The authors have declared that no competing interests exist.
Conceived and designed the experiments: SB JM AM. Analyzed the data: JM. Wrote the manuscript: SB JM. Commented on manuscript: AM.
In-vitro fertilization (IVF) is the treatment of choice for unresolved infertility. It comprises a number of key steps, each of which has to be negotiated before the next is attempted, but the factors which are associated with failure at each stage have not been reported.
We analyzed anonymised national data on women undergoing their first fresh autologous IVF and intracytoplasmic sperm injection (ICSI) cycle in the United Kingdom between 2000 and 2007 to predict factors associated with overall lack of livebirth as well as the chance of non-progress at different stages of an IVF cycle. A total of 121,744 women were included in this analysis. Multivariable models underlined the importance of increased female age and duration of infertility, lack of previous pregnancy, and a diagnosis of tubal or male factor infertility in predicting the risk of not having a live birth in an IVF treatment. At each stage, a woman’s chance of proceeding to the next stage of IVF treatment is affected by increased age and duration of infertility. The intention to use intra-cytoplasmic sperm injection (ICSI) is associated with a decreased risk of treatment failure in women starting an IVF cycle (RR 0.93, 99% CI 0.92, 0.94) but this association is reversed at a later stage once fertilisation has been confirmed (RR=1.01, 99%CI 1.00, 1.03).
Female age is a key predictor of failure to have a livebirth following IVF as well as the risk of poor performance at each stage of treatment. While increased duration of infertility is also associated with worse outcomes at every stage, its impact appears to be less influential. Women embarking on ICSI treatment for male factor infertility have a lower chance of treatment failure but this does not appear to be due to increased chances of implantation of ICSI embryos.
In-vitro fertilization (IVF) is the recommended treatment of choice for unresolved infertility (NCCWCH NICE, 2013). In 2011, over 48,147 women in the United Kingdom underwent a total of 61,726 cycles of IVF or intracytoplasmic sperm injection (ICSI) (HFEAhttp://www.hfea.gov.uk).
A number of studies in the literature have explored the impact of factors predicting the successful outcome of IVF in terms of pregnancy and/or livebirth. Most have relied on analyses of routinely collected data based on cycles of treatment and the number of co-variates have been in inverse proportion to the size of the dataset [
The Human Fertilisation and Embryology Authority (HFEA) has collected data on all licensed fertility treatments in the UK since 1991. Analysis of IVF and ICSI cycles from different time periods within this dataset by Templeton[
Both studies used cycles, rather than individual women as their unit of analysis, and focused on a global prediction of live birth. IVF comprises a number of key stages - including controlled ovarian stimulation oocyte retrieval, fertilisation, embryo transfer and confirmation of early pregnancy - each of which has to be negotiated before the next can be attempted. With a reported U.K. national live birth rates of 32% (HFEAhttp://www.hfea.gov.uk) in women aged 18-34 years, the majority of IVF attempts are not successful. Couples and clinicians are interested in understanding reasons for treatment failure and the role of clinical characteristics associated with non-progress to the next stage but none of the studies in the literature has addressed this. Additionally, recent years have seen the emergence of term singleton live birth[
The HFEA data set remains a rich source of material for investigating factors influencing the overall outcome of IVF as well as at each stage. In this study, using HFEA data from women in their first IVF cycles, we aimed to determine the chance of treatment failure (defined as absence of livebirth and term singleton livebirth) in women attempting IVF for the first time and to determine factors associated with the inability to progress on to the next stage of IVF. We also investigated the changes in the risk of unsuccessful treatment at each stage of treatment.
We analyzed anonymised HFEA data (
We utilised anonymised data from the HFEA register and included all cycles where women were undergoing their first, fresh, autologous IVF and ICSI cycles between January 2000 and December 2007. We excluded cycles involving egg donation or those initiated with the express purpose of storage of eggs/embryos rather than fresh embryo transfer. (
Poor ovarian response was defined as retrieval of three or less oocytes per woman[
Duration and cause of infertility were categorised in accordance with previous analyses of HFEA data[
We performed an analysis using data from all women embarking on their first cycles to assess associations with failure to achieve a live birth. We examined whether the association between prognostic factors and failure to achieve live birth changed over the course of treatment, by fitting the same model to the sample of women who achieved each stage in the course of treatment. The analysis at each stage in the IVF process was based on only those women who had reached the preceding stage. For example, in the analysis of ovarian response, all women were included; for fertilisation, the denominator was all women in whom at least one oocyte was mixed with sperm, for embryo transfer the denominator was all women where at least one embryo was created, and for positive pregnancy test the denominator was all women who had at least one embryo transferred. By utilising a prospectively collected database and clearly defining our cohort for every analyses, we could estimate the risk that a women would experience each specific outcome.
