Reducing the risk of high-order multiple pregnancy after ovarian stimulation with gonadotropins.

Background: The incidence of multiple gestation after therapy for infertility is especially high among women in whom ovulation is induced with gonadotropins. Whether the number of high-order multiple pregnancies (those with three or more fetuses) can be reduced is not known. Methods: We analyzed data on 3347 consecutive treatment cycles in 1494 infertile women, 441 of which resulted in pregnancy. The data collected included the peak serum estradiol concentration, the number of follicles 16 mm or larger in diameter, and the total number of follicles on the day of induction of ovulation with human chorionic gonadotropin. Receiver-operating-characteristic curves and ordinal logistic-regression analyses were used to identify values that predicted multiple conceptions. Results: Among the 441 pregnancies, 314 resulted from the conception of singletons, 88 of twins, 22 of triplets, 10 of quadruplets, 5 of quintuplets, and 2 of sextuplets. Neither the number of follicles 16 mm or larger nor peak serum estradiol concentrations greater than 2000 or 2500 pg per milliliter (7342 or 9178 pmol per liter) (the cutoff values currently in wide use) were significantly associated with the incidence of high-order multiple pregnancy. However, increasing total numbers of follicles and increasing peak serum estradiol concentrations correlated significantly with an increasing risk of high-order multiple pregnancy (P<0.001), as did younger age (P=0.008). The risk of high-order multiple pregnancy was significantly increased in women with a peak serum estradiol concentration of 1385 pg per milliliter (5084 pmol per liter) or higher (multivariate odds ratio, 1.9; 95 percent confidence interval, 1.3 to 2.8) or with seven or more follicles (multivariate odds ratio, 2.1; 95 percent confidence interval, 1.2 to 3.9) on the day of induction of ovulation. Conclusions: Gonadotropin stimulation that is less intensive than is currently customary may reduce the incidence of high-order multiple pregnancy in infertile women, though only to a limited extent and at the expense of overall pregnancy rates. (N Engl J Med 2000;343:2-7.) (C) 2000, Massachusetts Medical Society.