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Authors’ response for “antral follicle count in clinical practice: analyzing clinical relevance”
Authors’ response for ‘‘antral follicle count in clinical practice: analyzing clinical relevance’’ Daniel R. Grow, M.D., and Albert Hsu, M.D. Baystate Medical Center, Springfield, Massachusetts
We must not be so restrictive in our practices as to disallow patients the opportunity of genetic parenthood by refusing them IVF simply because of a low antral follicle count. (Fertil Steril 2011;95:484–5. 2011 by American Society for Reproductive Medicine.) Key Words: Antral follicle count, AFC, IVF, ovarian response, pregnancy, IVF cancellation rate, miscarriage, low responder
The authors are thankful for the thoughts and comments of Toth and Rosen regarding this work. Prospectively determined antral follicle counts predicted a threefold difference in ovarian response (eggs retrieved per 75 IU FSH) and a sixfold difference in cancellation rate for low ovarian response between the lowest and highest antral follicle count groups. Though age, FSH, and body mass index also correlated with ovarian response to gonadotropins, the relationships with these parameters were far weaker. Of more interest, antral follicle counts did not predict pregnancy rate or implantation rate in this study. The authors were intrigued with the report of Melo et al. (1), who in a study in 975 donor recipient pairs reported that antral follicle count was ineffective in predicting pregnancy outcome. This finding was counterintuitive to us, because other works have shown a good correlation between eggs retrieved and pregnancy rate across a spectrum of ages (2). Close inspection of this latter paper, however, reveals a well-known story, that, on average, young patients make more eggs than older patients and young patients have a better live birth rate than older patients. But what about patients within a defined age group? Does egg number predict egg function? Does a relationship between egg number and live birth exist within age groups? Furthermore, if antral follicle count predicts egg count and egg count predicts live birth, then antral follicle count should predict live birth. We could not demonstrate a relationship between egg count and pregnancy rate within age groups in our database. We then went on to look at antral follicle count relationships within age groups and stimulation protocol groups, and we were somewhat surprised by the findings that, in our relatively large database, antral follicle count predicts ovarian response but does not predict pregnancy rate within age groups. Contrary to early studies of antral follicle count, which described a correlation between antral follicle count and pregnancy outcome, there is a growing body of work suggesting otherwise. A recent meta-analysis that produced receiver-operator curves for 13 antral follicle count studies did not find a relationship between low antral follicle count and pregnancy (3, 4). Together these works suggest that, unlike age, antral follicle count is a pure marker of ovarian response and does not predict oocyte or embryo developmental competence or potential for pregnancy. Whereas there are ages that predict very low implantation rates, we cannot say the same for antral follicle count. Prediction of ovarian response is difficult, with polycystic ovary syndrome at one extreme and diminished ovarian reserve at the other, Received November 12, 2010; accepted November 22, 2010; published online December 23, 2010. D.R.G. has nothing to disclose. A.H. has nothing to disclose. Reprint requests: Daniel R. Grow, M.D., Department of Obstetrics and Gynecology, 759 Chestnut St., Springfield, MA 01199 (E-mail: Daniel. [email protected], [email protected]).
484
with the assisted reproductive technologies clinician reading the tea leaves of our trade (maternal age, basal FSH, the clomiphene citrate challenge test, exogenous FSH ovarian reserve test, anti-m€ ullerian hormone, inhibin, body mass index, prior experience, ovarian volume) to choose the ideal stimulation protocol, with little margin for error but high stakes for the self-pay patient. Our data support the premise that there are likely two antral follicle count thresholds to be mindful of—a lower antral follicle count threshold that suggests a risk of cycle cancellation and a higher antral follicle count threshold that suggests risk of ovarian hyperstimulation syndrome. Antral follicle count is not without errors, with many examples of antral follicle count poorly predicting oocytes retrieved, that is, the young patient taking prolonged oral contraceptives. Many of us have been fooled into using a higher dose of gonadotropin than needed for safe stimulation, but these cases are relatively uncommon. Suffice it to say that we have not yet arrived at the ultimate test. Rosen reminds us of the relationship between age, declining ovarian response, and declining egg quality and that it is convenient for us to think of this dyad of ovarian aging progressing in parallel. He suggests that in young patients the quantity of eggs may make up for poor quality, but in the older patient this cannot be so. He suggests that the lack of a relationship between antral follicle count and pregnancy outcome in older patients is hard to believe. We agree that these results are intriguing. However, the data presented suggest that the older low-responder patients in this study had implantation rates and live birth rates that were not less than those of the patients with higher antral follicle count. The data suggest that ovarian response and oocyte developmental competence are not necessarily linked. The recent Fertility and Sterility review (5) of standards supporting uniformity in the measurement of antral follicle count is much appreciated for advancing the collection of more standardized clinical data and communication about the utility of the data. Standardization will provide better data for outcomes research and within a practice allow enhanced safety when individualizing gonadotropin dosages or selecting a protocol type. Clearly more study is needed. One example is the ongoing effort to study the impact of antral follicle count in predicting live birth rates in natural cycle IVF. Our work does not have sufficient power to make definitive statements regarding the equivalent pregnancy outcomes in the patient with low antral follicle count undergoing aggressive stimulation protocols. However, once patients reached ET, antral follicle count ceased to be relevant, with similar implantation rates, pregnancy rates, and live birth rates regardless of baseline antral follicle count. We must not be so restrictive in our practices to disallow these patients the opportunity of genetic parenthood, by refusing them IVF simply for a low antral follicle count.