We examined likelihood of failure and factors associated with failure overall and at each stage in the IVF cycle using univariable and multivariable Poisson regressions with robust error variance[
Data from 121,744 women undergoing their first cycle of IVF or ICSI were included in this analysis (
Of women undergoing their first IVF or ICSI cycles 91,749 (75.4%) did not have a live birth. The factors associated with an overall unsuccessful treatment outcome were older age, increasing duration of infertility, no previous pregnancy and treatment by IVF (
P<0.001 | P<0.001 | |||||
18-34 | 63685 | 70.3% | 1.0 | 1.0 | ||
35-37 | 28867 | 75.2% | 1.07 (1.06, 1.08) | 1.07 (1.06, 1.08) | ||
38-39 | 14853 | 81.6% | 1.16 (1.15, 1.17) | 1.17 (1.15, 1.18) | ||
40-42 | 11140 | 90.0% | 1.28 (1.27, 1.29) | 1.29 (1.27, 1.30) | ||
43-44 | 2435 | 97.0% | 1.38 (1.37 , 1.40) | 1.39 (1.37, 1.41) | ||
45-50 | 764 | 98.2% | 1.40 (1.38, 1.42) | 1.41 (1.39, 1.43) | ||
Missing | 0 | |||||
P<0.001 | P<0.001 | |||||
<1 | 2017 | 67.8% | 0.90 (0.86, 0.94) | 0.89 (0.85, 0.92) | ||
1-3 | 45799 | 73.5% | 0.98 (0.97, 0.99) | 0.96 (0.95, 0.97) | ||
4-6 | 38029 | 75.4% | 1.0 | 1.0 | ||
7-9 | 12835 | 77.7% | 1.03 (1.02, 1.05) | 1.03 (1.01, 1.04) | ||
10-12 | 6762 | 78.9% | 1.05 (1.03, 1.07) | 1.03 (1.01, 1.05) | ||
>12 | 6529 | 81.8% | 1.09 (1.07, 1.10) | 1.04 (1.02, 1.06) | ||
Missing | 9773 (8.0%) | |||||
P<0.001 | P<0.001 | |||||
Tubal disease only | 20141 | 77.5% | 1.03 (1.02, 1.04) | 1.05 (1.04, 1.07) | ||
Ovulatory only | 8779 | 77.0% | 1.02 (1.01, 1.04) | 1.02 (1.00, 1.04) | ||
Male Factor Only | 37448 | 73.4% | 0.98 (1.96, 0.99) | 1.05 (1.03, 1.06) | ||
Unexplained | 32629 | 75.3% | 1.0 | 1.0 | ||
Endometriosis | 4097 | 73.3% | 0.97 (0.95, 1.00) | 1.0 (0.97, 1.02) | ||
Cervical Factors only | 52 | 88.5 | 1.17 (1.03, 1.34) | 1.16 (1.01, 1.34) | ||
Combination of Known factors | 14268 | 76.1% | 1.01 (1.00, 1.03) | 1.06 (0.04, 1.07) | ||
Missing | 4330 (3.6%) | |||||
P=0.001 | P<0.001 | |||||
Yes | 71683 | 75.9% | 1.0 | 1.0 | ||
No | 50061 | 75.0% | 0.99 (0.98, 1.00) | 1.04 (1.03, 1.05) | ||
P<0.001 | P<0.001 | |||||
IVF | 72410 | 77.5% | 1.0 | 1.0 | ||
ICSI | 49334 | 72.3% | 0.93 (0.93, 0.94) | 0.93 (0.92, 0.94) |
1 Multivariable risk ratio is adjusted for all variables listed in the table
2 P values obtained from multivariable model.
18-34 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 |
35-37 | 1.07 (1.06, 1.08) | 1.07 (1.06, 1.08) | 1.07 (1.06, 1.08) | 1.07 (1.06, 1.09) | 1.07 (1.06, 1.09) | 1.07 (1.05, 1.08) | 1.09 (1.07, 1.10) | 1.07 (1.06, 1.09) | 1.15 (1.09, 1.21) | 1.14 (1.08, 1.21) |
38-39 | 1.16 (1.15, 1.17) | 1.17 (1.15, 1.18) | 1.17 (1.15, 1.18) | 1.18 (1.16, 1.19) | 1.17 (1.15, 1.19) | 1.16 (1.14, 1.17) | 1.19 (1.17, 1.21) | 1.16 (1.15, 1.18) | 1.43 (1.34, 1.52) | 1.43 (1.34, 1.52) |
40-42 | 1.28 (1.27, 1.29) | 1.29 (1.27, 1.30) | 1.30 (1.28, 1.31) | 1.31 (1.29, 1.33) | 1.31 (1.29, 1.33) | 1.28 (1.26, 1.30) | 1.34 (1.32, 1.36) | 1.28 (1.26, 1.30) | 1.91 (1.79, 2.04) | 1.83 (1.69, 1.97) |
43-44 | 1.38 (1.37, 1.40) | 1.39 (1.37, 1.41) | 1.42 (1.40, 1.43) | 1.43 (1.41, 1.45) | 1.43 (1.41,1.45) | 1.38 (1.35, 1.40) | 1.47 (1.45, 1.49) | 1.37 (1.35, 1.40) | 2.68 (2.35, 3.06) | 2.39 (2.04, 2.80) |
45-50 | 1.40 (1.38, 1.42) | 1.41 (1.39, 1.43) | 1.43 (1.41, 1.46) | 1.46 (1.43, 1.49) | 1.45 (1.43, 1.48) | 1.39 (1.36, 1.42) | 1.49 (1.46, 1.52) | 1.38 (1.34, 1.41) | 2.58 (1.87, 3.55) | 2.50 (1.83, 3.43) |
