Between February 2016 and April 2019, 1578 participants consented and 619 couples were randomised: 310 to the fresh-embryo transfer arm and 309 to the freeze-all arm (Figure 5). One couple in the fresh-embryo transfer arm and two in the intervention arm withdrew consent to use their data; hence, the ITT analysis included 309 participants in the fresh-embryo transfer arm and 307 participants in the freeze-all arm.
FIGURE 5 Flow of participants. Reproduced from Maheshwari et al.,23 Elective freezing of embryos versus fresh embryo transfer in IVF: a multicentre randomized controlled trial in the UK (E-Freeze), Human Reproduction, 2022, deab279, by permission of European Society of Human Reproduction and Embryology. (Figure not reproduced here; see the original article.)
Recruitment and retention
When the trial initially started, in 2016, only the first cycle of IVF/ICSI was included. Owing to suboptimal recruitment (and after discussion with the funders), it was agreed that we could include the second and third cycles as well (decided on 12 April 2018).
A total of 1578 couples provided consent to be enrolled in the trial. The time between consent and randomisation varied from 10 to 80 days, with a mean of 55.5 days. A total of 959 (60.8%) couples who provided consent were not randomised; the main reason for this (49.6%) was not meeting the final eligibility criterion of at least three good-quality embryos on day 3. Other reasons are described in the flow chart in Figure 5. Some couples (n = 25) became pregnant spontaneously during the time between consent and randomisation.
The proportion of couples not randomised after providing consent remained constant throughout the trial (Figure 6), even after changing the inclusion criteria to incorporate second- and third-cycle treatments.
FIGURE 6 Proportion of consented and randomised participants. (Figure not reproduced here; see the original article.)
The monthly recruitment figures lagged behind target and plateaued after October 2018 (Figure 7). On 9 November 2018, the DMC recommended to the TSC that the trial should be halted, owing to the shortfall in recruitment and the high level of non-adherence. Following this recommendation, a joint meeting of the TSC and DMC was convened on 17 January 2019, with an independent chairperson because of disagreement between the TSC and the DMC, to agree scenarios for a monitoring meeting. After a monitoring meeting with the NIHR HTA programme on 29 January 2019, it was agreed that the trial would stop recruitment on 30 April 2019. It was felt that continuing the trial further would yield no benefit, as an adequate sample size was unlikely given the slow recruitment, compounded by non-adherence, which was particularly evident in the intervention arm (see Table 1).
FIGURE 7 Final recruitment figures. (Figure not reproduced here; see the original article.)
One-fifth of couples included in the analysis (117/616, 19%) did not adhere to their allocated intervention: 21 out of 309 (6.8%) in the fresh-embryo transfer arm and 96 out of 307 (31.3%) in the freeze-all arm. Non-adherence varied across clinics, with the rate in the intervention arm ranging from 0% to 86%. One clinic had a for-cause monitoring visit and was closed early in its recruitment, with non-adherence reaching almost 100%.
Table 1 shows the reasons for non-adherence in the trial arms. The most common reason for non-adherence in the freeze-all arm was patient choice (72% of those who did not receive their allocated intervention).
| Clinical characteristics | Freeze-all arm (N = 307) | Fresh-embryo transfer arm (N = 309) |
|---|---|---|
| Received frozen-embryo transfer, n (%) | 202 (65.8) | 21 (6.8) |
| Time from egg collection to frozen-embryo transfer (days), median (IQR) | 63 (33–97) | 105 (84–138) |
| Received frozen-embryo transfer within 3 months of egg collection,a n (%) | 145 (71.8) | 7 (33.3) |
| Received fresh-embryo transfer, n (%) | 96 (31.3) | 282 (91.3) |
| Reason embryo transfer type is different from allocation, n (%) | 96 | 21 |
| Embryos did not survive after thawing | 1 (1.0) | 0 (0.0) |
| OHSS | 0 (0.0) | 13 (61.9) |
| Not suitable to freeze | 13 (13.5) | 0 (0.0) |
| Other medical reason | 12 (12.5) | 4 (19.0) |
| Patient choice | 69 (71.9) | 3 (14.3) |
| Logistics | 1 (1.0) | 1 (4.8) |
| Received no embryo transfer, n (%) | 9 (2.9) | 6 (1.9) |
| Reason no embryos were transferred, n (%) | 9 | 6 |
| Embryos did not survive after thawing | 3 (33.3) | 0 (0.0) |
| OHSS | 0 (0.0) | 1 (16.7) |
| No suitable embryos | 3 (33.3) | 0 (0.0) |
| Other medical reason | 0 (0.0) | 1 (16.7) |
| Consent withdrawn | 2 (22.2) | 2 (33.3) |
| Other | 1 (11.1) | 2 (33.3) |
Recruitment by sites
Eighteen clinics across the UK signed up for the trial. Only 13 clinics randomised any participants, of which four randomised > 50 participants. The number of recruited participants from each clinic is presented in Table 2.
| Fertility clinica | Number of participants (%) | |
|---|---|---|
| Freeze-all arm (N = 307) | Fresh-embryo transfer arm (N = 309) | |
| 1 | 11 (3.6) | 11 (3.6) |
| 2 | 14 (4.6) | 11 (3.6) |
| 3 | 90 (29.3) | 92 (29.8) |
| 4 | 49 (16.0) | 48 (15.5) |
| 5 | 31 (10.1) | 30 (9.7) |
| 6 | 21 (6.8) | 29 (9.4) |
| 7 | 11 (3.6) | 11 (3.6) |
| 8 | 24 (7.8) | 23 (7.4) |
| 9 | 7 (2.3) | 7 (2.3) |
| 10 | 10 (3.3) | 8 (2.6) |
| 11 | 29 (9.4) | 30 (9.7) |
| 12 | 1 (0.3) | 1 (0.3) |
| 13 | 9 (2.9) | 8 (2.6) |
Data missingness
As is clear from Figures 8 and 9, there were very few missing data for all clinical outcomes. The emotions questionnaires were completed at consent and, again, at embryo transfer. The return rate was 97% for the first emotions questionnaire and > 70% for the second emotions questionnaire. Patients also completed an economics questionnaire, which had a return rate of > 70%.
FIGURE 8 Data missingness on CRFs. (Figure not reproduced here; see the original article.)
FIGURE 9 Data missingness for patient-completed questionnaires. fp, female participant; mp, male participant. (Figure not reproduced here; see the original article.)
Statistical analyses
Baseline comparability of randomised arms
The demographic and clinical characteristics at trial entry are described for all couples in the ITT population by trial arm.
Demographic characteristics at consent
Demographic characteristics at consent are described in Table 3.
