Prevention of multiple pregnancies in couples with unexplained or mild male subfertility.

In couples with unexplained subfertility or mild male subfertility and an
unfavourable prognosis for conception, intra-uterine insemination with
controlled ovarian hyperstimulation is standard treatment in the Netherlands.
The disadvantage of the adjuvant ovarian hyperstimulation is the risk of
multiple births. Multiple births present substantial perinatal risks to both
mother and infant. Mothers with multiples pregnancies have extremely high rates
of ante- and postpartum complications. Twins and triplets are at high risk to
be born prematurely with consequent increased morbidity, resulting in admission
to neonatal intensive care. Even so, mortality rates are high and costs for
society are astronomical.
Elective single embryo transfer (eSET) either in IVF cycles with mild ovarian
hyperstimulation or in the manipulated natural cycle (MNC) IVF are alternative
treatments that prevent multiple pregnancies. These interventions may therefore
be potentially more cost-effective than intra-uterine insemination with
controlled ovarian hyperstimulation.

1. To prevent multiple pregnancies and the concomittant neonatal mortality and
morbidity while retaining acceptable delivery rates in couples with unexplained
subfertility or mild male subfertility and poor fertility prospects.

2. To assess the preference of couples for the treatments under study and to
asses how couples value a twin as an outcome compared to a singleton or to no
pregnancy.

Multicenter RCT in all eight academic centers and their affiliated clinics in
the Netherlands.

ANALYSIS: Analyses will be on an intention to treat basis. Differences in
delivery rates per group will be expressed as relative risks and delivery rates
over time will be compared using life tables. In anticipation of a reduction of
the number of multiple pregnancies and the composite neonatal morbidity from
either MNC-IVF of IVF e-SET, we accept a reduction in live birth rate of 12.5%.
We need to randomise 3 groups of 200 couples.
A patient preference study will be performed to evaluate how couples value
multiple pregnancies and the adjacent neonatal morbidity relative to a
singleton pregnancy and to no pregnancy.
ECONOMIC EVALUATION: A cost-effectiveness analysis with costs of treatment
until 6 weeks after the term date within a time horizon of 10 months. A
literature search will be performed to estimate live-long costs due to
handicaps. We will perform a scenario analysis, in which we will model the
costs and effects of the three strategies in this perspective.

INTERVENTIONS: Group A- 6 cycles intra-uterine insemination with controlled
ovarian hyperstimulation. Group B - 6 cycles MNC-IVF followed by IVF-eSET.
Group C - 3 cycles of IVF-eSET plus cryo-cycles. The time horizon for the three
treatment strategies is 10 months.

A structured interview will be held (patient preference study). Furthermore
questionaires will be sent for details on associated direct costs of
professional care, and on indirect costs like transportation and productivity
loss at six time points (4 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks and 48
weeks after treatment start). Patients will be asked for information on the
health of the child 6 weeks after the expected day of delivery.