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Does dilation and curettage versus expectant management for spontaneous abortion in patients undergoing in vitro fertilization affect subsequent endometrial development?
Does dilation and curettage versus expectant management for spontaneous abortion in patients undergoing in vitro fertilization affect subsequent endometrial development? In in vitro fertilization patients, treatment of spontaneous abortion with dilation and curettage (D&C) versus expectant management has no long-term effect on subsequent endometrial development, as measured by change in endometrial thickness. A transient reduction in endometrial thickness was found within the first 6 months after D&C, which is a novel finding, but it is likely to have little or no effect on pregnancy rates given the small absolute effect on endometrial thickness. (Fertil Steril 2009;92:1776–9. 2009 by American Society for Reproductive Medicine.)
When first trimester spontaneous abortion (SAb) occurs, treatment options include surgical evacuation, medical therapy, or expectant management. Since many of these patients pursue further attempts at pregnancy, the potential effects of treatment on future fertility are a primary concern. There are no prior studies that have examined whether choice of management for SAb after assisted reproduction has an effect on endometrial receptivity of subsequent cycles. Since an adequate endometrium is a prerequisite for the process of embryo implantation (1), injury to the endometrium could potentially diminish subsequent endometrial development and thus receptivity in future cycles. The endometrium has a remarkable capacity for regeneration as demonstrated after menstruation and parturition (2, 3). Even after mechanical injury, endometrial recovery has been shown to occur with great rapidity. In postcurettage endometrial biopsies after voluntary abortion, progression to active proliferation occurs as early as postabortal day 10 and to secretory endometrium as early as postabortal day 11 (4). Histologic sections of rabbit endometrium examined immediately postcurettage and found to have denudation of an average of 70% of the surface area, often with full thickness involvement, demonstrate full regeneration after only Kimberly S. Moon, M.D.a Kevin S. Richter, Ph.D.b Michael J. Levy, M.D.b Eric A. Widra, M.D.a,b a Department of Obstetrics and Gynecology, Georgetown University Hospital, Washington, D.C. b Shady Grove Fertility Reproductive Science Center, Rockville, Maryland Received April 3, 2009; revised May 14, 2009; accepted May 16, 2009; published online June 27, 2009. K.S.M. has nothing to disclose. K.S.R. has nothing to disclose. M.J.L. has nothing to disclose. E.A.W. has nothing to disclose. Presented at the 64th Annual Meeting of the American Society for Reproductive Medicine, which was held in San Francisco, California, on November 8–12, 2008. Reprint requests: Kevin S. Richter, Ph.D., Shady Grove Fertility Reproductive Science Center, 15001 Shady Grove Road, Suite 400, Rockville, Maryland 20850 (FAX: 301-340-0623; E-mail: kevin.richter@ integramed.com).
1776
72 hours (5). While quick repair is demonstrated and an early return to basic function is suggested, these studies do not address whether the regenerated endometrium is optimal for implantation. Historically, first trimester SAb has been treated with surgical evacuation to reduce the potential complications of retained products of conception including hemorrhage and infection (6). Surgical treatment is most commonly completed by serial dilation of the cervix followed by insertion of a cannula with vacuum aspiration of the uterine contents. Some physicians use a sharp curette to confirm the completeness of the evacuation. Nonsurgical management, either expectant or medical, has more recently been advocated as an acceptable alternative to dilation and curretage (D&C) (6). There is a high rate of spontaneous resolution with expectant management without complications, especially with inevitable or incomplete abortions (7, 8). Expectant management is the only nonsurgical option included in the present study as the number of patients in the study period opting for medical management was limited. In the fertile population, patients who desire future pregnancy after early (<8 weeks) complete SAb managed expectantly have been found to have comparable pregnancy rates to the normal population (9). Further, when comparing surgical to expectant management after first trimester SAb, the evidence does not support a difference in subsequent pregnancy rates (10–12). The effect of curettage on future reproduction has also been well established in the literature from the study of elective terminations of pregnancy. Termination by vacuum aspiration is not associated with an increased risk of secondary infertility (13–18). We presume this to be true for the infertile population as well, excluding uterine causes of infertility. The outcomes of interest in this study are pregnancy and livebirth rates, however, the sample size required to detect a difference in these rates between the two study groups is beyond the scope of the current analysis. Therefore, endometrial thickness (ETh) measured by transvaginal ultrasound is used as a marker for endometrial receptivity. Transvaginal ultrasound, used routinely in assisted reproduction technologies (ART), can reliably measure ETh (19). Further, women have little cycle-to-cycle variation in ETh in repetitive cycles of ovarian stimulation (20) so changes
