Comparative, controlled trial of treatment of minor uterine cavity abnormalities diagnosed by office hysteroscopy screening in women indicated for IVF.

Despite advances in IVF procedures and the transfer of embryos of high
morphological quality, pregnancy rates from IVF remain around 30% per embryo
transfer procedure. Failure of transferred embryos to implant remains the most
important limiting factor determining in vitro fertilization (IVF) or intra
cytoplasmic sperm injection (ICSI) success rates. If progress is to be made in
improving implantation rates, a greater understanding of the factors which
determine successful implantation is required. Recurrent implantation failure
after IVF may be due to an endometrial, an embryo problem or both
Although the influence of uterine cavity abnormalities on outcome of
infertility treatment is largely unknown, treatment of these abnormalities has
been advocated on a wide scale without any evidence. Prospective and randomized
studies evaluating the consequences of predefined uterine cavity deformities
(septum arcuatus, bicornis) or intra cavitary abnormalities (submucosal myomas,
endometrial polyps, endometritis) on fertility outcome are very few. Therefore,
the influence of treatment of these abnormalities on fertility outcome is even
less well known. The current literature describes an incidence of unexpected
uterine abnormalities observed by hysteroscopy evaluation of ~ 40% in cases
with normal TVS and no clinical signs. In cases treated for the predefined
abnormality the increase in cumulative ongoing pregnancy rate after two
consecutive cycles of IVF/ICSI is estimated to be 15% (25 versus 40%)

To evaluate the impact of treatment of undetected, asymptomatic, predefined
uterine abnormalities on the success of IVF treatment

Patients scheduled for a first IVF/ICSI treatment at the VUB/Utrecht/Rotterdam
undergo a standard office hysteroscopy in the follicular phase of a cycle 1-3
months before starting the IVF/ICSI treatment. In the case of finding a
predefined intra uterine abnormality randomization will be carried out after
informed consent for endoscopy treatment versus no treatment. Shortly after the
hysteroscopy screening and procedure IVF/ICSI treatment is initiated and
outcome during a one year treatment period recorded.
Follow up of the study group will comprise the period of one year subsequent to
the initiation of the first IVF/ICSI treatment, in which any treatment cycle
and any pregnancy occurring will be recorded and defined.

Office Hysteroscopy procedure
Hysteroscopy will be performed under supervision of the same investigating team
(FB and MK) on an outpatient basis under paracervical block using in total 10
ml Xylocaine 1%. Hysteroscopy will be done with the use of a 5-mm
outer-diameter continuous flow hysteroscope with 5 French working channel and a
30o direction of view. The uterine cavity will be distended with the use of
physiologic saline infusion at a maximum pressure of 150 mmHg. The endocervical
canal, uterine cavity, tubal orifices and endometrium will be inspected
methodically and findings recorded into a standardised form. A sample of the
endometrium will be obtained for histologic examination by a gentle biopsy with
the Pipelle biopsy canulla. Pictures will be recorded and filed for each
patient with predefined abnormalities. Therapeutic hysteroscopy will be
performed in the same hysteroscopy session if the patient is randomized as such.

Intervention:
- Septum resection with Resectoscope Storz or Versapoint®.
- Polyps resection with Resectoscope Storz or Versapoint®
- Resection of the myoma with the Resectoscope Storz or Versapoint®
- Resection of the adhesions with Hysteroscopic scissors or Versapoint®
- Chronic and acute endometritis: Ofloxacinum 400mg/day orally should be used
during 5 days (both partners) and after the menstruation a new biopsy should be
taken to confirm the effect of the treatment. Alternative: Doxycline 100mg:
2x100mg on day one, followed by 100mg/day during 8 days.


Controlled ovarian hyperstimulation for IVF/ICSI
Rec-FSH or HMG, long (day 21) agonist protocol (Buserelin or Triptorelin) or
day 6 GnRH antagonist protocol (Ganirelix / Cetrorelix 0.25mg/d) will be used.
Final oocyte maturation by administration of 10.000 IU of HCG (Pregnyl®) as
soon as >= 3 follicles of >= 17 mm are present. Oocyte retrieval will be carried
out 36 hours after HCG administration. IVF/ICSI. ETd3/d5. Luteal phase
supplementation: 600mg natural micronised progesterone in three separate doses
(Utrogestan® / Progestan® 100mg 3x2/day) starting one day after oocyte
retrieval and continued until 7 weeks of gestation if pregnancy is achieved.

Burden
Patients indicated for IVF/ICSI undergo a routine hysteroscopic screening. In
the case of any predefined intra cavitary they will be randomised during the
procedure to either undergo or not undergo a surgical correction of the
abnormality. This will increase the time length of the procedure by a factor 2
to 3. In case inflammation of the endometrium will be diagnosed additional
treatment with antibiotics for 2 weeks will be prescribed.

Risks
Hysteroscopy procedures introduce a risk of procedure related complications,
like cervical or uterine perforation, intra-uterine infection or bleeding. Also
risk of cardiovascular compromise due to the use of local anaesthetics and
allergic reaction to antibiotic treatment are included. Based on existing
literature these risks are very limited (Sutton, 2006) and estimated to be
below 0,1%.