<1 | 0.90 (0.86, 0.94) | 0.89 (0.85, 0.92) | 0.90 (0.86, 0.94) | 0.88 (0.85, 0.92) | 0.89 (0.85, 0.94) | 0.88 (0.84, 0.92) | 0.88 (0.84, 0.93) | 0.87 (0.83, 0.92) | 1.06 (0.92, 1.22) | 1.02 (0.88, 1.17) |
1-3 | 0.98 (0.97, 0.99) | 0.96 (0.95, 0.97) | 0.98 (0.96, 0.99) | 0.96 (0.95, 0.97) | 0.98 (0.97, 0.99) | 0.96 (0.95, 0.98) | 0.98 (0.97,0.99) | 0.96 (0.95, 0.98) | 0.98 (0.93, 1.03) | 0.95 (0.90, 1.00) |
4-6 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 |
7-9 | 1.03 (1.02, 1.05) | 1.03 (1.01, 1.04) | 1.03 (1.02, 1.05) | 1.03 (1.01, 1.04) | 1.03 (1.01, 1.05) | 1.02 (1.01, 1.04) | 1.03 (1.01, 1.05) | 1.02 (1.0, 1.04) | 1.10 (1.02, 1.18) | 1.06 (0.99, 1.14) |
10-12 | 1.05 (1.03, 1.07) | 1.02 (1.01, 1.05) | 1.05 (1.02, 1.07) | 1.03 (1.01, 1.05) | 1.05 (1.02, 1.07) | 1.02 (1.00, 1.04) | 1.05 (1.03, 1.07) | 1.02 (1.00, 1.05) | 1.15 (1.05, 1.26) | 1.09 (0.99, 1.19) |
>12 | 1.09 (1.07, 1.10) | 1.04 (1.02, 1.06) | 1.09 (1.07, 1.11) | 1.04 (1.02, 1.06) | 1.09 (1.07, 1.11) | 1.03 (1.01, 1.06) | 1.10 (1.08, 1.12) | 1.04 (1.02, 1.06) | 1.24 (1.13, 1.36) | 1.09 (0.98, 1.20) |
Tubal disease only | 1.03 (1.02, 1.04) | 1.05 (1.04, 1.07) | 1.03 (1.02, 1.05) | 1.06 (1.05, 1.08) | 1.04 (1.02, 1.06) | 1.07 (1.06, 1.09) | 1.04 (1.03, 1.06) | 1.08 (1.06, 1.10) | 1.09 (1.03, 1.16) | 1.15 (1.08, 1.17) |
Ovulatory only | 1.02 (1.01, 1.04) | 1.02 (1.00, 1.04) | 1.01 (0.99, 1.03) | 1.01 (0.99, 1.03) | 1.01 (0.99, 1.03) | 1.01 (0.99, 1.03) | 0.99 (0.97, 1.02) | 1.00 (0.98, 1.02) | 1.02 (0.94, 1.11) | 1.07 (0.98, 1.17) |
Male Factor Only | 0.98 (1.96, 0.99) | 1.05 (1.03, 1.06) | 0.97 (0.97, 0.99) | 1.00 (0.99, 1.02) | 0.98 (0.97, 0.99) | 1.00 (0.98, 1.02) | 0.98 (0.97, 0.99) | 1.00 (0.99, 1.02) | 0.94 (0.89, 0.99) | 0.98 (0.91, 1.05) |
Unexplained | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 |
Endometriosis | 0.97 (0.95, 1.00) | 1.0 (0.97, 1.02) | 0.97 (0.94, 1.0) | 1.00 (0.97, 1.02) | 0.97 (0.94, 1.00) | 0.99 (0.96, 1.02) | 0.97 (0.94, 1.00) | 1.00 (0.96, 1.03) | 0.92 (0.82, 1.04) | 0.97 (0.86, 1.10) |
Cervical Factors only | 1.17 (1.03, 1.34) | 1.16 (1.01, 1.34) | 1.19 (1.02, 1.38) | 1.19 (1.01, 1.40) | 1.19 (1.01, 1.40) | 1.21 (1.01, 1.45) | 1.20 (0.99, 1.45) | 1.20 (0.96, 1.59) | 1.34 (0.41, 4.36) | 1.49 (0.45, 4.96) |
Combination of Known factors | 1.01 (1.00, 1.03) | 1.06 (0.04, 1.07) | 1.01 (0.99, 1.02) | 1.03 (1.01, 1.05) | 1.01 (0.99, 1.03) | 1.03 (1.01, 1.04) | 1.01 (0.99, 1.03) | 1.03 (1.01, 1.05) | 1.03 (0.96, 1.11) | 1.08 (1.00, 1.16) |
Yes | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 |
No | 0.99 (0.98, 1.00) | 1.04 (1.03, 1.05) | 0.99 (0.98, 1.00) | 1.03 (1.02, 1.04) | 0.99 (0.98, 0.99) | 1.03 (1.02, 1.04) | 0.98 (0.97, 0.99) | 1.03 (1.02, 1.04) | 0.90 (0.87, 0.94) | 0.99 (0.94, 1.03) |
IVF | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 |
ICSI | 0.93 (0.93, 0.94) | 0.93 (0.92, 0.94) | 0.98 (0.97, 0.99) | 1.00 (0.98. 1.01) | 0.99 (0.98, 1.0) | 1.01 (1.00, 1.03) | 0.99 (0.98, 1.00) | 1.02 (1.00, 1.03) | 0.96 (0.92, 1.00) | 1.04 (0.98, 1.10) |
1-4 | 1.27 (1.25, 1.28) | 1.21 (1.19, 1.22) | 1.25 (1.23, 1.27) | 1.19 (1.17, 1.21) | 1.25 (1.23, 1.27) | 1.14 (1.12, 1.17) | 1.29 (1.20, 1.39) | 1.20 (1.11, 1.30) | ||
5-9 | 1.10 (1.09, 1.12) | 1.09 (1.07, 1.10) | 1.10 (1.09, 1.12) | 1.08 (1.07, 1.10) | 1.11 (1.09, 1.12) | 1.08 (1.07, 1.10) | 1.13 (1.08, 1.19) | 1.11 (1.05, 1.17) | ||
10-14 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | ||
