- Email: [email protected]
Volume change of uterine myomas during pregnancy: Do myomas really grow?
Journal of Minimally Invasive Gynecology (2006) 13, 386 –390
Original articles
Volume change of uterine myomas during pregnancy: Do myomas really grow? Ahmad O. Hammoud, MD, Radwan Asaad, MD, Jay Berman, MD, Marjorie C. Treadwell, MD, Sean Blackwell, MD, and Michael P. Diamond, MD From the Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah (Dr. Hammoud); and the Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan (Drs. Asaad, Berman, Treadwell, Blackwell, and Diamond). KEYWORDS: Uterine myoma; Fibroids; Change in volume; Pregnancy
Abstract STUDY OBJECTIVE: To estimate changes in uterine myoma volume during pregnancy. DESIGN: Review of departmental electronic perinatal database and medical records. Canadian Task Force Classification II-3. SETTING: Obstetrical ultrasound unit in an academic tertiary care center. PATIENTS: One hundred-seven patients diagnosed with uterine myomas during pregnancy and who had two or more obstetrical ultrasounds in different periods of pregnancy. INTERVENTIONS: We analyzed the change in volume of uterine myomas between the first half of pregnancy (up until 19 weeks), third quarter (20 –30 weeks), and last quarter (31 weeks to term). The volume of largest uterine myoma was calculated using the formula Volume (mm3) ⫽ ⌸/6 ⫻ (length mm) ⫻ (width mm) ⫻ (height mm). MEASUREMENTS AND MAIN RESULTS: The mean age of the population was 31 ⫾ 6 years. Between the first and the second study periods, the percentage of uterine myomas that decreased in size was 55.1% (95% CI: 43– 66), with a mean decrease in volume of 35% ⫾ 4%; while the percentage of uterine myomas that enlarged was 44.9% (95% CI: 34 –56), with a mean increase in volume of 69% ⫾ 11%. Between the second and the third study periods, 75% (95% CI: 56 – 87) became smaller, with a mean decrease in volume of 30% ⫾ 3%; while 25% (95% CI: 13– 43) enlarged, with a mean increase in volume of 102% ⫾ 62%. CONCLUSION: Contrary to common belief, we found that uterine myomas commonly decrease in volume over the course of pregnancy. © 2006 AAGL. All rights reserved.
Uterine myomas are the most common pelvic tumor in reproductive-age women.1 Their prevalence in pregnancy is This manuscript was accepted as an oral presentation at the 34th annual meeting of the AAGL, Chicago, Illinois, November 9 –12, 2005. Corresponding author: Ahmad Hammoud, MD, University of Utah, Department of Obstetrics and Gynecology, Suite 2B200, 30 North 1900 East, Salt Lake City, Utah 84132. E-mail: [email protected] Submitted December 19, 2005. Accepted for publication April 13, 2006.
1553-4650/$ -see front matter © 2006 AAGL. All rights reserved. doi:10.1016/j.jmig.2006.04.003
estimated to be 0.1% to 3.9%.2 During pregnancy, the diagnosis is clinical when the uterine myomas are palpable or intraoperative during cesarean section delivery; however in the majority of cases, diagnosis is made using ultrasound.3 The change in size of uterine myomas during pregnancy remains controversial. It has been standard teaching that myomas grow during pregnancy under the influence of hormonal stimulation.4 –9 However, recent studies have shown that uterine myomas frequently remained
Hammoud et al Table 1 periods
Volume change of myomas during pregnancy
Volumes of myomas during the three study
Volume
Median (cm3)
Minimum - Maximum (cm3)
Up until 19 weeks 20–30 weeks 31–42 weeks
56.38 45.08 52.87
2.64 - 825.98 3.40 - 661.61 2.51 - 1976.94
unchanged in pregnancy or decreased in size.10 –13 In this study, our objective was to estimate the change in size of uterine myomas during pregnancy.