| Characteristic | Freeze-all arm (N = 307) | Fresh-embryo transfer arm (N = 309) |
|---|---|---|
| Woman’s age at ovarian stimulation (years) | ||
| < 35, n (%) | 153 (49.8) | 157 (50.8) |
| 35 to < 40, n (%) | 137 (44.6) | 139 (45.0) |
| ≥ 40, n (%) | 17 (5.5) | 13 (4.2) |
| Mean (SD) | 34.7 (3.8) | 34.6 (3.6) |
| Woman’s ethnicity, n (%) | ||
| White | 237 (82.0) | 221 (78.4) |
| Black | 8 (2.8) | 13 (4.6) |
| Asian | 28 (9.7) | 40 (14.2) |
| Mixed | 6 (2.1) | 5 (1.8) |
| Other | 10 (3.5) | 3 (1.1) |
| Not known | 12 | 16 |
| Missing | 6 | 11 |
| Woman’s smoking status, n (%) | ||
| Never smoked | 276 (89.9) | 282 (91.3) |
| Past smoker | 30 (9.8) | 26 (8.4) |
| Current smoker | 1 (0.3) | 1 (0.3) |
| Woman’s BMI (kg/m2) | ||
| Underweight (< 18.5), n (%) | 5 (1.6) | 5 (1.6) |
| Healthy weight (18.5–24.9), n (%) | 195 (63.7) | 187 (60.7) |
| Overweight (25–29.9), n (%) | 91 (29.7) | 102 (33.1) |
| Obese (30–34.9), n (%) | 12 (3.9) | 14 (4.5) |
| Very obese (> 35), n (%) | 3 (1.0) | 0 (0.0) |
| Mean (SD) | 24.1 (3.4) | 24.1 (3.2) |
| Missing, n | 1 | 1 |
| Type of infertility, n (%) | ||
| Primary | 237 (77.2) | 241 (78.0) |
| Secondary | 70 (22.8) | 68 (22.0) |
| Woman’s previous pregnancies, n (%) | ||
| 0 | 214 (69.7) | 220 (71.2) |
| 1 | 65 (21.2) | 63 (20.4) |
| 2 | 18 (5.9) | 16 (5.2) |
| > 2 | 10 (3.3) | 10 (3.2) |
| Woman’s previous live births, n (%) | ||
| 0 | 292 (95.1) | 295 (95.5) |
| 1 | 15 (4.9) | 12 (3.9) |
| 2 | 0 | 2 (0.6) |
| Main cause of infertility, n (%) | ||
| Ovulatory | 40 (13.0) | 32 (10.4) |
| Tubal | 29 (9.4) | 27 (8.7) |
| Endometriosis | 13 (4.2) | 11 (3.6) |
| Unexplained | 119 (38.8) | 131 (42.4) |
| Male factor, n (%) | 102 (33.2) | 102 (33.0) |
| Uterine | 1 (0.3) | 0 (0.0) |
| Low ovarian reserve | 2 (0.7) | 4 (1.3) |
| Other | 1 (0.3) | 2 (0.6) |
| Duration of infertility (months) | ||
| < 12, n (%) | 3 (1.0) | 3 (1.0) |
| 12 to < 24, n (%) | 31 (10.1) | 37 (12.0) |
| 24 to < 36, n (%) | 106 (34.5) | 99 (32.0) |
| 36 to < 48, n (%) | 80 (26.1) | 81 (26.2) |
| 48 to < 60, n (%) | 37 (12.1) | 38 (12.3) |
| ≥ 60, n (%) | 50 (16.3) | 51 (16.5) |
| Median (IQR) | 36 (24–48) | 36 (24–48) |
Age
The mean (SD) age of the female partner was 34.7 (3.8) years in the freeze-all arm and 34.6 (3.6) years in the fresh-embryo transfer arm. Most women (95.1%) were aged < 40 years and half (50.3%) were aged < 35 years. Age was a minimisation criterion.
Ethnicity
Women’s ethnicity was included in the eCRFs only part-way through the trial, on 12 April 2017. All attempts were made to collect these data retrospectively, but data were missing for some couples who were recruited prior to this date (freeze-all arm, n = 6; fresh-embryo transfer arm, n = 11). Most participants were of white ethnic background (80.2%) and 11.9% were Asian. A small proportion in both arms were of black, mixed or other ethnic backgrounds.
Woman’s smoking status
Regarding smoking status, 89.9% of women in the freeze-all arm and 91.3% in the fresh-embryo transfer arm had never smoked. A small proportion were previous smokers (9.8% in the freeze-all arm and 8.4% in the fresh-embryo transfer arm).
Woman’s body mass index
The mean body mass index (BMI) of the female partner was 24.1 kg/m2 (SD 3.4 kg/m2) in the freeze-all arm and 24.1 kg/m2 (SD 3.2 kg/m2) in the fresh-embryo transfer arm. Just over 60% were in the healthy weight category (as per internationally agreed criteria).24 Almost one-third of female participants were overweight and 4.2% were obese. Overall, 95.3% had a BMI of < 30 kg/m2.
Type of infertility
Most women (77.2% in the freeze-all arm and 78% in the fresh-embryo transfer arm) had primary infertility. One-fifth had secondary infertility in both arms (22.8% vs. 22% in the freeze-all and fresh-embryo transfer arms, respectively). The type of infertility was a minimisation criterion.
Previous pregnancies
Over two-thirds of the participants (69.7% in the freeze-all arm vs. 71.2% in the fresh-embryo transfer arm) had had no previous pregnancy. In both arms, most participants (> 95%) had not had a previous live birth.
Main cause of infertility
The male factor and unexplained infertility constituted > 70% of the causes of infertility (72.0% in the freeze-all arm and 75.4% in the fresh-embryo transfer arm), followed by ovulatory factor (13.0% in the freeze-all arm and 10.4% in the fresh-embryo transfer arm). In both arms, a large proportion of participants had unexplained infertility (38.8% in the freeze-all arm and 42.4% in the fresh-embryo transfer arm).
Duration of infertility (months)
The median (IQR) duration of infertility was 36 months (24–48 months) in both arms. Overall, 28.6% of patients had a duration of infertility of > 48 months.
The demographic characteristics of participants randomised to the freeze-all arm were similar whether or not they complied with the allocated intervention.
Characteristics of treatment pre randomisation
The characteristics of the IVF treatment pre randomisation are described in Table 4. All proportions were similar in both arms unless specified.
| Characteristic | Freeze-all arm (N = 307) | Fresh-embryo transfer arm (N = 309) |
|---|---|---|
| Endometrial scratch performed, n (%) | 4 (1.3) | 3 (1.0) |
| Stimulation regimen used, n (%) | 299 (97.4) | 301 (97.4) |
| Long | 73 (23.8) | 64 (20.7) |
| Short | 42 (13.7) | 48 (15.5) |
| Ultrashort | 7 (2.3) | 4 (1.3) |
| Antagonist | 177 (57.7) | 185 (59.9) |
| Total stimulation dose of FSH (IUs), mean (SD) | 2540 (1257) | 2543 (1259) |
| Adjuvants used (non-exclusive), n (%) | 9 (2.9) | 7 (2.3) |
| Aspirin | 0 (0.0) | 1 (0.3) |
| Heparin | 3 (1.0) | 0 (0.0) |
| Steroids | 2 (0.7) | 1 (0.3) |
| Growth hormone | 7 (2.3) | 6 (1.9) |
| DHEA | 0 (0.0) | 1 (0.3) |
| Blood test performed on day of trigger injection, n (%) | 135 (44.0) | 142 (46.0) |
| Trigger injection used, n (%) | ||
| Agonist | 19 (6.2) | 28 (9.1) |
| Dual trigger | 31 (10.1) | 32 (10.4) |
| HCG | 257 (83.7) | 249 (80.6) |
| Total number of eggs collected | ||
| 3–5, n (%) | 14 (4.6) | 16 (5.2) |
| 6–9, n (%) | 73 (23.8) | 77 (24.9) |
| 10–15, n (%) | 141 (45.9) | 121 (39.2) |
| > 15, n (%) | 79 (25.7) | 95 (30.7) |
| Median (IQR) | 12 (9–16) | 12 (9–17) |
| Method of insemination,a n (%) | ||
| IVF | 158 (51.5) | 159 (51.5) |
| ICSI | 139 (45.3) | 138 (44.7) |
| Split (IVF and ICSI) | 10 (3.3) | 12 (3.9) |
| Number of eggs fertilised normally (two pronuclei) | ||
| 3–5, n (%) | 69 (22.5) | 69 (22.3) |
| 6–9, n (%) | 139 (45.3) | 137 (44.3) |
| 10–15, n (%) | 76 (24.8) | 81 (26.2) |
| > 15, n (%) | 23 (7.5) | 22 (7.1) |
| Median (IQR) | 8 (6–11) | 8 (6–11) |
| Time lapse used, n (%) | 124 (40.4) | 126 (40.8) |
| Good-quality embryos created on day 3 | ||
| 3 or 4, n (%) | 131 (42.7) | 112 (36.2) |
| 5 or 6, n (%) | 70 (22.8) | 84 (27.2) |
| 7–10, n (%) | 80 (26.1) | 88 (28.5) |
| > 10, n (%) | 26 (8.5) | 25 (8.1) |
| Median (IQR) | 5 (3–7) | 5 (4–8) |
| Number of previous egg collections,a n (%) | ||
| 0 | 284 (92.5) | 286 (92.6) |
| 1 | 19 (6.2) | 17 (5.5) |
| 2 | 4 (1.3) | 5 (1.6) |
| ≥ 3 | 0 (0.0) | 1 (0.3) |
| Number of previous embryo transfers, n (%) | ||
| 0 | 284 (92.5) | 288 (93.2) |
| 1–3 | 22 (7.2) | 20 (6.5) |
| ≥ 4 | 1 (0.3) | 1 (0.3) |
Stimulation regimen and dose
The most common protocol used was an antagonist protocol (used in 58.8%), followed by a long protocol (used in 22.2%). The total stimulation dose was similar, with a mean dose of 2542 (SD 1257) international units (IUs). Most participants (> 80%) had human chorionic gonadotrophin (HCG) as a final booster injection, followed by dual trigger (10.2%) and, in a small proportion of participants, agonist trigger.