15-19 | 0.99 (0.97, 1.00) | 1.00 (0.98, 1.02) | 0.99 (0.97, 1.01) | 1.00 (0.98, 1.02) | 0.98 (0.96, 1.0) | 0.99 (0.97, 1.01) | 1.02 (0.95, 1.09) | 1.06 (0.99, 1.13) | ||
20+ | 1.05 (1.03, 1.07) | 1.07 (1.05, 1.09) | 1.06 (1.04, 1.08) | 1.07 (1.05, 1.09) | 0.96 (0.93, 0.98) | 0.97 (0.95, 1.00) | 0.98 (0.91, 1.06) | 1.01 (0.93, 1.10) | ||
One | 1.26 (1.25, 1.28) | 1.17 (1.15, 1.18) | 1.24 (1.14, 1.35) | 1.17 (1.07, 1.28) | ||||||
Two | 1.0 | 1.0 | 1.0 | 1.0 | ||||||
>Three | 1.14 (1.12, 1.16) | 1.04 (1.03, 1.06) | 1.29 (1.20, 1.39) | 1.06 (0.98, 1.15) | ||||||
0-25% | 0.92 (0.91, 0.94) | 1.03 (1.01, 1.05) | 0.98 (0.91, 1.04) | 1.05 (0.98.1.13) | ||||||
25-50% | 0.97 (0.96, 0.98) | 1.02 (1.01, 1.04) | 1.03 (0.98, 1.08) | 1.05 (0.99, 1.11) | ||||||
50-75% | 0.94 (0.93, 0.96) | 0.99 (0.98, 1.01) | 0.99 (0.94, 1.05) | 1.00 (0.94, 1.07) | ||||||
75-100% | 1.0 | 1.0 | 1.0 | 1.00 |
1 RR - risk ratio
Of all women starting their first IVF treatment cycle, 20,621 (16.9%) had 3 or fewer oocytes retrieved (
P<0.001 | P<0.001 | ||||
18-34 | 7533 (11.8%) | 1.0 | 1.0 | ||
35-37 | 4832 (16.7%) | 1.42 (1.35, 1.48) | 1.38 (1.32, 1.44) | ||
38-39 | 3406 (22.9%) | 1.94 (1.85, 2.03) | 1.87 (1.78, 1.97) | ||
40-42 | 3442 (30.9%) | 2.61 (2.49, 2.73) | 2.53 (2.41, 2.66) | ||
43-44 | 1018 (41.8%) | 3.53 (3.30, 3.78) | 3.39 (3.15, 3.65) | ||
45-50 | 390 (51.0%) | 4.31 (3.92, 4.75) | 3.95 (3.50, 4.40) | ||
P<0.001 | P<0.001 | ||||
<1 | 282 (14.0%) | 0.86 (0.74, 0.99) | 0.81 (0.70, 0.94) | ||
1-3 | 7253 (15.8%) | 0.97 (0.93, 1.01) | 0.93 (0.90, 0.97) | ||
4-6 | 6192 (16.3%) | 1.0 | 1.0 | ||
7-9 | 2311 (18.0%) | 1.11 (1.05, 1.17) | 1.12 (1.06, 1.18) | ||
10-12 | 1308 (19.4%) | 1.19 (1.11, 1.28) | 1.16 (1.08, 1.24) | ||
>12 | 1465 (22.4%) | 1.38 (1.29, 1.47) | 1.19 (1.11, 1.27) | ||
P<0.001 | P<0.001 | ||||
Tubal disease only | 3300 (16.4%) | 0.96 (0.91, 1.01) | 1.00 (0.95, 1.06) | ||
Ovulatory only | 1945 (22.2%) | 1.29 (1.22, 1.37) | 1.26 (1.18, 1.34) | ||
Male Factor Only | 5599 (15.0%) | 0.87 (0.83, 0.91) | 1.98 (1.88, 2.09) | ||
Unexplained | 5594(17.1%) | 1.0 | 1.0 | ||
Endometriosis | 757 (18.5%) | 1.08 (0.99, 1.18) | 1.16 (1.05, 1.27) | ||
Cervical Factors only | 12 (23.1%) | 1.35 (0.70, 2.59) | 1.21 (0.6, 2.45) | ||
Combination of Known factors | 2586 (18.1%) | 1.06 (1.00, 1.12) | 1.63 (1.54, 1.73) | ||
P<0.001 | P<0.001 | ||||
Yes | 8800 (17.6%) | 1.0 | 1.0 | ||
No | 11821 (16.5%) | 0.94 (0.91, 0.97) | 1.14 (1.10, 1.18) | ||
P<0.001 | P<0.001 | ||||
IVF | 16214 (22.4%) | 1.0 | 1.0 | ||
ICSI | 4407 (8.9%) | 0.40 (0.38, 0.42) | 0.29 (0.27, 0.30) | ||
P<0.001 | |||||
Yes | 20094 (16.6%) | ||||
No | 527 (93.3%) |
1 Poor ovarian response defined as 3 or less oocytes retrieved. In 40 women information on number of oocytes retrieved was missing.
2 Risk ratio adjusted for all variables listed (except for stimulated cycle where 99% of women included in multivariate model had stimulated cycle).
3 P values obtained from multivariable model.
Of all women who started their first IVF cycle, 62,239 (86.0%) had at least one egg inseminated and of all women who started their first ICSI cycle, 49,119 (99.6%) had at least one egg injected with sperm. Of these, in the IVF group 2,931 (4.7%) women had failed fertilisation, while the corresponding figure in the ICSI group was 1,087 (2.2%). Poor fertilisation (1-19% eggs fertilised) occurred in 2.5% of IVF cycles and 0.9% of ICSI cycles.