Fertility and Sterility Vol. 95, No. 2, February 2011 Copyright ª2011 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/$36.00 doi:10.1016/j.fertnstert.2010.11.053
REFERENCES 1. Melo MA, Garrido N, Alvarez C, Bellver J, Meseguer M, Pellicer A, et al. Antral follicle count (AFC) can be used in the prediction of ovarian response but cannot predict the oocyte/embryo quality or the in vitro fertilization outcome in an egg donation program. Fertil Steril 2009;91:148–56. 2. Yih MC, Spandorfer SD, Rosenwaks Z. Egg production predicts a doubling of in vitro
Fertility and Sterility
fertilization pregnancy rates even within defined age and ovarian reserve categories. Fertil Steril 2005;83:24–9. 3. Hendriks DJ, Mol BW, Bancsi LF, Te Velde ER, Broekmans FJ. Antral follicle count in the prediction of poor ovarian response and pregnancy after in vitro fertilization: a meta-analysis and comparison with basal follicle-stimulating hormone level. Fertil Steril 2005;83:291–301.
4. Broekmans FJ, Kwee J, Hendriks DJ, Mol BW, Lambalk CB. A systematic review of tests predicting ovarian reserve and IVF outcome. Hum Reprod Update 2006;12:685–718. 5. Broekmans FJ, de Ziegler D, Howles CM, Gougeon A, Trew G, Olivennes F. The antral follicle count: practical recommendations for better standardization. Fertil Steril 2010;94:1044–51.
485
We must not be so restrictive in our practices as to disallow patients the opportunity of genetic parenthood by refusing them IVF simply because of a low antral follicle count. (Fertil Steril 2011;95:484–5. 2011 by American Society for Reproductive Medicine.) Key Words: Antral follicle count, AFC, IVF, ovarian response, pregnancy, IVF cancellation rate, miscarriage, low responder
The authors are thankful for the thoughts and comments of Toth and Rosen regarding this work. Prospectively determined antral follicle counts predicted a threefold difference in ovarian response (eggs retrieved per 75 IU FSH) and a sixfold difference in cancellation rate for low ovarian response between the lowest and highest antral follicle count groups. Though age, FSH, and body mass index also correlated with ovarian response to gonadotropins, the relationships with these parameters were far weaker. Of more interest, antral follicle counts did not predict pregnancy rate or implantation rate in this study. The authors were intrigued with the report of Melo et al. (1), who in a study in 975 donor recipient pairs reported that antral follicle count was ineffective in predicting pregnancy outcome. This finding was counterintuitive to us, because other works have shown a good correlation between eggs retrieved and pregnancy rate across a spectrum of ages (2). Close inspection of this latter paper, however, reveals a well-known story, that, on average, young patients make more eggs than older patients and young patients have a better live birth rate than older patients. But what about patients within a defined age group? Does egg number predict egg function? Does a relationship between egg number and live birth exist within age groups? Furthermore, if antral follicle count predicts egg count and egg count predicts live birth, then antral follicle count should predict live birth. We could not demonstrate a relationship between egg count and pregnancy rate within age groups in our database. We then went on to look at antral follicle count relationships within age groups and stimulation protocol groups, and we were somewhat surprised by the findings that, in our relatively large database, antral follicle count predicts ovarian response but does not predict pregnancy rate within age groups. Contrary to early studies of antral follicle count, which described a correlation between antral follicle count and pregnancy outcome, there is a growing body of work suggesting otherwise. A recent meta-analysis that produced receiver-operator curves for 13 antral follicle count studies did not find a relationship between low antral follicle count and pregnancy (3, 4). Together these works suggest that, unlike age, antral follicle count is a pure marker of ovarian response and does not predict oocyte or embryo developmental competence or potential for pregnancy. Whereas there are ages that predict very low implantation rates, we cannot say the same for antral follicle count. Prediction of ovarian response is difficult, with polycystic ovary syndrome at one extreme and diminished ovarian reserve at the other, Received November 12, 2010; accepted November 22, 2010; published online December 23, 2010. D.R.G. has nothing to disclose. A.H. has nothing to disclose. Reprint requests: Daniel R. Grow, M.D., Department of Obstetrics and Gynecology, 759 Chestnut St., Springfield, MA 01199 (E-mail: Daniel. [email protected], [email protected]).
