Early versus late insemination relative to ovulation in subfertile couples: a trial-based cost-effectiveness study.

Intra-uterine insemination (IUI) combined with mild ovarian stimulation (MOS)
and triggering of ovulation by human chorionic gonadotropin (hCG) is a common
treatment for subfertility, with pregnancy rates varying between 7 and 12% per
cycle and estimated hospital costs of ¤ 850 per cycle (ESHRE Capri Workshop
Group, 2009; Steures et al., 2009). To couples who do not conceive after
several cycles of IUI-MOS, In Vitro Fertilization (IVF) treatment is offered,
with pregnancy rates varying between 26 and 28% per cycle and estimated
hospital costs of ¤4,500 per cycle (Fiddelers, 2010). The current practice in
IUI-MOS is to administer hCG for triggering of ovulation when the largest
follicle has reached a diameter of 16-18 mm, followed by IUI 32-36 hours later
(i.e. around the expected time of ovulation). However, clinical studies to
support this particular 32-36 hours interval between hCG and IUI are lacking
(Ragni et al., 2004; Snick et al., 2008; Cantineau et al., 2010). Studies on
natural conception have shown that the maximum probability of pregnancy occurs
with intercourse one day prior to ovulation (Dunson et al., 1999). Therefore,
it is hypothesized that IUI should be performed one day prior to ovulation as
triggered by hCG administration, rather than in the peri-ovulatory phase as is
current practice. Increasing the effectiveness of IUI-MOS would decrease the
need for additional IUI-MOS cycles and for subsequent IVF, resulting in
substantial health care cost-savings.

The main objective is to determine the effectiveness of IUI-MOS, comparing the
ongoing pregnancy rate of a treatment strategy comprising a maximum of four
cycles of IUI-MOS when performing IUI 32-36 hours after triggering of ovulation
by hCG (*late IUI*) with IUI at the time of triggering of ovulation by hCG
(*early IUI*). The secondary objective is to determine (ongoing) pregnancy rate
per cycle and per cause of subfertility, miscarriage rate, multiple pregnancy
rate, live birth rate and adverse events. The tertiary objective is to
determine the cost-effectiveness, cost-savings and budget impact resulting from
a reduction of the need for additional IUI-MOS cycles and subsequent IVF
treatment. Condition-specific questionnaires will be used to determine patient
satisfaction (PCQ-Infertility) and quality of life (FertiQol).

Multi-center open-label randomized controlled trial.

In group one (*late IUI*), IUI will be performed 32-36 hours after triggering
of ovulation by hCG, which is administered when the largest follicle has
reached a diameter of 16-18 mm. In group two ("early IUI"), IUI will be
performed at the time of triggering of ovulation by hCG, which is on the day
the largest follicle has reached a diameter of 16-18 mm.

Because only timing of IUI will be different in the two study groups, no burden
or risks are involved. No extra blood samples or extra visits are needed.
During each cycle, all couples are asked to fill in a questionnaire about
factors potentially influencing pregnancy rate (e.g. weight, smoking, natural
intercourse during treatment).