Fertility after ectopic pregnancy: the DEMETER randomized trial

Abstract

Does treatment for the resolution of ectopic pregnancy (EP) affect subsequent spontaneous fertility [occurrence of an intrauterine pregnancy (IUP)]? There is no significant difference in 2 years subsequent fertility neither between methotrexate and conservative surgery for less active EP nor between conservative and radical surgery for the most active EP. No randomized trial has compared radical and conservative surgery treatments. A recent review of the Cochrane database did not conclude about fertility due to insufficient data. Prospective studies from EP registries in two regions of France (Auvergne and Greater Lille) have suggested that fertility is similar after medical treatment and conservative surgery and lower after radical surgery. This randomized controlled trial included all women with an ultrasound-confirmed EP. Women were divided into two arms according to the activity of the EP (defined by Fernandez's score). In arm 1 (less active ectopic pregnancies, i.e. Fernandez's score <13 and no haemodynamic failure), medical treatment was considered practicable, and women were randomly allocated to conservative surgery with a systematic post-operative i.m. methotrexate injection within 24 h or to an i.m. methotrexate injection alone. In arm 2 (active ectopic pregnancies), medical treatment was considered impracticable, and, thus, all women had to undergo surgery; they were randomly allocated to either a radical or conservative procedure, the latter including a post-operative methotrexate injection. Sample sizes (n = 210 in arm 1 and n = 230 in arm 2) were computed to provide a statistical power of 80% to detect a 20% difference in subsequent cumulative fertility rates between treatments in each arm. The total duration of the trial was 5 years. The trial took place in 17 centres in France from 2005 to 2009. Two hundred and seven women were included in arm 1 and 199 in arm 2. Cumulative fertility curves were drawn with the Kaplan-Meier method and compared with the log-rank test. Hazard ratios (HRs) were computed with the Cox model. Analysis was performed according to the intention-to-treat principle. Arm 1: cumulative fertility curves were not significantly different between medical treatment and conservative surgery. HR was 0.85 (0.59-1.22) P = 0.37. The 2-year rates of IUP were 67% after medical treatment and 71% after conservative surgery. Arm 2: cumulative fertility curves were not significantly different between conservative and radical surgery. HR was 1.06 (0.69-1.63) P = 0.78. The 2-year rates of IUP were 70% after conservative surgery and 64% after radical surgery. Inclusion in this trial was more difficult than expected, especially in arm 2 in which women were reluctant to radical surgery. In consequence, the sample size was slightly lower than planned. However, due to a lower proportion of lost to follow-up than expected (10% instead of 15%), the statistical power remained very close to 80%. As it is a multicentre randomized trial, the results may be generalized with satisfactory confidence. The results of this trial invite gynaecologists to reconsider the management of EP and to modify balance between considerations of initial recovery and preservation of fertility. NCT00137982 on the WHO International Clinical Trials Registry Platform.