Fertility and Sterility Vol. 92, No. 5, November 2009 Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/09/$36.00 doi:10.1016/j.fertnstert.2009.05.045
TABLE 1 Sample sizes, patient age, post-SAb ETh, change in ETh, pregnancy rate, and live-birth rate according to SAb management and duration between treatments. D&C Diagnosis to subsequent treatment time No. of cycles Age, years Post-SAb ETh, mm Change in ETh (95% CI) Pregnancy rate (%) Live birth (%)
<6 months 176 37.0 10.9a,b 0.48e,f (0.8, 0.2) 75 (43) 61 (35)
No D&C >6 months 66 36.6 11.5a,c 0.26e,g (0.3, 0.9) 27 (41) 20 (30)
<6 months 54 37.2 11.6b,d 0.10f,h (0.8, 0.6) 23 (43) 20 (37)
>6 months 13 38.0 10.6c,d 0.25g,h (2.5, 2.0) 7 (54%) 5 (38%)
a
P ¼ .07 for D&C < 6 months versus > 6 months. P ¼ .054 for D&C < 6 months versus no D&C < 6 months. c P ¼ .25 for D&C > 6 months versus no D&C > 6 months. d P ¼ .18 for no D&C < 6 months versus > 6 months. e P ¼ .02 for D&C < 6 months versus > 6 months. f P ¼ .27 for D&C < 6 months versus no D&C < 6 months. g P ¼ .54 for D&C > 6 months versus no D&C > 6 months. h P ¼ .86 for no D&C < 6 months versus > 6 months. b
Moon. Correspondence. Fertil Steril 2009.
in thickness across cycles, if any, should reflect effects of interventions between the measurements. The existing literature reveals mixed results regarding the clinical significance of variation in ETh across patients when undergoing ART. Some reports show a correlation between greater ETh and pregnancy rates (21–24), while others have found no correlation (25–30). Still others have defined a threshold thickness above or below which pregnancy rates were lower (21, 26, 28, 31, 32). These discrepancies were addressed in two large retrospective analyses that found a steady gradual rise in pregnancy rates as ETh on the day of hCG administration increased throughout the range of thicknesses (33, 34). In the current study, this positive relationship between ETh and pregnancy rates is assumed. In summary, the primary objective of this study was to test the hypothesis that there is no effect on subsequent endometrial development after treatment of SAb with D&C versus expectant management in IVF patients. We plan to compare ETh at the time of hCG administration in the cycle that ended in SAb with the subsequent cycle. If this hypothesis is proven correct, it supports patient preference as the determining factor when making management decisions after SAb. Some patients prefer the benefits of a planned, immediate evacuation with cessation of bleeding and discomfort, while others favor the avoidance of surgery and its potential complications. The secondary objective of this study is to investigate whether there is a time interval to recovery of the endometrium by examining the difference, if any, in ETh over varying time periods from SAb to subsequent IVF cycle. Fertile patients are often advised to delay subsequent pregnancy after SAb for 2–3 months, although there are no reported data to support this recommendation (35–39). Finding no difference in ETh in the shorter versus longer term after treatment of SAb would be consistent with the existing literature and would be useful in counseling patients about when to initiate a subsequent IVF cycle. IVF cycles conducted between March 2002 and November 2006 at Shady Grove Fertility Reproductive Science Center were re-
Fertility and Sterility
viewed retrospectively. This research was approved by Schulman Associates Institutional Review Board. Data were abstracted from patient records. Patients were categorized according to whether or not a D&C was performed for the SAb. Patients included in the study were those undergoing IVF after an SAb in the preceding IVF cycle. Patients excluded were those who had an SAb after 12 weeks gestational age, those patients who required a repeat D&C for retained products of conception, and those patients opting for medical management of the SAb. The time interval between cycles was defined as the date of SAb diagnosis by ultrasound to the subsequent cycle initiation date. Ovarian stimulation was performed with gonadotropins in all cases. ETh was measured on the day of hCG administration in both the IVF cycle resulting in the SAb and the subsequent IVF cycle. Measurement of maximal endometrial diameter in the sagittal plane was performed using a GE LOGIQ 200 Ultrasound System with a 6.5 MHz endovaginal probe. Change in ETh (6ETh) between preand post-SAb treatment