OHSS may be caused by administration of human Chorionic Gonadotropin (hCG) and by pregnancy (endogenous hCG). Early OHSS usually occurs within 10 days after hCG administration and may be associated with an excessive ovarian response to gonadotropin stimulation. Late OHSS occurs more than 10 days after hCG administration, as a consequence of the hormonal changes with pregnancy. Because of the risk of developing OHSS, patients should be monitored for at least two weeks after hCG administration.

Women with known risk factors for a high ovarian response may be especially prone to the development of OHSS during or following treatment with Puregeon. For women having their first cycle of ovarian stimulation, for whom risk factors are only partially known, close observation for early signs and symptoms of OHSS is recommended.

To reduce the risk of OHSS, ultrasonographic assessments of follicular development should be performed prior to treatment and at regular intervals during treatment. The concurrent determination of serum oestradiol levels may also be useful. In ART there is an increased risk of OHSS with 18 or more follicles of 11 mm or more in diameter. When there are 30 or more follicles in total it is advised to withhold hCG administration.

Depending on the ovarian response, the following measurements can be considered to reduce OHSS:

- withhold further stimulation with a gonadotropin for a maximum of 3 days (coasting);

- withhold hCG and cancel the treatment cycle;

- administer a dose lower than 10,000 IU of urinary hCG for triggering final oocyte maturation, e.g. 5,000 IU urinary hCG or 250 micrograms rec-hCG (which is equivalent to approximately 6,500 IU of urinary hCG);

- cancel the fresh embryo transfer and cryopreserve embryos;

- avoid administration of hCG for luteal phase support.

If OHSS develops, standard and appropriate management of OHSS should be implemented and followed.

Multiple Pregnancy

Multiple pregnancies and births have been reported for all gonadotropin treatments, including Puregon.. Multiple gestation, especially high order, carries an increased risk of adverse maternal (pregnancy and delivery complications) and perinatal (low birth weight) outcomes. For anovulatory women undergoing ovulation induction, monitoring follicular development with transvaginal ultrasonography may aid in determining whether or not to continue the cycle in order to reduce the risk of multiple pregnancies. The concurrent determination of serum oestradiol levels may also be useful. The patients should be advised of the potential risks of multiple births before starting treatment.

In women undergoing Assisted Reproduction Technologies (ART) procedures, the risk of a multiple pregnancy is mainly related to the number of embryos transferred. When used for an ovulation induction cycle, appropriate FSH dose adjustment(s) should prevent multiple follicle development.

Ectopic Pregnancy

Infertile women undergoing ART, have an increased incidence of ectopic pregnancies. Early ultrasound confirmation that a pregnancy is intrauterine is therefore important.

Spontaneous Abortion

Rates of pregnancy loss in women undergoing assisted reproduction techniques are higher than in the normal population.

Vascular Complications

Thromboembolic events, both in association with and separate from OHSS, have been reported following treatment with gonadotropins, includin