Aromatase inhibitors, a new option for inducing ovulation

When used for ovarian stimulation, the short half-life of AIs and administration in the early follicular phase (several days before ovulation and fertilization occur) should ensure clearance of the drugs before implantation. Nevertheless, it is important to confirm that the patient is not pregnant before an AI is given. We recommend a pregnancy test before administering an AI for ovulation induction.

Mixed bag of data on pregnancy outcomes

Three large studies recently reported on pregnancy outcomes after infertility treatment with AIs.^9,36,37 The first was a cohort study comparing outcomes of 394 pregnancies achieved after treatment with letrozole (133 pregnancies) and other ovarian-stimulation agents, including clomiphene citrate (113 pregnancies) and gonadotropins (110 pregnancies), with a control group of 38 pregnancies achieved without ovarian stimulation.⁹ The study encompassed three tertiary referral centers over 2 years. Pregnancies conceived after treatment with an AI had rates of miscarriage and ectopic pregnancy comparable to all other groups. In addition, letrozole was associated with a significantly lower rate of multiple gestation than was clomiphene citrate.⁹

The second study, presented in abstract form, compared the outcome of 150 births after treatment with letrozole to a database of 36,050 normal deliveries.³⁶ Although the authors themselves stated that there was no statistically significant difference in the overall incidence of congenital malformation, they reported a higher incidence of locomotor malformation and cardiac anomaly in the infants conceived after treatment with letrozole.³⁶ They did not address this discrepancy or explain how locomotor malformation was assessed.

A closer look at the abstract reveals major methodological flaws that weaken the data and conclusions presented:

• The study was not well controlled. The treated patients (n=130) were infertile women, mainly suffering from PCOS and unexplained infertility, who had a mean age of 35.2 years. The control group included a database of spontaneously conceiving women who were significantly younger (mean age: 30.5 years). The control group also included deliveries in a low-risk hospital that refers out high-risk pregnancies to secondary and tertiary hospitals. These are important distinctions because women of advanced maternal age have an increased incidence of medical illnesses, making their pregnancies higher in risk.
• The incidence of multiple gestation was significantly higher among women treated for infertility than among women in the control group. It is well known that multiple gestations are at increased risk of fetal malformation compared with singleton pregnancies.
• The incidence of cardiac anomaly among women treated with letrozole did not differ significantly from the known incidence of cardiac malformation in the general population, but the authors concluded that the rate of cardiac malformation was significantly higher in the letrozole group than among controls. This is misleading because it was the control group that developed cardiac malformation at a significantly lower rate than in the general population. Such a low incidence of cardiac anomaly in a low-risk hospital setting is not surprising, because mothers would be transferred to a tertiary-care center once an anomaly was detected.
• Data on congenital malformation in the control group were collected from delivery records available in the maternity ward of the hospital. However, a significant percentage of congenital malformations, such as cardiac anomaly, are not detected until after the neonatal period.³⁶

It is also interesting that the results of this abstract have not been published in a peer-reviewed journal more than a year after its presentation.

The third study, which is more recent, compared the incidence of congenital malformation in 911 newborns conceived after treatment with letrozole (n=514) or clomiphene citrate (n=397).³⁷ It found no statistically significant difference between the groups. Congenital malformation was diagnosed in 2.4% and 4.8% of the letrozole- and clomiphene-treated groups, respectively, and major malformation occurred in 1.2% and 3% of the letrozole- and clomiphene-treated groups, respectively. These differences were not statistically significant, but there was a sevenfold increase in overall cardiac anomalies in the clomiphene-treated group, compared with the letrozole-treated group—and this difference was statistically significant. These findings warrant further investigation into the use of clomiphene citrate for induction of ovulation.