P=0.024 | P=0.001 | |||||
18-34 | 1.0 | 1.0 | 1.0 | 1.0 | ||
35-37 | 1.00 (0.91, 1.09) | 0.93 (0.85, 1.03) | 1.16 (0.98, 1.38) | 0.96 (0.80, 1.15) | ||
38-39 | 1.02 (0.90, 1.14) | 0.90 (0.79, 1.02) | 1.64 (1.35, 1.99) | 1.19 (0.96, 1.48) | ||
40-42 | 1.11 (0.98, 1.26) | 0.93 (0.81, 1.07) | 2.07 (1.69, 2.54) | 1.27 (1.01, 1.59) | ||
43-44 | 1.33 (1.05, 1.68) | 0.99 (0.76, 1.28) | 2.83 (2.00, 4.00) | 1.45 (0.99, 2.11) | ||
45-50 | 1.96 (1.41, 2.74) | 1.35 (0.94, 1.95) | 3.79 (2.25, 6.37) | 1.65 (0.94, 2.90) | ||
P<0.001 | P=0.035 | |||||
<1 | 0.78 (0.56, 1.07) | 0.95 (0.68, 1.31) | 0.88 (0.49, 1.58) | 0.95 (0.54, 1.68) | ||
1-3 | 0.87 (0.79. 0.95) | 0.90 (0.82, 0.99) | 0.95 (0.81, 1.12) | 0.96 (0.81, 1.13) | ||
4-6 | 1.0 | 1.0 | 1.0 | 1.0 | ||
7-9 | 1.15 (1.01, 1.30) | 1.24 (1.09, 1.40) | 1.12 (0.89, 1.41) | 1.09 (0.87, 1.38) | ||
10-12 | 1.03 (0.87, 1.22) | 1.19 (1.00, 1.41) | 1.42 (1.09, 1.85) | 1.35 (1.03, 1.77) | ||
>12 | 0.99 (0.83, 1.17) | 1.19 (0.99, 1.43) | 1.21 (0.91, 1.62) | 1.06 (0.78, 1.44) | ||
P<0.001 | P=0.224 | |||||
Tubal disease only | 0.60 (0.54, 0.67) | 0.64 (0.57, 0.71) | 1.22 (0.85, 1.75) | 1.26 (0.86, 1.85) | ||
Ovulatory only | 1.09 (0.97, 1.23) | 1.07 (0.94, 1.21) | 1.57 (1.07, 2.30) | 1.43 (0.96, 2.13) | ||
Male Factor Only | 1.29 (1.14, 1.47) | 1.29 (1.13, 1.48) | 1.08 (0.87, 1.34) | 1.16 (0.93, 1.45) | ||
Unexplained | 1.0 | 1.0 | 1.0 | 1.0 | ||
Endometriosis | 0.75 (0.62, 0.91) | 0.71 (0.58, 0.86) | 1.08 (0.54, 2.14) | 0.92 (0.43, 1.98) | ||
Cervical Factors only | 1.78 (0.67, 4.73) | 1.58 (0.55, 4.48) | - |
|||
Combination of Known factors | 0.93 (0.81, 1.07) | 0.94 (0.81, 1.08) | 1.14 (0.89, 1.47) | 1.17(0.90, 1.52) | ||
P<0.001 | P=0.006 | |||||
Yes | 1.0 | 1.0 | 1.0 | 1.0 | ||
No | 1.33 (1.23, 1.43) | 1.30 (1.19, 1.42) | 0.99 (0.86, 1.13) | 1.19 (1.01, 1.39) | ||
P<0.001 | P<0.001 | |||||
1-4 | 2.03 (1.83, 2.26) | 2.03 (1.81, 2.27) | 5.85 (4.83, 7.09) | 5.29 (4.31, 6.51) | ||
5-9 | 1.10 (0.99, 1.22) | 1.09 (0.98, 1.21) | 1.49 (1.21, 1.83) | 1.40 (1.13, 1.75) | ||
10-14 | 1.0 | 1.0 | 1.0 | 1.0 | ||
15-19 | 0.95 (0.82, 1.09) | 0.94 (0.81, 1.09) | 0.76 (0.56,1.05) | 0.73 (0.54, 1.02) | ||
20+ | 1.10 (0.95, 1.28) | 1.08 (0.92, 1.27) | 0.81 (0.56, 1.16) | 0.82 (0.56, 1.19) |
1 Poor fertilisation defined as failure or less than 20% of oocytes fertilised
2 Multivariable risk ratio is adjusted for all variables listed
3 P values obtained from multivariable model.
4 Women receiving ICSI with cause of infertility recorded as cervical factors only (n=4), were excluded from the analysis
Of women undergoing their first cycle of IVF and ICSI and having at least one embryo created, 4.9% (2882) and 4.3% (2081) of women respectively, failed to achieve embryo transfer. In women who received one or more embryos, similar proportions of those treated by IVF and ICSI failed to achieve a positive pregnancy test, 33, 839 (60%) and 27, 317 (59.4%) respectively.