cycles for each patient was calculated to control for interpatient variability. Post-SAb ETh and 6ETh were compared between treatment groups by t-test. Preliminary examination of ETh according to the number of months between SAb diagnosis and initiation of the subsequent cycle suggested consistently lower post-SAb ETh and negative 6ETh during the first 6 months after diagnosis followed by D&C. After D&C, 6ETh was significantly lower for cycles initiated less than 6 months versus greater than 6 months after SAb diagnosis (0.48 mm vs. 0.26 mm, P¼.02; Table 1), and the difference in post-SAb ETh was also marginally significant (10.9 mm, SD ¼ 2.2, range ¼ 5.5-–9.4; vs. 11.5 mm, SD ¼ 2.8, range ¼ 7.0–20.1; P¼.07; Table 1). All post-SAb cycles were therefore categorized as either greater than 6 months or less than 6 months after SAb diagnosis. After expectant management, 6ETh was very similar between cycles initiated less than 6 months versus greater than 6 months after SAb diagnosis (0.10 mm vs. 0.25 mm; P¼.86; Table 1), and the difference in post-SAb ETh was not significantly different (11.6 mm, SD ¼ 2.4, range
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7.8–19.4; vs. 10.6 mm, SD ¼ 2.3, range 7.5–15.0; P¼.18; Table 1). Among cycles initiated within 6 months of SAb diagnosis, there was a nearly significant difference in ETh after D&C versus expectant management (10.9 mm vs. 11.6 mm; P¼.054; Table 1). The change in ETh was significantly less than 0 after D&C within 6 months of SAb diagnosis but not significantly different from 0 in any other group. There were four cases of ETh <7 mm after D&C within 6 months of SAb diagnosis but none in any of the other subgroups. Pregnancy and live-birth rate were slightly but not significantly lower after D&C versus expectant management (PR.4 for all comparisons; Table 1). Using ETh as a marker for receptivity of the endometrium, we investigated whether D&C versus expectant management after SAb in an IVF cycle had an effect on endometrial development in subsequent IVF cycles. Since increasing ETh has a positive relationship with pregnancy rates, an intervention that reduces thickness could have important implications for future fertility. Our results support the hypothesis that in the long term (defined as a period greater than 6 months) there is no difference in ETh between D&C versus expectant management of SAb and no significant impairment of endometrial development after SAb in the IVF population. These results are consistent with previous studies in the fertile population and reaffirm patient preference as the determining factor in the management of SAb. It is important to realize that while we are really interested in endometrial receptivity and the resulting pregnancy and live-birth rates, we are only assessing these indirectly by ETh. The positive relationship between pregnancy rates and ETh has been confirmed in many previous studies (21–24, 33, 34). Our data show a slight trend toward decreased pregnancy and live-birth rates after D&C, although the
small sample size of the study is not adequately powered to analyze this outcome. We did observe a statistically significant reduction in ETh in subsequent treatment cycles performed within the first 6 months after D&C. This transient decrease is a novel finding and may reflect a delay in recovery secondary to mechanical injury from the curettage. Conceivably, this could support counseling patients to avoid D&C or to prolong the interval between IVF cycles after D&C; however, the small absolute reduction of approximately half a millimeter in ETh is likely to have little or no clinical benefit. Larger studies that have clearly documented a linear relationship between ETh and pregnancy rates suggest that this magnitude of difference in ETh would be associated with a reduction in pregnancy rates of no more than 1% or 2% (33, 34). In fact, relatively high pregnancy rates are achieved even with the thinnest linings (33, 34). Further, any benefit is likely more than offset by the age-related decline in fertility potential resulting from delaying treatment, particularly for women of advanced maternal age. Ideally, a randomized trial with a larger sample size comparing pregnancy and live-birth rates over varying intervals after D&C versus expectant management would be needed to establish whether a true window of reduced receptivity exists after curettage. However, in practice it is unlikely that a study will ever be conducted that is adequately powered (with a sample size of many thousands) to confirm the very small difference in pregnancy rates that could reasonably be expected to occur given the slight short-term reduction in ETh, and the value of attempting such a study is questionable. Thus, in the absence of evidence to the contrary, our results suggest that resolving SAb with D&C and proceeding with subsequent treatment after a minimal delay will not have a clinically significant adverse impact on future fertility treatments.