Material and methods After institutional review board approval, we conducted a review of our departmental electronic perinatal database and medical charts of patients who were seen in the obstetric ultrasound unit in the period from 1994 to 2004. Pregnant patients diagnosed with uterine myomas and who had two or more ultrasounds during different stages of pregnancy were included in the study. The location, number, and volume of the uterine myomas were followed. In this study, we analyzed the change in uterine myoma volume throughout pregnancy. The approximated uterine myoma volume was calculated by using the formula Volume ⫽ ⌸/6 ⫻ (length) ⫻ (width) ⫻ (height).14 When the patients had multiple uterine myomas, only the largest uterine myoma was followed, and identified throughout the remainder of pregnancy by its specific recorded location. In our practice, pregnant patients have a targeted ultrasound at 16 to 20 weeks of gestation for fetal anatomy scanning. This ultrasound was used as a reference point for the purpose of studying changes in volume of uterine myomas. As a result, we analyzed the change in volume of uterine myomas between three periods: the first study period (up until 19 weeks), second study period (20 –30 weeks), and the third study period (31– 42 weeks). Initially, the volume change was reported as the percentage change in volume of each uterine myoma. We calculated the frequency of increase or decrease in size between the above-mentioned periods of pregnancy. The mean change in volume was reported also in these two groups in the different study periods. If the data were normally distributed, the mean ⫾ SEM were used; and if the distribution were skewed, median and range were used. Previous reports tried to study the influence of myoma size on the direction of the volume change. Different thresholds were used empirically.10,12,13 In our analysis, a receiver operating characteristic (ROC) curve was used to identify a uterine myoma size that can predict
387 the direction of volume change. The area under the curve was calculated. The 2 test was used to compare frequencies. A p value ⬍.05 was considered statistically significant. Bonferroni correction was performed in case of multiple comparisons. All the statistical operations were performed using SPSS for Windows v13.0 (SPSS, Inc., Chicago, IL).
Results During the study period, 107 patients met our inclusion criteria. The mean age of patients was 31 ⫾ 6 years. The racial distribution of our population was as follows: 89.4% African American, 5.7% Caucasian, and 4.9% other races including Hispanic and Middle Eastern. As to the parity, 78.9% of the women were primiparous, and 21.1% were multiparous. The median volume of myomas in different study periods is given in Table 1. Using the formula Myoma volume ⫽ ⌸/6 ⫻ (mean diameter3), we calculated that the mean diameter of 4.8 cm corresponded to the mean volume in the first study period, 4.4 cm in the second study period, and 4.7 cm in the third study period. The volume change of uterine myomas between the different study periods was as follows: between the first and second study periods, the percentage of uterine myomas that decreased in size was 55.1% (95% CI: 43– 66), with a mean decrease in volume of 35% ⫾ 4%; while the percentage of uterine myomas that enlarged was 44.9% (95% CI: 34 –56), with a mean increase in volume of 69% ⫾ 11%. Between the second and third study periods, 75% (95% CI: 56 – 87) became smaller, with a mean decrease in volume of 30% ⫾ 3%; while 25% (95% CI: 13– 43) enlarged, with a mean increase in volume of 102% ⫾ 62%. In Table 2, the volume change was reclassified into three groups: increased in size (an increase of more than 10% in volume), decreased (a decrease of more than 10% in volume), and unchanged (a change of 10% or less in
Table 2 Uterine myoma volume change during pregnancy (when considering a change ⱕ10% as no change) No change Decrease Increase in size in size in size (%) (%) (%) p Change between first 12.9 and second study periods Change between 17.9 second and third study periods *Difference statistically significant.
47.1
40.0
.001*
64.3
17.8
.002*
388
Journal of Minimally Invasive Gynecology, Vol 13, No 5, September/October 2006 Table 3 Volume change between the second and third study periods in relation to myoma size Myoma mean diameter at the second study period ⱕ4 cm (%) ⬎ 4 cm (%) p No change in size Decrease in size Increase in size
40.0 20.0 40.0
5.9 88.2 5.9
.047* .001* .047*
*Difference statistically significant.
Figure 1 The receiver operating characteristic (ROC) curve of the myoma size that predicts a decrease between the first and second study periods. (Area under the curve [AUC] ⫽ 0. 573, p ⫽ .295.)
volume). The distribution reveals that 12.9% of myomas remained unchanged between the first and second study period, and 17.9% of myomas remaining unchanged between the second and third study period. Comparison of percentages within each study period is shown in Table 2. The ROC curves showed that the size of myomas was not useful to predict the direction of volume change between the first and second study periods (Figure 1). However, size was a good predictor for volume change between the second and third periods (Figure 2). The larger the myoma, the more likely it was to decrease in size during pregnancy. A volume corresponding to a
Figure 2 The ROC curve of the myoma size that predicts a decrease between the second and third study periods. A mean diameter of 4 cm had the best sensitivity and specificity to predict a decrease in size. (AUC ⫽ 0.829, p ⫽ .005.)
mean myoma diameter of more than 4 cm had the best trade-off between the sensitivity and specificity to predict a decrease in size between the second and third study periods. Table 3 shows the change in volume between the second and third study periods in myomas measuring 4 cm or less and more then 4 cm. A myoma with mean diameter of more than 4 cm in the second period was associated with a sensitivity of 88% (0.66 – 0.97) and a specificity of 80% (0.49 – 0.94) to predict a decrease in size.