Multivariable models showed the risk of a negative pregnancy test 2 weeks after embryo transfer in women who reached this stage, (using either IVF or ICSI generated embryos) increased with rising female age. Absence of a pregnancy was less likely in women with a short duration of infertility, but more likely in women with no previous pregnancy, low oocyte yield, poor embryo utilisation (<50%) and transfer of 1, 3 or 4 embryos (as opposed to 2) (
P <0.001 | P<0.001 | |||||
18-34 | 1.0 | 1.0 | 1.0 | 1.0 | ||
35-37 | 1.10 (1.08, 1.13) | 1.09 (1.06, 1.11) | 1.10 (1.07, 1.13) | 1.06 (1.05, 1.09) | ||
38-39 | 1.21 (1.18, 1.24) | 1.17 (1.14, 1.21) | 1.22 (1.18, 1.26) | 1.17 (1.13, 1.21) | ||
40-42 | 1.40 (1.37, 1.44) | 1.33 (1.30, 1.37) | 1.41 (1.37, 1.45) | 1.30 (1.26, 1.49) | ||
43-44 | 1.64 (1.59, 1.69) | 1.53 (1.48, 1.59) | 1.60 (1,54, 1.67) | 1.42 (1.36, 1.49) | ||
45-50 | 1.71 (1.64, 1.78) | 1.55 (1.47, 1.63) | 1.70 (1.62, 1.79) | 1.49 (1.40, 1.59) | ||
P<0.001 | P<0.001 | |||||
<1 | 0.78 (0.72, 0.86) | 0.78 (0.71, 0.85) | 0.80 (0.73, 0.89) | 0.80 (0.72, 0.88) | ||
1-3 | 0.98 (0.96, 1.00) | 0.96 (0.94, 0.98) | 0.96 (0.93, 0.98) | 0.95 (0.93, 0.97) | ||
4-6 | 1.0 | 1.0 | 1.0 | 1.0 | ||
7-9 | 1.02 (0.99, 1.06) | 1.01 (0.98, 1.04) | 1.03 (0.99, 1.06) | 1.02 (0.98, 1.05) | ||
10-12 | 1.04 (1.0, 1.08) | 1.01 (0.97, 1.05) | 1.05 (1.01, 1.10) | 1.03 (0.98, 1.07) | ||
>12 | 1.09 (1.05, 1.14) | 1.02 (0.98, 1.06) | 1.13 (1.08, 1.17) | 1.07 (1.02, 1.11) | ||
P<0.001 | P=0.002 | |||||
Tubal disease only | 1.05 (1.03, 1.07) | 1.10 (1.08, 1.13) | 1.07 (1.02, 1.13) | 1.09 (1.03, 1.15) | ||
Ovulatory only | 0.98 (0.95, 1.01) | 0.98 (0.95, 1.02) | 1.02 (0.96, 1.09) | 1.00 (0.94, 1.07) | ||
Male Factor Only | 0.95 (0.92, 1.0) | 0.98 (0.95, 1.02) | 0.98 (0.95, 1.01) | 1.01 (0.98, 1.05) | ||
Unexplained | 1.0 | 1.0 | 1.0 | 1.0 | ||
Endometriosis | 0.98 (0.94, 1.02) | 1.01 (0.67, 1.05) | 0.96 (0.86, 1.07) | 0.96 (0.86, 1.07) | ||
Cervical Factors only | 1.23 (0.93, 1.64) | 1.24 (0.91, 1.70) | - |
- |
||
Combination of known factors | 1.01 (0.98, 1.05) | 1.05 (1.01, 1.09) | 1.00 (0.96, 1.04) | 1.01 (0.97, 1.05) | ||
P<0.001 | P<0.001 | |||||
Yes | 1.0 | 1.0 | 1.0 | 1.0 | ||
No | 1.01 (0.99, 1.02) | 1.05 (1.03, 1.08) | 0.99 (0.97, 1.01) | 1.05 (1.03, 1.08) | ||
P<0.001 | P<0.001 | |||||
One | 1.39 (1.36, 1.41) | 1.26 (1.23, 1.29) | 1.41 (1.38, 1.44) | 1.26 (1.22, 1.29) | ||
Two | 1.0 | 1.0 | 1.0 | 1.0 | ||
Three/four | 1.18 (1.15, 1.22) | 1.06 (1.03, 1.10) | 1.16 (1.12, 1.20) | 1.05 (1.01, 1.09) | ||
P<0.001 | P<0.001 | |||||
1-4 | 1.35 (1.31, 1.38) | 1.20 (1.16, 1.23) | 1.38 (1.34, 1.42) | 1.21 (1.17, 1.25) | ||
5-9 | 1.13 (1.11, 1.16) | 1.11 (1.08, 1.14) | 1.15 (1.12, 1.18) | 1.11 (1.08, 1.14) | ||
10-14 | 1.0 | 1.0 | 1.0 | 1.0 | ||
15-19 | 0.96 (0.93, 1.0) | 0.98 (0.94, 1.01) | 0.95 (0.92, 0.99) | 0.96 (0.93, 1.00) | ||
20+ | 0.94 (0.90, 0.98) | 0.96 (0.92, 1.01) | 0.92 (0.88, 0.97) | 0.94 (0.90, 0.99) | ||
P<0.001 | P=0.002 | |||||
0-25% | 0.90 (0.88,0.93) | 1.05 (1.02, 1.09) | 0.86 (0.83, 0.89) | 1.02 (0.98, 1.06) | ||
25-50% | 0.95 (0.93, 0.97) | 1.01 (0.99, 1.04) | 0.94 (0.92, 0.99) | 1.03 (1.00, 1.06) | ||
50-75% | 0.91 (0.89, 0.93) | 0.98 (0.96, 1.01) | 0.90 (0.88, 0.93) | 0.99 (0.96, 1.02) | ||
