A randomised controlled trial comparing in vitro maturation of oocytes with in vitro fertilisation in women with an increased risk of ovarian hyperstimulation syndrome.

Current ART requires COH to increase the number of oocytes. COH can lead to
OHSS. In IVM immature oocytes are harvested from the ovaries without COH and
matured in vitro in approximately 30 hours. These in vitro matured oocytes can
be fertilised by IVF or ICSI. The first IVM-pregnancy was reported in 1991. It
is estimated that since then over 1100 IVM children have been born worldwide.
In recent years the IVM technique has become increasingly effective. In
observational studies the delivery rate of an IVM cycle was 10-15%. Due to the
absence of COH IVM has a potential benefit for patients with an increased risk
of developing OHSS, such as PCOS-patients. These potential benefits extend to
patient friendliness and reduced costs.

Primary objective: To evaluate the cumulative live birth rate for two treatment
strategies: 2 IVM/ICSI cycles versus 1 COH/IVF or COH/ICSI cycle.
Secondary Objectives: To evaluate the health and development of IVM/ICSI
children versus COH/IVF/ICSI children in 5 years* follow up program. To
evaluate the number and nature of adverse events during or following the two
treatment strategies. To evaluate the direct and indirect costs of the two
treatment strategies. To evaluate patients* quality of life during and after
the two treatment strategies.

Multicentre randomised clinical trial in 400 couples. The trial will be
preceded by a pilot study of 50 non-randomised IVM cycles for implementation of
the technique.

2 IVM/ICSI cycles or 1 COH/IVF or COH/ICSI cycle.

Advantages of IVM
The main advantage of IVM is that a number of oocytes can be retrieved without
COH. This makes it a more patient friendly procedure. The risk of OHSS is also
abolished and the costs per cycle are lower in IVM/ICSI than in COHIVF or
COH/ICSI. Severe OHSS occurs in 2% of IVF cycles, PCOS patients especially are
at risk. Severe OHSS can entail ascites, pleural effusion, dyspnoea, organ
failure and venous thrombosis or lung embolism. Also death from OHSS has
occurred. OHSS is treated by hospital admittance, intravenous fluids,
anticlotting therapy and draining of ascites (NVOG-guideline no. 11).

Disadvantages of IVM
The oocyte retrieval in IVM is technically more difficult and possibly more
painful. The efficiency per cycle is lower in IVM/ICSI than in COH/IVF of
COH/ICSI. IVM is more laborious for the IVF lab. The safety of IVM for the
offspring is still subject to debate.

Risks of IVM for the woman
Oocyte retrieval in IVM, as in IVF, has the risks of bleeding and infection.
Possibly these risks are larger in IVM as the retrieval is technically more
demanding and takes more time. Although it can be expected that IVM oocyte
retrieval is more painful, in a study on perception of pain, pain was less than
expected and acceptable to patients (Hildebrandt 2001). There are no published
studies in which IVM and IVF oocyte retrievals were compared directly.

Risks of IVM for the child
IVM is possibly associated with an increased risk for congenital abnormalities
and developmental disorders. Theoretically, such risks can arise from the use
of immature oocytes or disturbance of genetic imprinting during in vitro
maturation procedures. In some domestic animals IVM was associated with *large
offspring syndrome*. However, further animal studies showed that this syndrome
could not be attributed to IVM exclusively. Also super ovulation, prolonged
incubation time and the IVF procedure can be pointed out as risk factors for
the *large offspring syndrome* (Van Wagtendonk-de Leeuw et al., 2000). *Large
offspring syndrome* in humans has not been documented thus far. In the mouse
model, the long terms health effects of IVM on the offspring was studied and
appeared to be minimal apart from slight changes in pulse rate and cardiac
output (Eppig et al., 2009).
Health studies on IVM children are still limited, as summarised in the table in
Attachment 1. In all, group sizes are relatively small and follow up periods
short. In a single study children were monitored until the age of two years.
The studies on IVM children reported birth weights in the normal range,
therefore no signs of *large offspring syndrome* are present. Furthermore, the
incidence of congenital abnormalities is not increased in IVM children compared
to the general population.