Adjuvants
Most treatments did not have add-ons or adjuvants, including endometrial scratch. A total of ≈ 40% used time lapse as the incubator, but this was similar in both arms.
Number of eggs collected
The median (IQR) number of eggs collected was 12 (range 9–16 eggs), with > 10 eggs collected from 70.8% of participants and > 15 eggs collected from 28.2%; in the case of 30 participants, fewer than six eggs were collected.
Method of insemination
The eggs and sperm were mixed by IVF or ICSI, with an almost equal split between the two methods (IVF, 51.5%; ICSI, 45%). The method of insemination was a minimisation criterion.
Number of embryos
The median number of embryos created was 8 (IQR 6–11), with 45 couples having more than 15 embryos. The median number of good-quality embryos created on day 3 was 5 (IQR 3–7) in the freeze-all arm and 5 (IQR 4–8) in the fresh-embryo transfer arm. The number of good-quality embryos created on day 3 was a minimisation criterion.
Number of previous treatments
Despite the inclusion of second and third cycles, most couples recruited had not previously undergone egg collection (92.5%) or embryo transfer (92.9%).
The clinical pre-randomisation characteristics of those randomised to the freeze-all arm were similar whether or not they complied with the allocated intervention.
Clinical characteristics post randomisation
The clinical characteristics of the embryo and the endometrium, which were collected post randomisation, are described for the ITT population by trial arm in Table 5.
| Characteristic | Freeze-all arm (N = 307) | Fresh-embryo transfer arm (N = 309) |
|---|---|---|
| Had embryo transfer, effective, n | 298 | 303 |
| Stage of embryo at transfer, n (%) | ||
| Cleavage (day 3) | 11 (3.7) | 14 (4.6) |
| Cleavage (day 4) | 5 (1.7) | 6 (2.0) |
| Blastocyst (day 5) | 270 (90.6) | 281 (92.7) |
| Blastocyst (day 6) | 12 (4.0) | 1 (0.3) |
| < 3 days | 0 (0.0) | 1 (0.3) |
| Number of embryos transferred | ||
| 1, n (%) | 249 (83.6) | 247 (81.5) |
| 2, n (%) | – | 55 (18.2) |
| 3, n (%) | 49 (16.4) | 1 (0.3) |
| Median (IQR) | 1 (1–1) | 1 (1–1) |
| Number of remaining frozen embryos after transfera | ||
| 0, n (%) | 68 (22.8) | 61 (20.1) |
| 1, n (%) | 46 (15.4) | 52 (17.2) |
| 2, n (%) | 55 (18.5) | 55 (18.2) |
| ≥ 3, n (%) | 129 (43.3) | 135 (44.6) |
| Median (IQR) | 2 (1–4) | 2 (1–4) |
| Endometrial appearance, n (%) (percentage is of effective N: frozen, effective N = 167; fresh-embryo transfer, effective N = 169) | ||
| Triple layer | 152 (96.2) | 157 (96.3) |
| No triple layer | 6 (3.8) | 6 (3.7) |
| Unknown | 140 | 140 |
| Endometrial thickness (mm), mean (SD) (mean is of effective N: frozen, effective N = 188; fresh-embryo transfer, effective N = 189) | 9.3 (1.9) | 10.2 (2.3) |
| Not recorded, n | 119 | 120 |
Of those randomised, 298 out of 307 participants underwent embryo transfer in the freeze-all arm and 303 out of 309 participants underwent embryo transfer in the fresh-embryo transfer arm. Most transfers (93.8%) were at the blastocyst stage. Overall, > 80% of participants in both arms underwent single embryo transfer; the remaining participants had two embryos, except for one participant, who had three embryos.
The endometrial appearance was recorded in only half of the cases in both arms; in 96.3% of these cases, it was triple layer, with a mean thickness of > 9.3 mm (SD 1.9 mm) in the freeze-all arm and 10.2 mm (SD 2.3 mm) in the fresh-embryo transfer arm.
The number of embryos remaining frozen (i.e. spare embryos) after the first embryo transfer was similar in both arms (median 2, IQR 1–4); 78.5% of couples had at least one remaining embryo frozen after embryo transfer.
The clinical characteristics post randomisation of those randomised to the freeze-all arm were similar whether or not they complied with the allocated intervention.
Post-randomisation characteristics of those who received frozen-embryo transfer
As shown in Table 6, 202 couples in the freeze-all arm and 21 couples in the fresh-embryo transfer arm received frozen-embryo transfer. Most couples had embryos frozen by vitrification (88.1% in the freeze-all arm and 95.2% in the fresh-embryo transfer arm). Most embryos were frozen at the blastocyst stage. The median number of embryos frozen among those who underwent frozen-embryo transfer was 4 (IQR 3–6). The median number of embryos thawed was one. One-fifth (19.8%) of those randomised to the freeze-all arm and 14.3% of those randomised to the fresh-embryo transfer arm who underwent frozen transfer had more than one embryo thawed. Very few embryos were thawed and discarded (i.e. this occurred in a total of 19 couples). The most common method used for endometrial preparation was artificial cycle with oestrogen and progesterone, or downregulation with gonadotropin-releasing hormone (GnRH) agonist.
| Characteristic | Freeze-all arm (N = 307) | Fresh-embryo transfer arm (N = 309) |
|---|---|---|
| Received frozen transfer, n | 202 | 21 |
| Method of embryo freezing, n (%) | ||
| Vitrification | 178 (88.1) | 20 (95.2) |
| Slow freezing | 24 (11.9) | 1 (4.8) |
| Number of embryos frozen | ||
| 1, n (%) | 16 (7.9) | 1 (4.8) |
| 2, n (%) | 34 (16.8) | 2 (9.5) |
| ≥ 3, n (%) | 152 (75.2) | 18 (85.7) |
| Median (IQR) | 4 (3 to 6) | 4 (4 to 6) |
| Number of embryos thawed | ||
| 1, n (%) | 162 (80.2) | 18 (85.7) |
| 2, n (%) | 34 (16.8) | 2 (9.5) |
| ≥ 3, n (%) | 6 (3.0) | 1 (4.8) |
| Median (IQR) | 1 (1 to 1) | 1 (1 to 1) |
| Number of embryos thawed and discarded | ||
| 1, n (%) | 15 (7.4) | 0 |
| 2, n (%) | 2 (1.0) | 1 (4.8) |
| ≥ 3, n (%) | 1 (0.5) | 0 |
| Median (IQR) | 0 (0 to 0) | 0 (0 to 0) |
| Number of embryos thawed and refrozen, n (%) | ||
| ≥ 3 | 1 (0.5) | 0 |
| Number of embryos remaining frozen | ||
| 0, n (%) | 28 (13.9) | 1 (4.8) |
| 1, n (%) | 33 (16.3) | 4 (19.0) |
| 2, n (%) | 40 (19.8) | 1 (4.8) |
| ≥ 3, n (%) | 101 (50.0) | 15 (71.4) |
| Median (IQR) | 3 (1 to 4) | 3 (2 to 5) |
| Method of endometrial preparation for transfer, n (%) | ||
| Natural cycle | 6 (3.0) | 6 (28.6) |
| Natural cycle with HCG | 4 (2.0) | 0 |
| Artificial cycle with oestrogen and progesterone | 130 (64.4) | 7 (33.3) |
| Artificial cycle with oestrogen and progesterone and downregulation with GnRH agonist | 47 (23.3) | 6 (28.6) |
| Artificial cycle with oestrogen, progesterone and antagonist | 14 (6.9) | 2 (9.5) |
| Other | 1 (0.5) | 0 |
| Time from egg collection to embryo freezing, n (%) | ||
| Cleavage (day 3) | 14 (6.9) | 0 |
| Cleavage (day 4) | 3 (1.5) | 0 |
| Blastocyst (day 5) | 175 (86.6) | 19 (90.5) |
| Blastocyst (day 6) | 10 (5.0) | 1 (4.8) |
| < 3 days | 0 | 1 (4.8) |
Primary outcome
Intention-to-treat analysis
The ITT analysis (Table 7) showed that the healthy baby rate (i.e. term singleton live birth with appropriate weight for gestation) was 20.3% in the freeze-all arm and 24.4% in the fresh-embryo transfer arm (p = 0.28). There was no statistical difference with/without adjustment of confounding factors (adjusted RR 0.84, 95% CI 0.62 to 1.15). The proportion of singletons born was 27.7% in the freeze-all arm and 34.0% in the fresh-embryo transfer arm. The proportion of babies born at term was 25.4% in the freeze-all arm and 30.2% in fresh-embryo transfer arm. Similarly, the proportion with an appropriate weight for gestation was 22.5% in the freeze-all arm and 26.9% in the fresh-embryo transfer arm.