75-100% | 1.0 | 1.0 | 1.0 | 1.0 |
1 Multivariable risk ratio is adjusted for all variables listed
2 P values obtained from multivariable model.
4 Women receiving ICSI with cause of infertility recorded as cervical factors only (n=4), were excluded from the analysis
A total of 41,221 women had positive pregnancy test. Of these, 11,466 (27.8%) failed to achieve a live birth and 21,421 (52.0%) failed to achieve a term, singleton live birth (
P<0.001 | P<0.001 | |||||
18-34 | 1.0 | 1.0 | 1.0 | 1.0 | ||
35-37 | 1.15 (1.09, 1.21) | 1.14 (1.08, 1.21) | 0.96 (0.93, 0.99) | 0.96 (0.93, 0.99) | ||
38-39 | 1.43 (1.34, 1.52) | 1.43 (1.34, 1.52) | 0.98 (0.94, 1.02) | 0.98 (0.94, 1.02) | ||
40-42 | 1.91 (1.79, 2.04) | 1.83 (1.69, 1.97) | 1.11 (1.05, 1.16) | 1.07 (1.01, 1.14) | ||
43-44 | 2.68 (2.35, 3.06) | 2.39 (2.04, 2.80) | 1.39 (1.24, 1.55) | 1.29 (1.13, 1.48) | ||
45-50 | 2.58 (1.87, 3.55) | 2.50 (1.83, 3.42) | 1.56 (1.28, 1.91) | 1.46 (1.14, 1.87) | ||
P<0.001 | P<0.001 | |||||
<1 | 1.06 (0.92, 1.22) | 1.02 (0.88, 1.17) | 0.95 (0.87, 1.04) | 0.94 (0.86, 1.03) | ||
1-3 | 0.98 (0.93, 1.03) | 0.95 (0.90, 1.00) | 0.97 (0.94, 1.0) | 0.96 (0.94, 0.99) | ||
4-6 | 1.0 | 1.0 | 1.0 | 1.0 | ||
7-9 | 1.10 (1.02, 1.18) | 1.06 (0.99, 1.14) | 1.00 (0.96, 1.05) | 1.00 (0.95, 1.04) | ||
10-12 | 1.15 (1.05, 1.26) | 1.08 (0.99, 1.19) | 1.03 (0.98, 1.09) | 1.01 (0.96, 1.07) | ||
>12 | 1.24 (1.13, 1.36) | 1.09 (0.98, 1.20) | 1.07 (1.01, 1.14) | 1.05 (0.99, 1.12) | ||
P<0.001 | P<0.001 | |||||
Tubal disease only | 1.09 (1.03, 1.16) | 1.15 (1.08, 1.23) | 1.06 (1.03, 1.10) | 1.05 (1.01, 1.09) | ||
Ovulatory only | 1.02 (0.94, 1.11) | 1.07 (0.98,1.17) | 1.06 (1.00, 1.11) | 1.05 (1.00, 1.11) | ||
Male Factor Only | 0.94 (0.89, 0.99) | 0.98 (0.91, 1.05) | 0.96 (0.93, 1.00) | 0.97 (0.93, 1.01) | ||
Unexplained | 1.0 | 1.0 | 1.0 | 1.0 | ||
Endometriosis | 0.92 (0.82, 1.04) | 0.97 (0.86, 1.10) | 1.01 (0.94, 1.08) | 1.01 (0.94, 1.09) | ||
Cervical Factors only | 1.34 (0.41, 4.36) | 1.49 (0.45, 4.96) | 1.45 (0.86, 2.46) | 1.52 (0.93, 2.50) | ||
Combination of Known factors | 1.03 (0.96, 1.11) | 1.08 (1.00, 1.16) | 1.04 (1.0, 1.09) | 1.04 (1.00, 1.09) | ||
P=0.427 | P=0.007 | |||||
Yes | 1.0 | 1.0 | 1.0 | 1.0 | ||
No | 0.90 (0.97, 0.94) | 0.99 (0.94, 1.03) | 0.96 (0.94, 0.99) | 0.97 (0.94, 1.00) | ||
P<0.001 | P<0.001 | |||||
One | 1.24 (1.14, 1.35) | 1.17 (1.07, 1.28) | 0.78 (0.72, 0.83) | 0.79 (0.73, 0.85) | ||
Two | 1.0 | 1.0 | 1.0 | 1.0 | ||
Three/four | 1.29 (1.20, 1.39) | 1.06 (0.98, 1.15) | 1.15 (1.10, 1.20) | 1.11 (1.06, 1.17) | ||
P<0.001 | P=0.227 | |||||
1-4 oocytes | 1.29 (1.20, 1.39) | 1.20 (1.11, 1.30) | 0.95 (0.90, 1.0) | 0.98 (0.93, 1.04) | ||
5-9 oocytes | 1.13 (1.08, 1.19) | 1.11 (1.05, 1.17) | 1.0 (0.97, 1.03) | 1.00 (0.96, 1.03) | ||
10-14 oocytes | 1.0 | 1.0 | 1.0 | 1.0 | ||
15-19 oocytes | 1.02 (0.95, 1.09) | 1.06 (0.99, 1.13) | 1.01 (0.98, 1.05) | 1.02 (0.98, 1.08) | ||
20+ oocytes | 0.98 (0.91, 1.06) | 1.01 (0.93, 1.10) | 1.03 (0.98, 1.07) | 1.03 (0.98, 1.08) | ||
P=0.128 | P=0.572 | |||||
IVF | 1.0 | 1.0 | 1.0 | 1.0 | ||
ICSI | 0.96 (0.92, 1.00) | 1.04 (0.98, 1.10) | 0.96 (0.94, 0.99) | 0.99 (0.96, 1.03) | ||
P=0.061 | P=0.940 | |||||
0-25% | 0.98 (0.91, 1.04) | 1.05 (0.98, 1.13) | 1.01 (0.97, 1.05) | 0.99 (0.95, 1.04) | ||
25-50% | 1.03 (0.98, 1.08) | 1.05 (0.99, 1.11) | 1.01 (0.98, 1.05) | 1.00 (0.97, 1.03) | ||
50-75% | 0.99 (0.94, 1.05) | 1.00 (0.94, 1.07) | 1.03 (1.0, 1.07) | 1.00 (0.97, 1.04) | ||
75-100% | 1.0 | 1.0 | 1.0 | 1.0 |
1 Term singleton live birth was defined as a single baby born at 37 weeks or greater gestation
2 Multivariable risk ratio is adjusted for all variables listed in table
3 P values obtained from multivariable model
The results of this study underline the importance of increased female age and duration of infertility, lack of previous pregnancy and tubal and male factor infertility in predicting the risk of not having a livebirth in an IVF treatment. At each stage, a woman’s chance of proceeding to the next phase of IVF treatment is affected by increased age and duration of infertility. The intention to perform ICSI is associated with a decreased risk of treatment failure in women starting an IVF cycle but this association is reversed at a later stage once fertilisation has been confirmed. Other factors such as cause of infertility, number of oocytes retrieved and number of embryos replaced also play a role in determining poor intermediate outcomes.
