Natural ovulation versus programmed regimens before frozen embryo transfer in ovulatory women: multicentre,...

To test the hypothesis that women assigned to a natural ovulation regimen before frozen embryo transfer compared with a programmed regimen would have an increased chance of a healthy live birth and a reduced risk of pre-eclampsia or eclampsia.

Multicentre, randomised, parallel group, assessor blinded clinical trial.

24 academic fertility centres in China.

4376 ovulatory women (aged 20-40 years) planning to undergo a frozen single blastocyst transfer.

Eligible participants were randomised (1:1) to receive a natural ovulation regimen or a programmed regimen of hormone replacement for endometrial preparation. Endometrial preparation and frozen embryo transfer timing were determined in the natural ovulation regimen group by monitoring natural follicle development and measuring serum levels of luteinising hormone, oestradiol, and progesterone. In the programmed regimen group, endometrial preparation was achieved by sequential administration of oestrogen and progesterone.

Primary outcomes were a healthy live birth and pre-eclampsia or eclampsia after a frozen embryo transfer. Secondary outcomes were cycle cancellation, biochemical pregnancy, clinical pregnancy, ongoing pregnancy, pregnancy loss, ectopic pregnancy, live birth, birth weight, and maternal, fetal, and neonatal complications.

In the intention-to-treat analyses, 910 (41.6%) of 2185 patients in the natural ovulation regimen group and 890 (40.6%) of 2191 in the programmed regimen group achieved a healthy live birth (relative ratio 1.03 (95% confidence interval (CI) 0.96 to 1.10); P=0.49). The risk of pre-eclampsia was lower in the natural ovulation regimen group among patients who achieved clinical pregnancy than in the programmed regimen group (2.9% (38 of 1302) v 4.6% (61 of 1326); 0.63 (0.43 to 0.94); P=0.02). The incidences of early pregnancy loss (12.1% (158 of 1302) v 15.2% (201 of 1326); 0.80 (0.66 to 0.97)), placental accreta spectrum (1.8% (24 of 1302) v 3.6% (48 of 1326); 0.51 (0.31 to 0.83)), caesarean section (69.5% (776 of 1117) v 75.6% (831 of 1100); 0.92 (0.87 to 0.97)), and postpartum haemorrhage (2.0% (22 of 1117) v 6.1% (67 of 1100); 0.32 (0.20 to 0.52)) were lower in the natural ovulation regimen group. No differences between groups were observed for birth weight or neonatal complications. The rate of cycle cancellation was higher in the natural ovulation regimen (16.2% (354 of 2185) v 11.5% (251 of 2191), P<0.001). The prespecified per protocol and subgroup analyses yielded results consistent with the intention-to-treat analyses.

In ovulatory women, a natural ovulation regimen for endometrial preparation was as effective as programmed regimen in terms of achieving a healthy live birth after frozen embryo transfer, but with a lower risk of maternal complications during pregnancy.

Chinese Clinical Trial Registry ChiCTR2200057990.