Discussion A review of three commonly used textbooks demonstrates that the classic teaching is uterine myomas increase in size during pregnancy. Williams Obstetrics states that, “Normal rapid uterine (myoma) expansion during pregnancy results from a complex mechanism mediated not only by estrogen and progesterone but also by growth factors.”5 In Comprehensive Gynecology, the author states that, “Myomas often enlarge during pregnancy.”6 And in Current Obstetrics & Gynecology, the behavior of myomas during pregnancy was described as follows: “During the second and third trimesters of pregnancy, myomas may rapidly increase in size.”7 These statements were challenged by many reports that showed a tendency for many myomas to remain unchanged or to decrease in size during pregnancy. LevToaff et al found that 58% and 55.3% of the small uterine myomas (⬍6 cm) did not change in size during the first and second trimesters, respectively. In the third trimester, 60.9% of the small uterine myomas did not change in size, and 34.8% decreased in size. Of large uterine myomas (ⱖ6 cm), 80% increased in size during first trimester, and 48.3% decreased in size in the second trimester. Finally, in the third trimester, 58.8% of the large uterine myomas increased in size, while 29.4% did not change in size.10 Aharoni et al reported that only 22% of uterine myomas increased in size, 59% changed less than 10% of the initial volume, and 19% decreased in size.11 Rosati et al found that 31.6% of uterine myomas increased in size, 60.6% had no change in size, and 7.8% decreased in size.12 Strobelt et al showed that 62.7% of uterine myomas disappeared during pregnancy.13
Hammoud et al
Volume change of myomas during pregnancy
The notion that uterine myomas increase in size in pregnancy stems from literature that antedates the era of ultrasound. The clinical diagnosis of myomas in pregnancy proved to be inaccurate. Muram et al found that in pregnant patients who had myomas, only 42% of the myomas were diagnosed by physical examination. In most instances, the clinical diagnosis was made when the neoplasm was large. When the myoma was 3 to 5 cm in diameter, the rate of detection on physical examination was only 12.5%.3 This controversy regarding the change in volume of uterine myomas probably was first questioned in 1959 by Lamb and Greene, long before the ultrasound era.15 They proposed three mechanisms for what they called “the apparent growth” of uterine myomas in pregnancy. First, the apparent increase is an increase in the palpable area without increase in mass.15 The second mechanism is the hypertrophy and/or hyperplasia of smooth muscle and connective tissue. Lamb and Greene showed that late in pregnancy, the mean diameter of the leiomyoma cell remained approximately the same as in early pregnancy, but the mean diameter of the myometrial cell increased by 50%.15 The third mechanism is the swelling due to degenerative changes. This theory was not supported by LevToaff et al who found that out of 10 patients who had degeneration none had a significant change in myomas size.10 On the contrary, degeneration was used to explain the decrease in size of myomas. Strobelt et al postulated that stretching of the myometrium due to progressive expansion of the amniotic cavity and degenerative changes related to ischemia may lead to shrinkage or disappearance of the tumor.13 This later assumption is supported in part by the early works of Sampson16 and Faulkner17 who suggested that arterial supply of leiomyomas is from one or more arteries entering from the periphery and encircling the tumor. Sampson was the first to postulate that degeneration occurs when the myoma migrates upward and loses its blood supply.16 Faulkner also demonstrated that red degeneration is due to a vascular accident.18 A fourth mechanism, not mentioned by Lamb and Greene, is the growth in response to increased estrogen and progesterone levels during pregnancy. The hormonal dependence of uterine myomas was first explained by Tamaya et al who found that estrogen- and progesteronereceptor levels were higher in the myoma cells compared with the myometrium.19 However, the relationship between estrogen and progesterone levels and myomas growth proved later to be more complex. Maruo et al20 showed that progesterone has a dual role, stimulatory and inhibitory on myoma cell growth and survival, depending on the local growth factor environment.20 In support of the dual effect of progesterone on myomas, Maruo et al reported that during use of levonorgestrel- releasing intrauterine devices, uterine myomas can increase in size, stay the same, or shrink. These latter findings explain
389 why in our study as well as in other reports, myomas remained unchanged, decreased in size, or enlarged.20
Conclusion Our findings showed that, contrary to common belief, a substantial percentage of myomas decrease in volume during the course of pregnancy. This study serves as an “eye opener” to the literature regarding the volume change of uterine myomas during pregnancy. The limitations of our study are common to many of the previously reported studies. Its retrospective nature dictated the inclusion of patients who had two or more ultrasounds and imposed also the choice of the anatomy scan as a reference point. By doing this, we missed any volume change that might happen in the first trimester and early second trimester. Another limitation is that the ultrasound examinations of the patients were performed in similar pregnancy periods but not always at the same gestational age. The different intervals between ultrasound examinations should not affect the frequencies of increase or decrease in size that we reported; however, they might affect the mean increase or decrease in size.
