancy/ or (fertil* or infertil* or pregnan*).tw.)
11941
68 (Metformin/ or metformin*.tw.) and (exp pregnancy/ or exp infertility/ or exp fertility/ or polycystic ovary syndrome/ or exp ovary/ or (infertil* or fertil* or pregnan* or pcos or polycystic ovar* syndrome*).tw. or ovulation.mp.)
1183
69 ((ovar* or laparoscop* or diathermy or PCOS or polycystic or laser or zona) adj5 drilling).tw. 358 70 ((ovarian or ovary or ovaries) adj2 (electrocoagul* or electrocaut*)).tw. 61
71 Endometrial Ablation Techniques/ 150
72 (fimbriolys* or fimbrioplast* or adhesiolys*).tw. 961 73 ((surg* or excis* or ablat*) adj5 endometr*).tw. 4359
74 or/10-73 291897