| Outcome | Freeze-all arm (N = 307) | Fresh-embryo transfer arm (N = 309) | RR (95% CI) | p-value | |
|---|---|---|---|---|---|
| Unadjusted | Adjusteda | ||||
| Singleton baby born at term with an appropriate weight for gestation, n (%) (percentage is of effective N: frozen, effective N = 306; fresh-embryo transfer, effective N = 308) | 62 (20.3) | 75 (24.4) | 0.83 (0.62 to 1.12) | 0.84 (0.62 to 1.15) | 0.275 |
| Missing, n | 1 | 1 | |||
| Singleton, n (%) | 85 (27.7) | 105 (34.0) | |||
| Born at term, n (%) (percentage is of effective N: frozen, effective N = 307; fresh-embryo transfer, effective N = 308) | 78 (25.4) | 93 (30.2) | |||
| Missing, n | 0 | 1 | |||
| Appropriate weight for gestation, n (%) (percentage is of effective N: frozen, effective N = 306; fresh-embryo transfer, effective N = 308) | 69 (22.5) | 83 (26.9) | |||
| Missing, n | 1 | 1 | |||
Sensitivity analysis by compliance status of the freeze-all arm
When the analysis for the primary outcome was undertaken by compliance status of those randomised to the freeze-all arm, there was no difference in the outcome healthy baby rate between those who complied and those who did not comply with the allocated intervention (21.3% vs. 20.0%, respectively) (Table 8).
| Outcome | Treatment received, n (%) | |
|---|---|---|
| Frozen-embryo transfer (N = 202) | Fresh-embryo transfer (N = 96) | |
| Singleton baby born at term with an appropriate weight for gestation | 43 (21.3) | 19 (20.0) |
| Missing | 0 | 1 |
| Singleton | 56 (27.7) | 29 (30.2) |
| Born at term | 52 (25.7) | 26 (27.1) |
| Appropriate weight for gestation | 46 (22.8) | 23 (24.2) |
| Missing | 0 | 1 |
Sensitivity analysis: complier-average causal effect
The CACE RR was 0.77 (0.204/0.264). This was calculated for participants with no missing primary outcome data.
The values in Table 9 are calculated for the would-be non-compliers and would-be compliers of the fresh-embryo transfer arm, assuming the same non-compliance rate and event rate as the non-compliers of the freeze-all arm.20 The CACE RR suggests that there is no difference in the healthy baby rate between the two arms.
| As per compliance status | Freeze-all arm (N = 306) | Fresh-embryo transfer arm (N = 308) | CACE RR (95% CI) | |||
|---|---|---|---|---|---|---|
| Compliance, n (%) | Primary outcome (n/N) | Event rate (%) | Primary outcome (n/N) | Event rate (%) | ||
| Compliers | 211 (69.0) | 43/211 | 20.4 | 56/212 | 26.4 | 0.77 (0.44 to 1.10) |
| Non-compliers | 95 (31.0) | 19/95 | 20.0 | 19/96 | 20.0 | |
| Total | 62/306 | 20.3 | 75/308 | 24.4 | ||
Exploratory analysis on primary outcome
In both arms, the healthy baby rate did not differ depending on whether the analysis was restricted to those who had received the allocated intervention (p = 0.45) or the analysis was undertaken as treated (p = 0.59) (Table 10).
| Analysis | Freeze-all arm | Fresh-embryo transfer arm | RR (95% CI) | p-value | |
|---|---|---|---|---|---|
| Unadjusted | Adjusteda | ||||
| Restricted per-protocol | |||||
| Total couples, excluding those who did not receive their allocated intervention, n | 202 | 282 | |||
| Singleton baby born at term with appropriate weight for gestation, n (%) (percentage is of effective N: frozen, effective N = 202; fresh-embryo transfer, effective N = 281) | 43 (21.3) | 70 (24.9) | 0.85 (0.61 to 1.19) | 0.87 (0.59 to 1.26) | 0.453 |
| Missing, n | 0 | 1 | |||
| As treated | |||||
| Total couples receiving each allocation, N | 223 | 378 | |||
| Singleton baby born at term with appropriate weight for gestation, n (%) (percentage is of effective N: frozen, effective N = 202; fresh-embryo transfer, effective N = 376) | 48 (21.5) | 89 (23.7) | 0.91 (0.67 to 1.24) | 0.91 (0.64 to 1.29) | 0.593 |
| Missing, n | 0 | 2 | |||
Subgroup analysis
The prespecified subgroup analysis for the primary outcome of healthy baby rate was undertaken based on the age of the female partner, number of previous embryo transfers, stage and number of embryos, and fertility clinic. As shown in Figure 10, there was no statistical difference in the healthy baby rate in different age groups (< 35, 35 to < 40 and > 40 years), number of previous embryo transfers (0 or ≥ 1), whether the transfer was undertaken at the cleavage or blastocyst stage, or whether one or two embryos were transferred (Table 11). There was a difference in the healthy baby rate between clinics; however, this is unlikely to be meaningful because of the very small numbers recruited by most clinics. Exploratory analyses were undertaken for method of endometrial preparation and type of freezing. Most frozen-embryo transfers were hormonally mediated and most embryos were frozen by vitrification.
FIGURE 10 Subgroup analysis of the primary outcome. Adjusted for minimisation factors at randomisation. p-values from test of heterogeneity. Reproduced from Maheshwari et al.,23 Elective freezing of embryos versus fresh embryo transfer in IVF: a multicentre randomized controlled trial in the UK (E-Freeze), Human Reproduction, 2022, deab279, by permission of European Society of Human Reproduction and Embryology. (Figure not reproduced here; see the original article.)