REFERENCES 1. Achache H, Revel A. Endometrial receptivity markers, the journey to successful embryo implantation. Hum Reprod Update 2006;12:731–46. 2. Ferenczy A. Studies of the cytodynamics of human endometrial regeneration. I. Scanning electron microscopy. Am J Obstet Gynecol 1976;124:64–74. 3. Salamonsen LA. Tissue injury and repair in the female human reproductive tract. Reproduction 2003;125:301–11. 4. Reyniak JV, Gordon M, Stone ML, Sedlis A. Endometrial regeneration after voluntary abortion. Obstet Gynecol 1975;45:203–10. 5. Schenker JG, Sacks MI, Polishuk WZ. Regeneration of rabbit endometrium following curettage. Am J Obstet Gynecol 1971;111:970–8. 6. Nanda K, Peloggia A, Grimes D, Lopez L, Nanda G. Expectant versus surgical treatment for miscarriage (Review). Cochrane Database Syst Rev 2006; (2)CD003518. 7. Nielson S, Hahlin M. Expectant management of first-trimester spontaneous abortion. Lancet 1995;345:84–6. 8. Wieringa-de Waard M, Vos J, Bonsel GJ, Bindels PJ, Ankum WM. Management of miscarriage: a randomized controlled trial of expectant versus surgical evacuation. Hum Reprod 2002;17: 2445–50. 9. Kaplan B, Pardo J, Rabinerson D, Fisch B, Neri A. Future fertility following conservative management of complete abortion. Hum Reprod 1996;11:92–4.
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10. Ben-Baruch G, Schiff E, Moran O, Menashe Y, Mashiach S, Menczer J. Curettage vs. nonsurgical management in women with early spontaneous abortions. The effect on fertility. J Reprod Med 1991;36:644–6. 11. Blohm F, Hahlin M, Nielsen S, Milsom I. Fertility after a randomised trial of spontaneous abortion managed by surgical evacuation or expectant treatment. Lancet 1997;349:995. 12. Chipchase J, James D. Randomised trial of expectant versus surgical management of spontaneous miscarriage. Br J Obstet Gynaecol 1997;104:840–1. 13. Atrash HK, Hogue CJ. The effect of pregnancy termination on future reproduction. Baillieres Clin Obstet Gynaecol 1990;4:391–405. 14. Daling JR, Spadoni LR, Emanuel I. Role of induced abortion in secondary infertility. Obstet Gynecol 1981;57:59–61. 15. Frank P, McNamee R, Hannaford P, Kay C, Hirsch S. The effect of induced abortion on subsequent fertility. Br J Obstet Gynaecol 1993;100: 575–80. 16. Obel EB. Fertility following legally induced abortion. Acta Obstet Gynecol Scand 1979;58:539–42. 17. Stubblefield PG, Monson RR, Schoenbaum SC, Wolfson CE, Cookson DJ, Ryan KJ. Fertility after induced abortion: a prospective follow-up study. Obstet Gynecol 1984;62:186–93. 18. World Health Organization. Secondary infertility following induced abortion. World Health Organi-
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zation Task Force on sequelae of abortion, special programme of research, development and research training in human reproduction. Stud Fam Plann 1984;15:291–5. Fleischer AC, Kalemeris GC, Entman SS. Sonographic depiction of the endometrium during normal cycles. Ultrasound Med Biol 1986;12:271–7. Basir GS, O Ws So WW, Ng EH, Ho PC. Evaluation of cycle-to-cycle variation of endometrial responsiveness using transvaginal sonography in women undergoing assisted reproduction. Ultrasound Obstet Gynecol 2002;19:484–9. Abdalla HI, Brooks AA, Johnson MR, Kirkland A, Thomas A, Studd JW. Endometrial thickness: a predictor of implantation in ovum recipients? Hum Reprod 1994;9:363–5. Glissant A, de Mouzon J, Frydman R. Ultrasound study of the endometrium during in vitro fertilization cycles. Fertil Steril 1985;44:786–90. Gonen Y, Casper RF, Jacobson W, Blankier J. Endometrial thickness and growth during ovarian stimulation: a possible predictor of implantation in in vitro fertilization. Fertil Steril 1989;52:446–50. Kovacs P, Matyas S, Boda K, Kaali SG. The effect of endometrial thickness on IVF/ICSI outcome. Hum Reprod 2003;18:2337–41. Bassil S. Changes in endometrial thickness, width, length and pattern in predicting pregnancy outcome during ovarian stimulation in in vitro fertilization. Ultrasound Obstet Gynecol 2001;18:258–63.
