Drugs in infertility and fetal safety

To evaluate the safety of drugs used in infertility treatment.

Literature search using the keywords birth defect, congenital malformation, clomiphene, aromatase inhibitor, letrozole, gonadotropin, metformin, gonadotropin releasing hormone agonist and antagonist, progesterone, progestin, and estrogen. We conducted the search in Medline, EMBASE, and Cochrane Database of systematic reviews.

The available data suggest that clomiphene treatment, especially after several cycles, might be associated with a slightly higher risk of neural tube defects and severe hypospadias in the offspring. Letrozole and metformin do not appear to be teratogenic. The existing data concerning gonadotropin preparations suggest that there is no evidence of teratogenicity, yet, information after 1991 is lacking. Micronized progesterone, which is widely used in in vitro fertilization treatment, does not appear to increase the risk of nongenital birth defects; however, there might be a possible weak association between other progestational agents and hypospadias.

Infertility per se is a risk factor for congenital anomalies. Repeated clomiphene treatment might be associated with a slightly higher risk of hypospadias and neural tube defect. However, the overall increased risk related to various fertility drugs is only 1% to 2%.