| Subgroup analysis | Freeze-all arm (N = 307) | Fresh-embryo transfer arm (N = 309) | RRa (95% CI) | Interaction p-value |
|---|---|---|---|---|
| Woman’s age (years), n/N (%) | 0.100 | |||
| < 35 | 29/153 (19.0) | 45/156 (28.8) | 0.67 (0.31 to 1.45) | |
| 35 to < 40 | 32/136 (23.5) | 28/139 (20.1) | 1.15 (0.60 to 2.18) | |
| ≥ 40 | 1/17 (5.9) | 2/13 (15.4) | 0.41 (0.04 to 4.10) | |
| Fertility clinic, n/N (%) | < 0.001 | |||
| 1 | 2/11 (18.2) | 4/11 (36.4) | 0.45 (0.11 to 1.78) | |
| 2 | 2/13 (15.4) | 3/11 (27.3) | 0.60 (0.12 to 3.00) | |
| 3 | 15/90 (16.7) | 22/92 (23.9) | 0.67 (0.37 to 1.20) | |
| 4 | 9/49 (18.4) | 14/48 (29.2) | 0.68 (0.33 to 1.44) | |
| 5 | 5/31 (16.1) | 9/30 (30.0) | 0.54 (0.20 to 1.42) | |
| 6 | 7/21 (33.3) | 6/29 (20.7) | 1.62 (0.65 to 4.02) | |
| 7 | 4/11 (36.4) | 1/11 (9.1) | 4.46 (0.55 to 36.01) | |
| 8 | 3/24 (12.5) | 4/23 (17.4) | 0.73 (0.18 to 2.93) | |
| 9 | 2/7 (28.6) | 2/7 (28.6) | 0.87 (0.18 to 4.20) | |
| 10 | 0/10 (0.0) | 2/8 (25.0) | – | |
| 11 | 11/29 (37.9) | 7/30 (23.3) | 1.77 (0.79 to 3.97) | |
| 12 | 1/1 (100.0) | 0/1 (0.0) | – | |
| 13 | 1/9 (11.1) | 1/7 (14.3) | 0.88 (0.07 to 10.75) | |
| Previous embryo transfers, n/N (%) | 0.132 | |||
| 0 | 55/283 (19.4) | 72/288 (25.0) | 0.79 (0.56 to 1.10) | |
| ≥ 1 | 7/23 (30.4) | 3/20 (15.0) | 1.95 (0.67 to 5.69) | |
| Stage of embryo at transfer, n/N (%) | 0.821 | |||
| Cleavage | 1/16 (6.3) | 1/20 (5.0) | 1.16 (0.08 to 16.52) | |
| Blastocyst | 61/281 (21.7) | 73/281 (26.0) | 0.84 (0.61 to 1.16) | |
| Missing, n | 9 | 7 | ||
| Embryos transferred | 0.227 | |||
| Single, n/N (%) | 50/248 (20.2) | 66/247 (26.7) | 0.76 (0.55 to 1.05) | |
| Multiple, n/N (%) | 12/49 (24.5) | 9/55 (16.4) | 1.47 (0.58 to 3.75) | |
| Missing, n | 9 | 6 | ||
| Received frozen-embryo transfer, n | 202 | 21 | ||
| Method of endometrial preparation for transfer | ||||
| Natural cycle, n/N (%) | 0/10 (0.0) | 0/6 (0.0) | ||
| Hormone replacement cycle, n/N (%) | 43/191 (22.5) | 5/15 (33.3) | ||
| Missing, n | 1 | 0 | ||
| Method of embryo freezing, n/N (%) | ||||
| Vitrification | 37/178 (20.8) | 5/20 (25.0) | ||
| Slow freezing | 6/24 (25.0) | 0/1 (0.0) | ||
| Overall, n/N (%) | 62/306 (20.3) | 75/308 (24.4) | 0.84 (0.62 to 1.15) | 0.275 |
| Missing, n | 1 | 1 | ||
Secondary outcomes
Maternal safety: ovarian hyperstimulation syndrome
The risk of OHSS was lower in the freeze-all arm (3.6%) than in the fresh-embryo transfer arm (8.1%); however, this difference did not reach statistical significance (RR 0.44, 99% CI 0.15 to 1.30). The severity of OHSS was mild to moderate in the freeze-all arm, whereas six (1.9%) women had severe OHSS in the fresh-embryo transfer arm (Table 12).
| OHSS | Freeze-all arm (N = 307), n (%) | Fresh-embryo transfer arm (N = 309), n (%) | RR (99% CI) | |
|---|---|---|---|---|
| Unadjusted | Adjusteda | |||
| Women with OHSS | 11 (3.6) | 25 (8.1) | 0.44 (0.18 to 1.10) | 0.44 (0.15 to 1.30) |
| Severity | ||||
| Mild | 6 (2.0) | 7 (2.3) | ||
| Moderate | 5 (1.6) | 12 (3.9) | ||
| Severe | 0 (0.0) | 6 (1.9) | ||
Measures of clinical effectiveness
Table 13 presents the measures of clinical effectiveness.
| Measure | Freeze-all arm (N = 307) | Fresh-embryo transfer arm (N = 309) | RR (99% CI) | |
|---|---|---|---|---|
| Unadjusted | Adjusteda | |||
| Live birth episode, n (%) | 87 (28.3) | 106 (34.3) | 0.83 (0.61 to 1.13) | 0.83 (0.65 to 1.06) |
| Singleton baby, n (%) | 85 (27.7) | 105 (34.0) | 0.81 (0.60 to 1.11) | 0.82 (0.64 to 1.06) |
| Singleton baby born at term, n (%) (percentage is of effective N: frozen, effective N = 307; fresh-embryo transfer, effective N = 308) | 78 (25.4) | 93 (30.2) | 0.84 (0.60 to 1.18) | 0.85 (0.67 to 1.08) |
| Missing, n | 0 | 1 | ||
| Singleton baby with appropriate weight for gestation, n (%) (percentage is of effective N: frozen, effective N = 306; fresh-embryo transfer, effective N = 308) | 68 (22.2) | 83 (26.9) | 0.82 (0.57 to 1.19) | 0.83 (0.55 to 1.26) |
| Missing, n | 1 | 1 | ||
| Pregnancy test 2 weeks after embryo transfer, n (%) | ||||
| Positive | 139 (45.3) | 154 (49.8) | 0.91 (0.73 to 1.13) | 0.91 (0.77 to 1.08) |
| Negative | 159 (51.8) | 149 (48.2) | ||
| Clinical pregnancy, n (%) | 104 (33.9) | 124 (40.1) | 0.84 (0.64 to 1.11) | 0.85 (0.65 to 1.11) |
| EPS performed, n (%) | 129 (42.0) | 139 (45.0) | ||
| Ongoing pregnancy, n/N (%) | 104/129 (80.6) | 123/139 (88.5) | ||
| Ectopic pregnancy, n/N (%) | 3/129 (2.3) | 5/139 (3.6) | ||
| Pregnancy of unknown location, n/N (%) | 3/129 (2.3) | 0/139 | ||
| Miscarriage, n/N (%) | 19/129 (14.7) | 11/139 (7.9) | ||
| EPS not performed, n (%) | 178 (58.0) | 170 (55.0) | ||
| Pregnancy lost before date of scan, n/N (%) | 10/178 (5.6) | 15/139 (8.8) | ||
| No embryo transfer or negative pregnancy test, n/N (%) | 165/178 (92.7) | 155/139 (91.2) | ||
| Other, n/N (%) | 3/178 (1.7) | 0/139 (0.0) | ||
There was no significant difference in the live birth rate between the freeze-all arm and the fresh-embryo transfer arm (28.3% vs. 34.3%; adjusted RR 0.83, 99% CI 0.65 to 1.06).
The singleton baby rate was 27.7% in the freeze-all arm and 34.0% in the fresh-embryo transfer arm, but the difference was not statistically significant (adjusted RR 0.82, 99% CI 0.64 to 1.06).
The rate of singleton babies born at term was 25.4% in the freeze-all arm and 30.2% in the fresh-embryo transfer arm. There was no statistically significant difference (adjusted RR 0.85, 99% CI 0.67 to 1.08). The details of gestational age were missing for one baby in the fresh-embryo transfer arm.
The rate of singleton babies with an appropriate weight for their gestational age was 22.2% in the freeze-all arm and 26.9% in the fresh-embryo transfer arm. There was no statistically significant difference (adjusted RR 0.83, 99% CI 0.55 to 1.26). Details were missing for one baby in each arm.
The rate of positive pregnancy tests was 45.3% in the freeze-all arm and 49.8% in the fresh-embryo transfer arm. There was no statistically significant difference (adjusted RR 0.91, 99% CI 0.77 to 1.08).
The clinical pregnancy rate was 33.9% in the freeze-all arm and 40.1% in the fresh-embryo transfer arm. There was no statistically significant difference (adjusted RR 0.85, 99% CI 0.65 to 1.11).