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26. Oliveira JB, Baruffi RL, Mauri AL, Petersen CG, Borges MC, Franco JG Jr. Endometrial ultrasonography as a predictor of pregnancy in an in-vitro fertilization programme after ovarian stimulation and gonadotrophin-releasing hormone and gonadotrophins. Hum Reprod 1997;12:2515–8. 27. Puerto B, Creus M, Carmona F, Civico S, Vanrell JA, Balasch J. Ultrasonography as a predictor of embryo implantation after in vitro fertilization: a controlled study. Fertil Steril 2003;79: 1015–22. 28. Rashidi BH, Sadeghi M, Jafarabadi M, Nejad ES. Relationships between pregnancy rates following in vitro fertilization or intracytoplasmic sperm injection and endometrial thickness and pattern. Eur J Obstet Gynecol Reprod Biol 2005;120: 179–84. 29. Schild RL, Knobloch C, Dorn C, Fimmers R, van der Ven H, Hansmann M. Endometrial receptivity in an in vitro fertilization program assessed by spiral artery blood flow, endometrial thickness, endome-
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trial volume, and uterine artery blood flow. Fertil Steril 2001;75:361–6. Yuval Y, Lipitz S, Dor J, Achiron R. The relationship between endometrial thickness, and blood flow and pregnancy rates in in-vitro fertilization. Hum Reprod 1999;14:1067–71. Gonen Y, Casper RF. Prediction of implantation by the sonographic appearance of the endometrium during controlled ovarian stimulation for in vitro fertilization (IVF). J In Vitro Fert Embryo Transf 1990;7:146–52. Weissman A, Gotlieb L, Casper RF. The detrimental effect of increased endometrial thickness on implantation and pregnancy rates and outcome in an in vitro fertilization program. Fertil Steril 1999;71:147–9. Richter KS, Bugge KR, Bromer JG, Levy MJ. Relationship between endometrial thickness and embryo implantation, based on 1294 cycles of in vitro fertilization with transfer of two blastocyst-stage embryos. Fertil Steril 2006;87:53–9.
34. Al-Ghamdi A, Coskun S, Al-Hassan S, Al-Rejjal R, Awartani K. The correlation between endometrial thickness and outcome of in vitro fertilization and embryo transfer (IVF-ET) outcome. Reprod Biol Endocrinol 2008;6:37. 35. Ali SM, Hecht BR. Attempting pregnancy after miscarriage and curettage—what is the minimum interval? Int J Gynaecol Obstet 1994;45:275–9. 36. Goldstein RR, Croughan MS, Robertson PA. Neonatal outcomes in immediate versus delayed conceptions after spontaneous abortion: a retrospective case series. Am J Obstet Gynecol 2002;186:1230–6. 37. Rud B, Klunder K. The course of pregnancy following spontaneous abortion. Acta Obstet Gynecol Scand 1985;64:277–8. 38. Vlaanderen W, Fabriek LM, van Tuyll van Serooskerken C. Abortion risk and pregnancy interval. Acta Obstet Gynecol Scand 1988;67:139–40. 39. Wyss P, Biedermann K, Huch A. Relevance of the miscarriage-new pregnancy interval. J Perinat Med 1994;22:235–41.