This is the first study to conduct an analysis based on women as opposed to cycles using a large national IVF database with total capture of all treatments. It is also the first to attempt to identify factors affecting global failure as well as those influencing women’s chances of progressing onto the next stage of treatment. In recognition of a healthy baby as a key outcome of IVF, the results include factors which affect the chance of not having a singleton term livebirth.
As the study is based on routinely collected data, we were not able to adjust for a number of known and potential confounders such as smoking, body mass index and paternal age which are not captured at all within this dataset. In addition we were unable to examine the influence of tests of ovarian reserve or embryo quality as these data are not collected, although we did attempt to examine embryo quality through our derived variable embryo utilisation. To maintain confidentiality, maternal age was only available grouped into categories – this inevitably impacted on the accuracy of the model to estimate the effect of increasing age on treatment outcomes. There were some missing data for some of the variables. In order to analyse outcomes in women as opposed to cycles we focused on first cycles only and are therefore unable to identify factors associated with live births resulting from multiple IVF cycles including fresh and frozen embryo transfers.
A number of previous studies (including two based on the HFEA database) have estimated factors affecting outcomes in IVF[
A more recent study, based on the analysis of HFEA data between 2003 and 2007, examined the predictors of live birth in 144,018 IVF and intracytoplasmic sperm injection (ICSI) cycles[
Our results, based on the same dataset but using a different timeframe and adopting a woman based approach, corroborate the findings of these earlier studies in confirming the pivotal role of these predictive variables.
A preliminary analysis of these data, to investigate the factors associated with failure to achieve pregnancy in women undergoing first IVF and ICSI cycles that reached embryo transfer [
A systematic review of studies by Loendersloot[
Few large studies are able to report on the predictive power of embryo quality[
Although the importance of these predictive factors has been known for some time, their relative importance at each stage of the treatment, in terms of predicting overall success as well as the chance of proceeding to the next stage has not been reported previously. This has been addressed in this study, and while the factors are the same it is interesting to see how their influence changes over the course of an IVF cycle. The association between ICSI and lower risk of treatment failure is particularly interesting. Previous work[
Our results suggest that increased female age is a key determinant of treatment failure - globally as well as at each stage. Though less pronounced, the influence of duration of infertility is present at all stages except in the prediction of fertilisation following insemination or injection of embryos. Lack of previous pregnancy also has a negative effect all along the course of treatment up to the point of confirmation of biochemical pregnancy. Tubal infertility with associated hydrosalpinx affects the chance of implantation of a transferred embryo – an observation that has been reported previously and has been considered to be due to the effect of secretions in the fallopian tube which may potentially flow into the endometrial cavity and impair the quality of the deciduas. This effect has clinical relevance as a Cochrane review has confirmed doubling of IVF related pregnancy rates after salpingectomy in women with hydrosalpinges[
The ability to predict chances of pregnancy and livebirth is critical to decision making around IVF. In cases where the outcome is in doubt, IVF itself is often seen as a prognostic exercise which is able to reveal which women are likely to respond to ovarian stimulation and produce good quality embryos. The ability to identify factors associated with failure at each stage of the treatment has the ability to refine decision making around proceeding with treatment – especially where the prognosis changes during treatment. For example a 40 year old woman with a poor oocyte yield is more likely to be unsuccessful than one with a better oocyte yield. This information can be quantified and can potentially lead to more sophisticated strategies for individualised decision making such that women can be counselled appropriately regarding risks of non pregnancy leading to live birth at each stage.
This strategy opens up the possibilities of new and more nuanced methods of analyses of the U.K. national IVF dataset. The ability to link cycles within women offers an opportunity to develop woman based models in IVF – with better prediction of cumulative outcomes over a number of fresh and frozen IVF cycles.
Female age is a key predictor of failure to have a livebirth following IVF as well as the risk of poor performance at each stage of treatment. While increased duration of infertility is also associated with worse outcomes at every stage, its impact appears to be less influential. Absence of a previous pregnancy did not impact on ovarian stimulation and pregnancy loss but does affect the chances of fertilisation and positive pregnancy test. Women embarking on ICSI treatment for male factor infertility have a lower chance of treatment failure but this does not appear to be due to increased chances of implantation of ICSI embryos.
We thank Katie Wilde, for her help in data manipulation, Sohinee Bhattacharya for commenting on the manuscript and Margery Heath for secretarial assistance.