Complications of pregnancy and delivery
Tables 14 (ITT analysis) and 15 (clinically relevant denominators) present the complications in pregnancy and delivery. All complications in pregnancy and delivery are described in text with the clinically relevant denominator.
| Complication | Freeze-all arm (N = 307) | Fresh-embryo transfer arm (N = 309) | RR (99% CI) | |
|---|---|---|---|---|
| Unadjusted | Adjusteda | |||
| Vanishing twin/triplet, n (%) | 4 (1.3) | 4 (1.3) | 1.01 (0.16 to 6.15) | – |
| Pregnancy loss, n (%) | ||||
| Miscarriage | 44 (14.3) | 40 (12.9) | 1.11 (0.66 to 1.87) | 1.09 (0.72 to 1.66) |
| Early (< 12 weeks’ gestation) | 34 (79.1) | 34 (85.0) | ||
| Late (12 to < 24 weeks’ gestation) | 9 (20.9) | 6 (15.0) | ||
| Gestational age unknown | 1 | 0 | ||
| Ectopic | 3 (1.0) | 6 (1.9) | 0.50 (0.08 to 3.07) | – |
| Termination | 2 (0.7) | 2 (0.6) | 1.01 (0.08 to 13.12) | – |
| Pregnancy of unknown location | 3 (1.0) | 0 (0.0) | ||
| GDM, n (%) (percentage is of effective N: frozen, effective N = 305; fresh-embryo transfer, effective N = 306) | 4 (1.3) | 4 (1.3) | 1.00 (0.16 to 6.13) | – |
| Missing | 2 | 3 | ||
| Multiple pregnancy, n (%) | 8 (2.6) | 5 (1.6) | 1.61 (0.38 to 6.89) | – |
| Multiple births, n (%) | 2 (0.7) | 1 (0.3) | 2.01 (0.09 to 46.88) | – |
| Hypertensive disorder, n (%) (percentage is of effective N: frozen, effective N = 305; fresh-embryo transfer, effective N = 306) | 8 (2.6) | 7 (2.3) | 1.15 (0.31 to 4.28) | – |
| Chronic hypertension | 0 (0.0) | 1 (0.3) | ||
| Pregnancy-induced hypertension | 4 (1.3) | 5 (1.6) | ||
| Pre-eclampsia | 5 (1.6) | 1 (0.3) | ||
| Eclampsia | 0 (0.0) | 0 (0.0) | ||
| Missing | 2 | 3 | ||
| Most severe hypertensive disorder experienced, n (%) (percentage is of effective N: frozen, effective N = 305; fresh-embryo transfer, effective N = 306) | ||||
| Chronic hypertension | 0 (0.0) | 1 (0.3) | ||
| Pregnancy-induced hypertension | 3 (1.0) | 5 (1.6) | ||
| Pre-eclampsia | 5 (1.6) | 1 (0.3) | ||
| Eclampsia | 0 (0.0) | 0 (0.0) | ||
| Missing | 2 | 3 | ||
| Antepartum haemorrhage (non-exclusive), n (%) (percentage is of effective N: frozen, effective N = 304; fresh-embryo transfer, effective N = 306) | 12 (3.9) | 13 (4.2) | 0.93 (0.34 to 2.55) | – |
| Placenta praevia | 1 (0.3) | 4 (1.3) | ||
| Placental abruption | 2 (0.7) | 1 (0.3) | ||
| Other | 4 (1.3) | 6 (2.0) | ||
| Unexplained | 6 (2.0) | 4 (1.3) | ||
| Missing | 3 | 3 | ||
| Onset of labour, n (%) (percentage is of effective N: frozen, effective N = 303; fresh-embryo transfer, effective N = 307) | ||||
| Spontaneous | 28 (9.2) | 50 (16.3) | 0.57 (0.32 to 1.00) | 0.57 (0.33 to 1.01) |
| Induced | 37 (12.2) | 39 (12.7) | ||
| Planned caesarean section | 18 (5.9) | 15 (4.9) | ||
| Missing | 4 | 2 | ||
| Mode of delivery, n (%) (percentage is of effective N: frozen, effective N = 303; fresh-embryo transfer, effective N = 307) | ||||
| Normal vaginal delivery | 28 (9.2) | 38 (12.4) | 0.75 (0.41 to 1.37) | 0.75 (0.54 to 1.05) |
| Instrumental vaginal delivery | 20 (6.6) | 30 (9.8) | 0.68 (0.33 to 1.38) | 0.69 (0.39 to 1.21) |
| Caesarean section | 35 (11.6) | 36 (11.7) | 0.99 (0.55 to 1.75) | 0.99 (0.67 to 1.47) |
| Missing | 4 | 2 | ||
| Preterm delivery (< 37 completed weeks of gestation), n (%) (percentage is of effective N: frozen, effective N = 307; fresh-embryo transfer, effective N = 308) | 9 (2.9) | 12 (3.9) | 0.75 (0.25 to 2.30) | – |
| Missing | 0 | 1 | ||
| Very preterm delivery (< 32 completed weeks of gestation), n (%) (percentage is of effective N: frozen, effective N = 307; fresh-embryo transfer, effective N = 308) | 2 (0.7) | 5 (1.6) | 0.40 (0.05 to 3.43) | – |
| Missing | 0 | 1 | ||
| Low birthweight (< 2500 g at birth), n (%) (percentage is of effective N: frozen, effective N = 306; fresh-embryo transfer, effective N = 309) | 7 (2.3) | 13 (4.2) | 0.54 (0.17 to 1.79) | – |
| Missing | 1 | 0 | ||
| Very low birthweight (< 1500 g at birth), n (%) (percentage is of effective N: frozen, effective N = 306; fresh-embryo transfer, effective N = 309) | 1 (0.3) | 8 (2.6) | 0.13 (0.01 to 1.92) | – |
| Missing | 1 | 0 | ||
| High birthweight (> 4000 g at birth), n (%) (percentage is of effective N: frozen, effective N = 306; fresh-embryo transfer, effective N = 309) | 10 (3.3) | 10 (3.2) | 1.01 (0.33 to 3.14) | – |
| Missing | 1 | 0 | ||
| Customised birthweight centile (in live births), mean (SD) (mean is of effective N: frozen, effective N = 306; fresh-embryo transfer, effective N = 308) | 53.1 (27.9) | 45.3 (27.9) | – | – |
| Missing, n | 1 | 1 | ||
| High weight for gestational age (> 90th centile), n (%) (percentage is of effective N: frozen, effective N = 306; fresh-embryo transfer, effective N = 308) | 9 (2.9) | 10 (3.2) | 0.91 (0.28 to 2.90) | – |
| Missing | 1 | 1 | ||
| Low weight for gestational age (< 10th centile), n (%) (percentage is of effective N: frozen, effective N = 306; fresh-embryo transfer, effective N = 308) | 8 (2.6) | 12 (3.9) | 0.67 (0.21 to 2.13) | – |
| Missing | 1 | 1 | ||
| Congenital anomaly/birth defect, n (%) (percentage is of effective N: frozen, effective N = 305; fresh-embryo transfer, effective N = 308) | 6 (2.0) | 7 (2.3) | 0.87 (0.21 to 3.57) | – |
| Tongue tie | 1 (0.3) | 2 (0.6) | ||
| Cleft palate | 1 (0.3) | 2 (0.6) | ||
| Other | 3 (1.0) | 1 (0.3) | ||
| Missing | 2 | 1 | ||
| Perinatal mortality up to 28 days after birth, n (%) | 1 (0.3) | 0 (0.0) | – | – |
| Stillbirth | 0 (0.0) | 0 (0.0) | ||
| Neonatal death up to 28 days after birth | 1 (0.3) | 0 (0.0) | ||
| Complication | Freeze-all arm, n (%) | Fresh-embryo transfer arm, n (%) | RR (99% CI) | |
|---|---|---|---|---|
| Unadjusted | Adjusteda | |||
| Women with a positive pregnancy test at 2 weeks ± 3 days after embryo transfer | ||||
| Sample size | 139 | 154 | ||
| Miscarriage | 44 (31.7) | 40 (26.0) | 1.22 (0.76 to 1.96) | 1.18 (0.76 to 1.84) |
| Early (< 12 weeks’ gestation) | 34/43 (79.1) | 34/40 (85.0) | ||
| Late (12 to < 24 weeks’ gestation) | 9/43 (20.9) | 6/40 (15.0) | ||
| Gestation unknown | 1 | 0 | ||
| Multiple pregnancy | 8 (5.8) | 5 (3.2) | 1.77 (0.42 to 7.46) | – |
| Pregnant women with an ongoing pregnancy resulting in delivery | ||||
| Sample size | 87 | 106 | ||
| GDM (percentage is of effective N: frozen, effective N = 85; fresh-embryo transfer, effective N = 103) | 4 (4.7) | 4 (3.9) | 1.21 (0.20 to 7.20) | – |
| Missing | 2 | 3 | ||
| Multiple pregnancy | 4 (4.6) | 4 (3.8) | 1.22 (0.20 to 7.25) | – |
| Hypertensive disorder (percentage is of effective N: frozen, effective N = 85; fresh-embryo transfer, effective N = 103) | 8 (9.4) | 7 (6.8) | 1.38 (0.39 to 4.97) | – |
| Chronic hypertension | 0 | 1 (1.0) | ||
| Pregnancy-induced hypertension | 4 (4.7) | 5 (4.9) | ||