484
with the assisted reproductive technologies clinician reading the tea leaves of our trade (maternal age, basal FSH, the clomiphene citrate challenge test, exogenous FSH ovarian reserve test, anti-m€ ullerian hormone, inhibin, body mass index, prior experience, ovarian volume) to choose the ideal stimulation protocol, with little margin for error but high stakes for the self-pay patient. Our data support the premise that there are likely two antral follicle count thresholds to be mindful of—a lower antral follicle count threshold that suggests a risk of cycle cancellation and a higher antral follicle count threshold that suggests risk of ovarian hyperstimulation syndrome. Antral follicle count is not without errors, with many examples of antral follicle count poorly predicting oocytes retrieved, that is, the young patient taking prolonged oral contraceptives. Many of us have been fooled into using a higher dose of gonadotropin than needed for safe stimulation, but these cases are relatively uncommon. Suffice it to say that we have not yet arrived at the ultimate test. Rosen reminds us of the relationship between age, declining ovarian response, and declining egg quality and that it is convenient for us to think of this dyad of ovarian aging progressing in parallel. He suggests that in young patients the quantity of eggs may make up for poor quality, but in the older patient this cannot be so. He suggests that the lack of a relationship between antral follicle count and pregnancy outcome in older patients is hard to believe. We agree that these results are intriguing. However, the data presented suggest that the older low-responder patients in this study had implantation rates and live birth rates that were not less than those of the patients with higher antral follicle count. The data suggest that ovarian response and oocyte developmental competence are not necessarily linked. The recent Fertility and Sterility review (5) of standards supporting uniformity in the measurement of antral follicle count is much appreciated for advancing the collection of more standardized clinical data and communication about the utility of the data. Standardization will provide better data for outcomes research and within a practice allow enhanced safety when individualizing gonadotropin dosages or selecting a protocol type. Clearly more study is needed. One example is the ongoing effort to study the impact of antral follicle count in predicting live birth rates in natural cycle IVF. Our work does not have sufficient power to make definitive statements regarding the equivalent pregnancy outcomes in the patient with low antral follicle count undergoing aggressive stimulation protocols. However, once patients reached ET, antral follicle count ceased to be relevant, with similar implantation rates, pregnancy rates, and live birth rates regardless of baseline antral follicle count. We must not be so restrictive in our practices to disallow these patients the opportunity of genetic parenthood, by refusing them IVF simply for a low antral follicle count.
Fertility and Sterility Vol. 95, No. 2, February 2011 Copyright ª2011 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/$36.00 doi:10.1016/j.fertnstert.2010.11.053
REFERENCES 1. Melo MA, Garrido N, Alvarez C, Bellver J, Meseguer M, Pellicer A, et al. Antral follicle count (AFC) can be used in the prediction of ovarian response but cannot predict the oocyte/embryo quality or the in vitro fertilization outcome in an egg donation program. Fertil Steril 2009;91:148–56. 2. Yih MC, Spandorfer SD, Rosenwaks Z. Egg production predicts a doubling of in vitro
Fertility and Sterility
fertilization pregnancy rates even within defined age and ovarian reserve categories. Fertil Steril 2005;83:24–9. 3. Hendriks DJ, Mol BW, Bancsi LF, Te Velde ER, Broekmans FJ. Antral follicle count in the prediction of poor ovarian response and pregnancy after in vitro fertilization: a meta-analysis and comparison with basal follicle-stimulating hormone level. Fertil Steril 2005;83:291–301.
4. Broekmans FJ, Kwee J, Hendriks DJ, Mol BW, Lambalk CB. A systematic review of tests predicting ovarian reserve and IVF outcome. Hum Reprod Update 2006;12:685–718. 5. Broekmans FJ, de Ziegler D, Howles CM, Gougeon A, Trew G, Olivennes F. The antral follicle count: practical recommendations for better standardization. Fertil Steril 2010;94:1044–51.
485