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When first trimester spontaneous abortion (SAb) occurs, treatment options include surgical evacuation, medical therapy, or expectant management. Since many of these patients pursue further attempts at pregnancy, the potential effects of treatment on future fertility are a primary concern. There are no prior studies that have examined whether choice of management for SAb after assisted reproduction has an effect on endometrial receptivity of subsequent cycles. Since an adequate endometrium is a prerequisite for the process of embryo implantation (1), injury to the endometrium could potentially diminish subsequent endometrial development and thus receptivity in future cycles. The endometrium has a remarkable capacity for regeneration as demonstrated after menstruation and parturition (2, 3). Even after mechanical injury, endometrial recovery has been shown to occur with great rapidity. In postcurettage endometrial biopsies after voluntary abortion, progression to active proliferation occurs as early as postabortal day 10 and to secretory endometrium as early as postabortal day 11 (4). Histologic sections of rabbit endometrium examined immediately postcurettage and found to have denudation of an average of 70% of the surface area, often with full thickness involvement, demonstrate full regeneration after only Kimberly S. Moon, M.D.a Kevin S. Richter, Ph.D.b Michael J. Levy, M.D.b Eric A. Widra, M.D.a,b a Department of Obstetrics and Gynecology, Georgetown University Hospital, Washington, D.C. b Shady Grove Fertility Reproductive Science Center, Rockville, Maryland Received April 3, 2009; revised May 14, 2009; accepted May 16, 2009; published online June 27, 2009. K.S.M. has nothing to disclose. K.S.R. has nothing to disclose. M.J.L. has nothing to disclose. E.A.W. has nothing to disclose. Presented at the 64th Annual Meeting of the American Society for Reproductive Medicine, which was held in San Francisco, California, on November 8–12, 2008. Reprint requests: Kevin S. Richter, Ph.D., Shady Grove Fertility Reproductive Science Center, 15001 Shady Grove Road, Suite 400, Rockville, Maryland 20850 (FAX: 301-340-0623; E-mail: kevin.richter@ integramed.com).
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72 hours (5). While quick repair is demonstrated and an early return to basic function is suggested, these studies do not address whether the regenerated endometrium is optimal for implantation. Historically, first trimester SAb has been treated with surgical evacuation to reduce the potential complications of retained products of conception including hemorrhage and infection (6). Surgical treatment is most commonly completed by serial dilation of the cervix followed by insertion of a cannula with vacuum aspiration of the uterine contents. Some physicians use a sharp curette to confirm the completeness of the evacuation. Nonsurgical management, either expectant or medical, has more recently been advocated as an acceptable alternative to dilation and curretage (D&C) (6). There is a high rate of spontaneous resolution with expectant management without complications, especially with inevitable or incomplete abortions (7, 8). Expectant management is the only nonsurgical option included in the present study as the number of patients in the study period opting for medical management was limited. In the fertile population, patients who desire future pregnancy after early (<8 weeks) complete SAb managed expectantly have been found to have comparable pregnancy rates to the normal population (9). Further, when comparing surgical to expectant management after first trimester SAb, the evidence does not support a difference in subsequent pregnancy rates (10–12). The effect of curettage on future reproduction has also been well established in the literature from the study of elective terminations of pregnancy. Termination by vacuum aspiration is not associated with an increased risk of secondary infertility (13–18). We presume this to be true for the infertile population as well, excluding uterine causes of infertility. The outcomes of interest in this study are pregnancy and livebirth rates, however, the sample size required to detect a difference in these rates between the two study groups is beyond the scope of the current analysis. Therefore, endometrial thickness (ETh) measured by transvaginal ultrasound is used as a marker for endometrial receptivity. Transvaginal ultrasound, used routinely in assisted reproduction technologies (ART), can reliably measure ETh (19). Further, women have little cycle-to-cycle variation in ETh in repetitive cycles of ovarian stimulation (20) so changes