References 1. Marshall LM, Spiegelman D, Barbieri RL, et al. Variation in the incidence of uterine leiomyoma among premenopausal women by age and race. Obstet Gynecol. 1997;90:967–973. 2. Cooper NP, Okolo S. Uterine myomas in pregnancy: common but poorly understood. Obstet Gynecol Surv. 2005;60:132–138. 3. Muram D, Gillieson M, Walters JH. Myomas of the uterus in pregnancy: ultrasonographic follow-up. J Am Obstet Gynecol. 1980;138: 16 –19. 4. Wallach E, Vlahos F. Uterine myomas: an overview of development, clinical features, and management. Obstet Gynecol. 2004;104:393– 406. 5. Cunningham FG, et al. Abnormalities of the reproductive tract. In: Cunningham FG, Hauth JC, Leveno KJ, Gilstrap L, Bloom SL, Wenstrom KD, eds. Williams Obstetrics. 22nd ed. New York, NY: McGraw-Hill; 2005:XX. 6. Stenchever MA, et al. Benign gynecologic lesions vulva, vagina, cervix, uterus, oviduct, ovary. In: Stenchever MA, Droegemueller W, Herbst AL, Mishell DR, eds. Comprehensive Gynecology. 4th ed. St. Louis, MO: Mosby; 2001:XX. 7. Evantash E, Hill EC, Pernoll ML. Benign disorders of the uterine cervix. In: DeCherney AH, Nathan L, eds. Current Obstetrics & Gynecology. 9th ed. New York, NY: Lange Medical Books/McGrawHill; 2003:XX. 8. Kamat N, Telkar H, Ramani S, Thakker A. Ruptured degenerated uterine fibroid diagnosed by imaging. Obstet Gynecol. 2001;98:961– 963. 9. Donnez J, Pirard C, Smets M, et al. Unusual growth of a myoma during pregnancy. Fertil Steril. 2002;78:632– 633. 10. Lev-Toaff AS, Coleman BG, Arger PH, Mintz MC, Arenson RL, Toaff ME. Leiomyomas in pregnancy: sonographic study. Radiology. 1987;164:375–380. 11. Aharoni A, Reiter A, Golan D, Paltiely Y, Sharf M. Patterns of growth of uterine leiomyomas during pregnancy: a prospective longitudinal study. Br J Obstet Gynaecol. 1988;95:510 –513.
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12. Rosati P, Exacoustos C, Mancuso S. Longitudinal evaluation of uterine myoma growth during pregnancy: a sonographic study. J Ultrasound Med. 1992;11:5115. 13. Strobelt N, Ghidini A, Cavallone M, Pensabene I, Ceruti P, Vergani P. Natural history of uterine leiomyomas in pregnancy. J Ultrasound Med. 1994;13:399 – 401. 14. Flierman PA, Oberye JJ, van der Hulst VP, de Blok S. Rapid reduction of leiomyoma volume during treatment with the GnRH antagonist ganirelix. BJOG. 2005;112:638 – 642. 15. Lamb JE, Greene RR. A microscopic study of the growth of leiomyomas of the uterus during pregnancy. Surg Gynecol Obstet. 1959;108: 575–581.