| Pre-eclampsia | 5 (5.9) | 1 (1.0) | ||
| Eclampsia | 0 | 0 | ||
| Missing | 2 | 3 | ||
| Most severe hypertensive disorder experienced (percentage is of effective N: frozen, effective N = 85; fresh-embryo transfer, effective N = 103) | ||||
| Chronic hypertension | 0 | 1 (1.0) | ||
| Pregnancy induced hypertension | 3 (3.5) | 5 (4.9) | ||
| Pre-eclampsia | 5 (5.9) | 1 (1.0) | ||
| Eclampsia | 0 | 0 | ||
| Missing | 2 | 3 | ||
| Antepartum haemorrhage (percentage is of effective N: frozen, effective N = 84; fresh-embryo transfer, effective N = 103) | 11 (13.1) | 12 (11.7) | 1.12 (0.41 to 3.07) | – |
| Placenta praevia | 1 (1.2) | 4 (3.9) | ||
| Placental abruption | 2 (2.4) | 1 (1.0) | ||
| Other | 4 (4.8) | 6 (5.8) | ||
| Unexplained | 5 (6.0) | 3 (2.9) | ||
| Missing | 3 | 3 | ||
| Preterm delivery (< 37 completed weeks of gestation) (percentage is of effective N: frozen, effective N = 87; fresh-embryo transfer, effective N = 105) | 9 (10.3) | 12 (11.4) | 0.91 (0.31 to 2.65) | – |
| Missing | 0 | 1 | ||
| Very preterm delivery (< 32 completed weeks of gestation) (percentage is of effective N: frozen, effective N = 87; fresh-embryo transfer, effective N = 105) | 2 (2.3) | 5 (4.8) | 0.48 (0.06 to 4.03) | – |
| Missing | 0 | 1 | ||
| Onset of labour (percentage is of effective N: frozen, effective N = 83; fresh-embryo transfer, effective N = 104) | ||||
| Spontaneous | 28 (33.7) | 50 (48.1) | 0.70 (0.44 to 1.13) | 0.69 (0.43 to 1.11) |
| Induced | 37 (44.6) | 39 (37.5) | ||
| Planned caesarean section | 18 (21.7) | 15 (14.4) | ||
| Missing | 4 | 2 | ||
| Babies born | ||||
| Sample size | 89 | 107 | ||
| Mode of delivery for each baby (percentage is of effective N: frozen, effective N = 85; fresh-embryo transfer, effective N = 105) | ||||
| Normal vaginal delivery | 28 (32.9) | 38 (36.2) | 0.91 (0.54 to 1.53) | 0.92 (0.63 to 1.33) |
| Instrumental vaginal delivery | 20 (23.5) | 30 (28.6) | 0.82 (0.43 to 1.56) | 0.84 (0.56 to 1.27) |
| Caesarean section | 37 (43.5) | 37 (35.2) | 1.24 (0.77 to 1.97) | 1.21 (0.98 to 1.51) |
| Missing | 4 | 2 | ||
| Low birthweight (< 2500 g at birth) (percentage is of effective N: frozen, effective N = 88; fresh-embryo transfer, effective N = 105) | 8 (9.1) | 14 (13.1) | 0.69 (0.24 to 2.05) | – |
| Missing | 1 | 0 | ||
| Very low birthweight (< 1500 g at birth) (percentage is of effective N: frozen, effective N = 88; fresh-embryo transfer, effective N = 85) | 1 (1.1) | 8 (7.5) | 0.15 (0.01 to 2.28) | – |
| Missing | 1 | 0 | ||
| High birthweight (> 4000 g at birth) (percentage is of effective N: frozen, effective N = 88; fresh-embryo transfer, effective N = 85) | 10 (11.4) | 10 (9.3) | 1.22 (0.41 to 3.62) | – |
| Missing | 1 | 0 | ||
| High weight for gestational age (> 90th centile) (percentage is of effective N: frozen, effective N = 88; fresh-embryo transfer, effective N = 106) | 9 (10.2) | 10 (9.4) | 1.08 (0.35 to 3.33) | – |
| Missing | 1 | 1 | ||
| Low weight for gestational age (< 10th centile) (percentage is of effective N: frozen, effective N = 88; fresh-embryo transfer, effective N = 106) | 9 (10.2) | 12 (11.3) | 0.90 (0.31 to 2.64) | – |
| Missing | 1 | 1 | ||
| Congenital anomaly/birth defect (percentage is of effective N: frozen, effective N = 87; fresh-embryo transfer, effective N = 106) | 5 (5.7) | 5 (4.7) | 1.22 (0.25 to 5.95) | – |
| Tongue tie | 1 (1.1) | 2 (1.9) | ||
| Cleft palate | 1 (1.1) | 2 (1.9) | ||
| Other | 3 (3.4) | 1 (0.9) | ||
| Missing | 2 | 1 | ||
| Perinatal mortality up to 28 days after birth | 1 (1.1) | 0 | ||
| Stillbirth | 0 | 0 | ||
| Neonatal death up to 28 days after birth | 1 (1.1) | 0 | ||
Early-pregnancy loss
There were three ectopic pregnancies in the freeze-all arm and six in the fresh-embryo transfer arm (RR 0.50, 99% CI 0.08 to 3.07) (see Table 14). Two participants underwent a termination in each arm.
There was no statistically significant difference in the risk of miscarriage in pregnancies as a result of frozen-embryo transfer compared with that of fresh-embryo transfer (31.7% vs. 26.0%, respectively) (adjusted RR 1.18, 99% CI 0.76 to 1.84) (see Table 15).
Multiple pregnancies
There were four cases of vanishing twins in each arm. There were eight cases of multiple pregnancy in the freeze-all arm and five in the fresh-embryo transfer arm (see Table 14). For births, only two couples had multiple births in the freeze-all arm and one couple had a multiple birth in the fresh-embryo transfer arm.
Obstetric complications:
There was no difference in the risk of GDM in pregnancies as a result of frozen-embryo transfer and pregnancies as a result of fresh-embryo transfer (4.7% vs. 3.9%, respectively; RR 1.21, 99% CI 0.20 to 7.20).
There was no difference in the risk of hypertensive disorder in pregnancies as a result of frozen-embryo transfer and pregnancies as a result of fresh-embryo transfer (9.4% vs. 6.8%, respectively) (RR 1.38, 99% CI 0.39 to 4.97). There were no cases of eclampsia in the trial. There were five cases of pre-eclampsia (5.9%) in women who were pregnant as a result of frozen-embryo transfer and one (1%) in a woman pregnant as a result of fresh-embryo transfer.
The risk of antepartum haemorrhage was 13.1% in the freeze-all arm and 11.7% in the fresh-embryo transfer arm (RR 1.12, 99% CI 0.41 to 3.07) (see Table 15).
The risk of preterm delivery was 10.3% in deliveries in the freeze-all arm and 11.4% in those in the fresh-embryo transfer arm (RR 0.91, 99% CI 0.31 to 2.65). There was no difference in the risk of very preterm delivery between the freeze-all arm (2.3%) and the fresh-embryo transfer arm (4.8%) (RR 0.48, 99% CI 0.06 to 4.03).
There were no statistical differences between groups (adjusted RR 0.69, 99% CI 0.43 to 1.11) in the proportion of women undergoing spontaneous labour (frozen-embryo transfer arm, 33.7%, vs. fresh-embryo transfer arm, 48.1%), induced labour (44.6% vs. 37.5%, respectively) or planned caesarean section (21.7% vs. 14.4%, respectively). Data on onset of labour were missing for six couples (four in the frozen-embryo arm and two in the fresh-embryo arm).
A total of 196 babies (89 in the freeze-all arm and 107 in the fresh-embryo transfer arm) were born. In both arms, one-third of babies (freeze-all arm, 32.9%, vs. fresh-embryo transfer arm, 36.2%) were born by normal vaginal delivery (adjusted RR 0.92, 99% CI 0.63 to 1.33). The corresponding figures for instrumental vaginal delivery were 23.5% and 28.6%, respectively (adjusted RR 0.84, 99% CI 0.56 to 1.27), and for caesarean section were 43.5% and 35.2%, respectively (adjusted RR 1.21, 99% CI 0.98 to 1.51). Six couples (four in the freeze-all arm and two in the fresh-embryo transfer arm) had missing outcome data for mode of delivery.