Fertility and Sterility Vol. 92, No. 5, November 2009 Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/09/$36.00 doi:10.1016/j.fertnstert.2009.05.045
TABLE 1 Sample sizes, patient age, post-SAb ETh, change in ETh, pregnancy rate, and live-birth rate according to SAb management and duration between treatments. D&C Diagnosis to subsequent treatment time No. of cycles Age, years Post-SAb ETh, mm Change in ETh (95% CI) Pregnancy rate (%) Live birth (%)
<6 months 176 37.0 10.9a,b 0.48e,f (0.8, 0.2) 75 (43) 61 (35)
No D&C >6 months 66 36.6 11.5a,c 0.26e,g (0.3, 0.9) 27 (41) 20 (30)
<6 months 54 37.2 11.6b,d 0.10f,h (0.8, 0.6) 23 (43) 20 (37)
>6 months 13 38.0 10.6c,d 0.25g,h (2.5, 2.0) 7 (54%) 5 (38%)
a
P ¼ .07 for D&C < 6 months versus > 6 months. P ¼ .054 for D&C < 6 months versus no D&C < 6 months. c P ¼ .25 for D&C > 6 months versus no D&C > 6 months. d P ¼ .18 for no D&C < 6 months versus > 6 months. e P ¼ .02 for D&C < 6 months versus > 6 months. f P ¼ .27 for D&C < 6 months versus no D&C < 6 months. g P ¼ .54 for D&C > 6 months versus no D&C > 6 months. h P ¼ .86 for no D&C < 6 months versus > 6 months. b
Moon. Correspondence. Fertil Steril 2009.
in thickness across cycles, if any, should reflect effects of interventions between the measurements. The existing literature reveals mixed results regarding the clinical significance of variation in ETh across patients when undergoing ART. Some reports show a correlation between greater ETh and pregnancy rates (21–24), while others have found no correlation (25–30). Still others have defined a threshold thickness above or below which pregnancy rates were lower (21, 26, 28, 31, 32). These discrepancies were addressed in two large retrospective analyses that found a steady gradual rise in pregnancy rates as ETh on the day of hCG administration increased throughout the range of thicknesses (33, 34). In the current study, this positive relationship between ETh and pregnancy rates is assumed. In summary, the primary objective of this study was to test the hypothesis that there is no effect on subsequent endometrial development after treatment of SAb with D&C versus expectant management in IVF patients. We plan to compare ETh at the time of hCG administration in the cycle that ended in SAb with the subsequent cycle. If this hypothesis is proven correct, it supports patient preference as the determining factor when making management decisions after SAb. Some patients prefer the benefits of a planned, immediate evacuation with cessation of bleeding and discomfort, while others favor the avoidance of surgery and its potential complications. The secondary objective of this study is to investigate whether there is a time interval to recovery of the endometrium by examining the difference, if any, in ETh over varying time periods from SAb to subsequent IVF cycle. Fertile patients are often advised to delay subsequent pregnancy after SAb for 2–3 months, although there are no reported data to support this recommendation (35–39). Finding no difference in ETh in the shorter versus longer term after treatment of SAb would be consistent with the existing literature and would be useful in counseling patients about when to initiate a subsequent IVF cycle. IVF cycles conducted between March 2002 and November 2006 at Shady Grove Fertility Reproductive Science Center were re-
Fertility and Sterility
viewed retrospectively. This research was approved by Schulman Associates Institutional Review Board. Data were abstracted from patient records. Patients were categorized according to whether or not a D&C was performed for the SAb. Patients included in the study were those undergoing IVF after an SAb in the preceding IVF cycle. Patients excluded were those who had an SAb after 12 weeks gestational age, those patients who required a repeat D&C for retained products of conception, and those patients opting for medical management of the SAb. The time interval between cycles was defined as the date of SAb diagnosis by ultrasound to the subsequent cycle initiation date. Ovarian stimulation was performed with gonadotropins in all cases. ETh was measured on the day of hCG administration in both the IVF cycle resulting in the SAb and the subsequent IVF cycle. Measurement of maximal endometrial diameter in the sagittal plane was performed using a GE LOGIQ 200 Ultrasound System with a 6.5 MHz endovaginal probe. Change in ETh (6ETh) between preand post-SAb treatment cycles for each patient was calculated to control for interpatient variability. Post-SAb ETh and 6ETh were compared between treatment groups by t-test. Preliminary examination of ETh according to the number of months between SAb diagnosis and initiation of the subsequent cycle suggested consistently lower post-SAb