A 30-year-old woman was treated with Synarela (nafarelin) nasal spray at a dose of 20 ug twice dail

Fråga: A 30-year-old woman was treated with Synarela (nafarelin) nasal spray at a dose of 20 ug twice daily as part of a programme intended to facilitate conception. The treatment started about 4 days after ovulation and was maintained for about 3 weeks. The drug is categorized as B:3 in the Swedish Drug Catalogue (FASS) as teratogenicity has been shown in rats.

What risk of teratogenicity could be assigned to the present pregnancy?

Sammanfattning: There is no solid evidence that the fetal risk in this case is significantly higher than the normal fetal risk and there is no information available that would justify advice to perform a therapeutic abortion.

Svar: Nafarelin is a synthetic analogue of the gonadotrophin-releasing hormone GnRH (1,2). The administration of this decapeptide induces release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary, but this effect decreases markedly with repeated administration of the drug as the pituitary becomes desensitized or down regulated (1). The synthetic analogue is about 200 times more potent than the endogenous peptide (1). The drug has been used in a variety of conditions and is formally approved and indicated for endometriosis. Among other indications are hirsutism and leiomyoma of the uterus. It has also been tried as a contraceptive in women and in treatment of precocious puberty with success in certain patients of both sexes. This type of drug has been successfully used in benign prostatic hypertrophy and in prostatic carcinoma (1). Another use is to combine GnRH analogues with later stimulation by administering LH and FSH as human menopausal gonadotrophin. This regimen will facilitate follicular maturation and subsequent embryo transfer in in vitro fertilisation programmes(1).

The potential teratogenicity of the actual treatment is difficult to assess. We have made a thorough Medline search which failed to reveal any publications on the matter. A number of animal studies has been performed by the manufacturer. In studies where the drug was given for a substantial portion of gestation or even after delivery a number of adverse effects related to the hormone suppressive effects of nafarelin were seen (3). Among these were complicated labour, bloody vaginal discharge, poor maternal care and increased pup mortality. In one study 4 of 80 fetuses in the highest dose group showed: "mild hemimelia; syndactyly; reduced amniotic fluid volume; irregular body contour of head, neck and back; misshapen radius, ulna and fibula; and, laterally compressed cranium" (3). Studies made in rabbits and mice have not revealed teratogenic effects (3).

The manufacturer has knowledge of about 45 reports of pregnant women who have been exposed to nafarelin. As of now, 28 of these pregnancies have terminated, resulting in 19 live-born infants (1 pair of twins born 5 weeks too early, one of whom had immature lung function). One baby had a finger malformation known to occur in the family. There was one case of fused suture lines. There was an increased rate of spontaneous abortions (5 cases) and 5 women chose to have therapeutic abortions (3).

Prof Källen has reviewed the potential of ovulation inducers to cause malformation (4). This class of drug is suspected of carrying an increased risk of low grade that is related to the hormonal effects. However, a large prospective study on clomiphene-treated pregnancies did not show any significantly increased malformation rate (6). After consultation with Prof Källen (7) the following is concluded: the animal findings can hardly be used for any reliable estimation of the fetal risk in humans. On formal grounds the fetal risk has to be judged increased, but the global risk will be very little different from the so-called normal malformation risk, which is estimated to be about 2 per cent. 1 Chrisp P, Goa KL: Nafarelin. A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Clinical Potential in Sex Hormone-Related Conditions. Drugs 1990; 39: 522-551

2 FASS 1993
3 Data on file provided by Syntex
4 Personal communication Anita Sandahl, Syntex
5 Källen B: Läkemedel och missbildning. Läkemedelsboken 1992: 735

6 Kurachi K, Aono T, Minagawa J, Miyake A: Congenital malformations of newborn infants after clomiphene-induced ovulation. Fertil Steril 1983; 40: 187-189 7 Prof B Källen, personal communication