The details of obstetric complications, with clinically relevant denominators, are reported in Table 15.
Neonatal outcomes
The risk of having a baby with a low birthweight was not statistically significantly different in the freeze-all arm and the fresh-embryo transfer arm (9.1% vs. 13.1%, respectively; RR 0.69, 99% CI 0.24 to 2.05). Similarly, the risk of delivering a low-birthweight baby was not significantly different between arms (1.1% vs. 7.5%, respectively; RR 0.15, 99% CI 0.01 to 2.28).
There was no statistically significant difference between arms in the proportion of babies born with a high birthweight (freeze-all arm, 11.4%, vs. fresh-embryo transfer arm, 9.3%; RR 1.22, 99% CI 0.41 to 3.62).
There was no statistically significant difference between arms in the risk of having a baby with a high birthweight for gestational age (freeze-all arm, 10.2%, vs. fresh-embryo transfer arm, 9.4%; RR 1.08, 99% CI 0.35 to 3.33).
There was no statistically significant difference between arms in the risk of having a baby with a low birthweight for gestational age (freeze-all arm, 10.2%, vs. fresh-embryo transfer arm, 11.3%; RR 0.90, 99% CI 0.31 to 2.64).
There was no difference between arms in the rate of congenital anomalies (freeze-all arm, 5.7%, vs. fresh-embryo transfer arm, 4.7%; RR 1.22, 99% CI 0.25 to 5.95). There was one neonatal death in the freeze-all arm and no neonatal deaths in the fresh-embryo transfer arm.
The details of neonatal outcomes, with clinically relevant denominator, are reported in Table 15.
Measures of effectiveness of the process of freezing embryos
The following measures were used to determine the effectiveness of the freezing process:
- the total number of embryos frozen, thawed and transferred for all randomised couples
- the proportion of thawed embryos that were then transferred for all randomised couples
- no embryos surviving after thawing, leading to no embryo transfer.
To transfer 248 embryos, 280 embryos had to be thawed (i.e. 88.6% of embryos were suitable for transfer after being thawed) (Table 16).
| Measure | Couples (N = 616) |
|---|---|
| Total number of embryos | |
| Frozen | 967 |
| Thawed | 280 |
| Transferred | 248 |
| Percentage of thawed embryos that were then transferred | 88.6 |
Three couples in the freeze-all arm did not have any embryos to transfer because their embryos did not survive the freezing–thawing process (Table 17).
| Freeze-all arm (N = 307) | Fresh-embryo transfer arm (N = 309) | |
|---|---|---|
| No embryos survived thawing, leading to no embryo transfer, n (%) | 3 (1.0) | 0 (0.0) |
Evaluation of emotional status
The couples’ emotional state was assessed using the STAI questionnaire.16 Both partners completed the questionnaire at two time points (at consent and at embryo transfer).
Table 18 reports the data from the STAI questionnaire.
| Parameters | Freeze-all arm (N = 307) | Fresh-embryo transfer arm (N = 309) | MD (99% CI) | |
|---|---|---|---|---|
| Unadjusteda | Adjustedb | |||
| Consent | ||||
| Emotional state score | ||||
| Female partner complete responses, n | 295 | 295 | ||
| STAI score, mean (SD) | 35.8 (10.2) | 35.0 (10.5) | ||
| Male partner complete responses, n | 294 | 295 | ||
| STAI score, mean (SD) | 30.6 (8.8) | 29.9 (8.1) | ||
| Overall satisfaction with the IVF treatment process at consent, n/N (%) | ||||
| Female partner | ||||
| Very satisfied | 179/296 (60.5) | 174/294 (59.2) | ||
| Satisfied | 96/296 (32.4) | 102/294 (34.7) | ||
| Neither satisfied nor dissatisfied | 19/296 (6.4) | 17/294 (5.8) | ||
| Dissatisfied | 1/296 (0.3) | 1/294 (0.3) | ||
| Very dissatisfied | 1/296 (0.3) | 0/294 | ||
| Missing | 11 | 15 | ||
| Male partner | ||||
| Very satisfied | 190/295 (64.4) | 181/294 (61.6) | ||
| Satisfied | 87/295 (29.5) | 102/294 (34.7) | ||
| Neither satisfied nor dissatisfied | 17/295 (5.8) | 11/294 (3.7) | ||
| Dissatisfied | 1/295 (0.3) | 0/294 | ||
| Very dissatisfied | 0/295 | 0/294 | ||
| Missing | 12 | 15 | ||
| At embryo transfer | ||||
| Emotional state scores | ||||
| Female partner complete responses, nc | 218 | 227 | ||
| STAI score, mean (SD) | 38.2 (11.4) | 37.4 (10.8) | 0.0 (–2.4 to 2.3) | 0.0 (–2.2 to 2.2) |
| Male partner complete responses, nc | 203 | 218 | ||
| STAI score, mean (SD) | 33.5 (11.0) | 32.4 (9.1) | 0.1 (–1.9 to 2.2) | 0.1 (–2.4 to 2.6) |
| Overall satisfaction with the IVF treatment process at embryo transfer, n/N (%) | ||||
| Female partner | ||||
| Very satisfied | 119/217 (54.8) | 151/231 (65.4) | ||
| Satisfied | 78/217 (35.9) | 68/231 (29.4) | ||
| Neither satisfied nor dissatisfied | 8/217 (3.7) | 9/231 (3.9) | ||
| Dissatisfied | 3/217 (1.4) | 2/231 (0.9) | ||
| Very dissatisfied | 9/217 (4.1) | 1/231 (0.4) | ||
| Missing | 90 | 78 | ||
| Male partner | ||||
| Very satisfied | 123/203 (60.6) | 141/219 (64.4) | ||
| Satisfied | 68/203 (33.5) | 71/219 (32.4) | ||
| Neither satisfied nor dissatisfied | 9/203 (4.4) | 3/219 (1.4) | ||
| Dissatisfied | 2/203 (1.0) | 3/219 (1.4) | ||
| Very dissatisfied | 1/203 (0.5) | 1/219 (0.5) | ||
| Missing | 104 | 90 | ||
Emotional state score
A total of 295 women and 294 men in the freeze-all arm and 295 women and 295 men in the fresh-embryo transfer arm completed the questionnaire at consent. A total of 218 women and 203 men in the freeze-all arm and 227 women and 218 men in the fresh-embryo transfer arm completed the questionnaire at embryo transfer.
At the time of consent, the mean STAI score for female partners was 35.8 (SD 10.2) in the freeze-all arm and 35.0 (SD 10.5) in the fresh-embryo transfer arm. At embryo transfer, the mean STAI score for female partners was 38.2 (SD 11.4) in the freeze-all arm and 37.4 (SD 10.8) in the fresh-embryo transfer arm. There was no statistical difference between the two arms (adjusted MD 0.0, 99% CI –2.2 to 2.2).
At the time of consent, the mean STAI score for male partners was 30.6 (SD 8.8) in the freeze-all arm and 29.9 (SD 8.1) in fresh-embryo transfer arm. At embryo transfer, the mean STAI score for male partners was 33.5 (SD 11.0) in the freeze-all arm and 32.4 (SD 9.1) in the fresh-embryo transfer arm. There was no statistical difference between the two arms (adjusted MD 0.1, 99% CI –2.4 to 2.6).
Satisfaction with process at consent and embryo transfer
Most female partners who responded (92.9% in the freeze-all arm and 93.9% in the fresh-embryo transfer arm) were either satisfied or very satisfied at the time of consent.
Most female partners (90.8% in the freeze-all arm and 94.8% in the fresh-embryo transfer arm) were either satisfied or very satisfied at the time of embryo transfer.
Most male partners who responded (93.9% in the freeze-all arm and 96.3% in the fresh-embryo transfer arm) were either satisfied or very satisfied at the time of consent.
Most male partners (94.1% in the freeze-all arm and 96.8% in the fresh-embryo transfer arm) were either satisfied or very satisfied at the time of embryo transfer.
Serious adverse events
There were 30 AEs reported, as per the SAE reporting described in Chapter 2. None was directly related to the intervention. Two cases of ectopic pregnancies were assessed by the PI as related; however, the chief investigator and the sponsor’s assessment found that they were unrelated. Details of all SAEs are given in Appendix 4.