ETh and negative 6ETh during the first 6 months after diagnosis followed by D&C. After D&C, 6ETh was significantly lower for cycles initiated less than 6 months versus greater than 6 months after SAb diagnosis (0.48 mm vs. 0.26 mm, P¼.02; Table 1), and the difference in post-SAb ETh was also marginally significant (10.9 mm, SD ¼ 2.2, range ¼ 5.5-–9.4; vs. 11.5 mm, SD ¼ 2.8, range ¼ 7.0–20.1; P¼.07; Table 1). All post-SAb cycles were therefore categorized as either greater than 6 months or less than 6 months after SAb diagnosis. After expectant management, 6ETh was very similar between cycles initiated less than 6 months versus greater than 6 months after SAb diagnosis (0.10 mm vs. 0.25 mm; P¼.86; Table 1), and the difference in post-SAb ETh was not significantly different (11.6 mm, SD ¼ 2.4, range
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7.8–19.4; vs. 10.6 mm, SD ¼ 2.3, range 7.5–15.0; P¼.18; Table 1). Among cycles initiated within 6 months of SAb diagnosis, there was a nearly significant difference in ETh after D&C versus expectant management (10.9 mm vs. 11.6 mm; P¼.054; Table 1). The change in ETh was significantly less than 0 after D&C within 6 months of SAb diagnosis but not significantly different from 0 in any other group. There were four cases of ETh <7 mm after D&C within 6 months of SAb diagnosis but none in any of the other subgroups. Pregnancy and live-birth rate were slightly but not significantly lower after D&C versus expectant management (PR.4 for all comparisons; Table 1). Using ETh as a marker for receptivity of the endometrium, we investigated whether D&C versus expectant management after SAb in an IVF cycle had an effect on endometrial development in subsequent IVF cycles. Since increasing ETh has a positive relationship with pregnancy rates, an intervention that reduces thickness could have important implications for future fertility. Our results support the hypothesis that in the long term (defined as a period greater than 6 months) there is no difference in ETh between D&C versus expectant management of SAb and no significant impairment of endometrial development after SAb in the IVF population. These results are consistent with previous studies in the fertile population and reaffirm patient preference as the determining factor in the management of SAb. It is important to realize that while we are really interested in endometrial receptivity and the resulting pregnancy and live-birth rates, we are only assessing these indirectly by ETh. The positive relationship between pregnancy rates and ETh has been confirmed in many previous studies (21–24, 33, 34). Our data show a slight trend toward decreased pregnancy and live-birth rates after D&C, although the
small sample size of the study is not adequately powered to analyze this outcome. We did observe a statistically significant reduction in ETh in subsequent treatment cycles performed within the first 6 months after D&C. This transient decrease is a novel finding and may reflect a delay in recovery secondary to mechanical injury from the curettage. Conceivably, this could support counseling patients to avoid D&C or to prolong the interval between IVF cycles after D&C; however, the small absolute reduction of approximately half a millimeter in ETh is likely to have little or no clinical benefit. Larger studies that have clearly documented a linear relationship between ETh and pregnancy rates suggest that this magnitude of difference in ETh would be associated with a reduction in pregnancy rates of no more than 1% or 2% (33, 34). In fact, relatively high pregnancy rates are achieved even with the thinnest linings (33, 34). Further, any benefit is likely more than offset by the age-related decline in fertility potential resulting from delaying treatment, particularly for women of advanced maternal age. Ideally, a randomized trial with a larger sample size comparing pregnancy and live-birth rates over varying intervals after D&C versus expectant management would be needed to establish whether a true window of reduced receptivity exists after curettage. However, in practice it is unlikely that a study will ever be conducted that is adequately powered (with a sample size of many thousands) to confirm the very small difference in pregnancy rates that could reasonably be expected to occur given the slight short-term reduction in ETh, and the value of attempting such a study is questionable. Thus, in the absence of evidence to the contrary, our results suggest that resolving SAb with D&C and proceeding with subsequent treatment after a minimal delay will not have a clinically significant adverse impact on future fertility treatments.
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