Human Reproduction, Vol. 17, No. 5, 1411,
May 2002
© 2002 European Society of Human Reproduction and Embryology
Prevention of high order multiple pregnancy
1 Fertility Institute of New Orleans, 6020 Bullard Avenue, New Orleans, Louisiana 70128, USA E-mail: info{at}fertilityinstitute.com
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Dear Sir,
We read with interest the analysis by Tur et al. in which they conclude that high order multiple pregnancy (HOMP), defined as 
3 gestational sacs, following HMG can be predicted by the number of follicles 10 mm and estradiol levels >862 pg/ml on the day of HCG administration, and by age 
32 years (Tur et al., 2001
). However, they do not recommend a specific `cut off' follicle number above which HCG administration may be usefully withheld in order to prevent or reduce HOMPs. Two recent studies indicate that such a number can be determined, provided that follicles 12 mm are counted.
Gleicher et al. reported no HOMP when <10 total follicles were present or estradiol levels were <405 pg/ml before ovulation, but was unable to predict HOMP by counting follicles 16 mm (Gleicher et al., 2000). They did not report results by patient age. We (Dickey et al., 2001a) reported a 4% HOMP rate in women 34 years old when fewer than six pre-ovulatory follicles 12 mm were present on the day of HCG administration or estradiol levels measured by radioimmunoassay were <1000 pg/ml, compared with a 14% HOMP rate when there were six or more follicles 12 mm or estradiol levels were 1000 pg/ml. However, for women age 35–42 years, the HOMP rate was 5% when there were six or more follicles 12 mm or estradiol levels were 1000 pg/ml.
In a further analysis (Dickey et al., 2002), we concluded that if HCG had been withheld for women 35 years old when six or more follicles were 12 mm, 34% of cycles would have been cancelled and the pregnancy rate in the remaining patients would have been 19%. For women 35–42 years old, no cycle cancellations would be necessary. Furthermore, only half (2%) of patients with 3 gestational sacs and age <35 years would give birth to triplets or more due to spontaneous reduction (Dickey et al., 2001b). This low incidence, which could be further reduced by selection reduction, is comparable with the 2.4% incidence of triplet and quadruplet births following IVF reported for 18 European countries during 1998 (Ngyen and Anderson, 2001).
The reason that previous studies have failed to find a relationship between follicle number and HOMP is that follicles <15–16 mm must be counted on the day of HCG administration (or the day of ovulation). This was exemplified in our study where 22% of HOMP occurred when fewer than three pre-ovulatory follicles were 15 mm, and 55% of HOMP occurred when fewer than 3 follicles were 18 mm.
Clear guidelines for cancellation, in order to reduce high order multiple pregnancies, can and should be established, based on the number of 10–12 mm pre-ovulatory follicles and patient's age. We agree with Tur et al. that prospective studies are warranted to determine if withholding HCG on the basis of follicle number or estradiol level and age is effective in reducing HOMP without unduly affecting overall pregnancy rates (Tur et al., 2001). However, while those studies are being designed and carried out, HOMP may be reduced by two-thirds through withholding HCG when six or more follicles are 12 mm or 10 follicles are 10 mm, based on the information at hand.
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Dickey, R.P., Taylor, S.N., Lu, P.Y., Sartor, B.M., Rye, P.H. and Pyrzak, P. (2001a) Relationship of follicle numbers and estradiol levels to multiple implantation of 3608 intrauterine insemination cycles. Fertil. Steril., 75, 69–78.[ISI][Medline]
Dickey, R.P., Taylor, S.N., Lu, P.Y., Sartor, B.M., Rye, P.H. and Pyrzak, P. (2001b) Risks of multiple pregnancy—the decision belongs to whom? Letter to the Editor. Fertil. Steril., 76, 425–426.
Dickey, R.P., Taylor, S.N., Lu, P.Y., Sartor, B.M., Storment, J.M., Rye, P.H., Pelletier, W.D., Zehnder, J.L. and Matulich, E.M. (2002) Spontaneous reduction of multiple pregnancy: incidence and effect on outcome. Am. J. Obstet. Gynecol., 186, 77–83.[ISI][Medline]
Gleicher, N., Oleske, D.M., Tur-Kaspa, I., Vidali, A. and Karande, V. (2000) Reducing the risk of high-order multiple pregnancy after ovarian stimulation with gonadotropins. N. Engl. J. Med., 343, 2–7.
Ngyen, K.G. and Anderson, A.N. (2001) Assisted reproductive technology in Europe, 1998. Results generated from European Registers by ESHRE. Hum. Reprod., 16, 2459–2471.
Tur, R., Barri, P.N., Coroleu, B., Buxaderas, R., Martinez, F. and Balasch, J. (2001) Risk factors for high-order multiple implantation after ovarian stimulation with gonadotropins: evidence from a large series of 1878 consecutive pregnancies in a single centre. Hum. Reprod., 16, 2124–2129.
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