16. Sampson J. Blood supply of uterine myomata. Surg Gynecol Obstet. 1912;14:215–234. 17. Faulkner RE. Blood vessels of the myomatous uterus. Am J Obstet Gynecol. 1944;47:185–197. 18. Faulkner R. Red degeneration of the uterine myoma. Am J Obstet Gynecol. 1947;53:474 – 482. 19. Tamaya T, Fujimoto J, Okada H. Comparison of cellular levels of steroid receptors in uterine leiomyoma and myometrium. Acta Obstet Gynecol Scand. 1985;64:307–309. 20. Maruo T, Ohara N, Wang J, Matsuo H. Sex steroidal regulation of uterine leiomyoma growth and apoptosis. Hum Reprod Update. 2004; 10:207–220.
Original articles
Volume change of uterine myomas during pregnancy: Do myomas really grow? Ahmad O. Hammoud, MD, Radwan Asaad, MD, Jay Berman, MD, Marjorie C. Treadwell, MD, Sean Blackwell, MD, and Michael P. Diamond, MD From the Department of Obstetrics and Gynecology, University of Utah, Salt Lake City, Utah (Dr. Hammoud); and the Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan (Drs. Asaad, Berman, Treadwell, Blackwell, and Diamond). KEYWORDS: Uterine myoma; Fibroids; Change in volume; Pregnancy
Abstract STUDY OBJECTIVE: To estimate changes in uterine myoma volume during pregnancy. DESIGN: Review of departmental electronic perinatal database and medical records. Canadian Task Force Classification II-3. SETTING: Obstetrical ultrasound unit in an academic tertiary care center. PATIENTS: One hundred-seven patients diagnosed with uterine myomas during pregnancy and who had two or more obstetrical ultrasounds in different periods of pregnancy. INTERVENTIONS: We analyzed the change in volume of uterine myomas between the first half of pregnancy (up until 19 weeks), third quarter (20 –30 weeks), and last quarter (31 weeks to term). The volume of largest uterine myoma was calculated using the formula Volume (mm3) ⫽ ⌸/6 ⫻ (length mm) ⫻ (width mm) ⫻ (height mm). MEASUREMENTS AND MAIN RESULTS: The mean age of the population was 31 ⫾ 6 years. Between the first and the second study periods, the percentage of uterine myomas that decreased in size was 55.1% (95% CI: 43– 66), with a mean decrease in volume of 35% ⫾ 4%; while the percentage of uterine myomas that enlarged was 44.9% (95% CI: 34 –56), with a mean increase in volume of 69% ⫾ 11%. Between the second and the third study periods, 75% (95% CI: 56 – 87) became smaller, with a mean decrease in volume of 30% ⫾ 3%; while 25% (95% CI: 13– 43) enlarged, with a mean increase in volume of 102% ⫾ 62%. CONCLUSION: Contrary to common belief, we found that uterine myomas commonly decrease in volume over the course of pregnancy. © 2006 AAGL. All rights reserved.
Uterine myomas are the most common pelvic tumor in reproductive-age women.1 Their prevalence in pregnancy is This manuscript was accepted as an oral presentation at the 34th annual meeting of the AAGL, Chicago, Illinois, November 9 –12, 2005. Corresponding author: Ahmad Hammoud, MD, University of Utah, Department of Obstetrics and Gynecology, Suite 2B200, 30 North 1900 East, Salt Lake City, Utah 84132. E-mail: [email protected] Submitted December 19, 2005. Accepted for publication April 13, 2006.
1553-4650/$ -see front matter © 2006 AAGL. All rights reserved. doi:10.1016/j.jmig.2006.04.003
estimated to be 0.1% to 3.9%.2 During pregnancy, the diagnosis is clinical when the uterine myomas are palpable or intraoperative during cesarean section delivery; however in the majority of cases, diagnosis is made using ultrasound.3 The change in size of uterine myomas during pregnancy remains controversial. It has been standard teaching that myomas grow during pregnancy under the influence of hormonal stimulation.4 –9 However, recent studies have shown that uterine myomas frequently remained
Hammoud et al Table 1 periods
Volume change of myomas during pregnancy
Volumes of myomas during the three study
Volume
Median (cm3)
Minimum - Maximum (cm3)
Up until 19 weeks 20–30 weeks 31–42 weeks
56.38 45.08 52.87
2.64 - 825.98 3.40 - 661.61 2.51 - 1976.94
unchanged in pregnancy or decreased in size.10 –13 In this study, our objective was to estimate the change in size of uterine myomas during pregnancy.
Material and methods After institutional review board approval, we conducted a review of our departmental electronic perinatal database and medical charts of patients who were seen in the obstetric ultrasound unit in the period from 1994 to 2004. Pregnant patients diagnosed with uterine myomas and who had two or more ultrasounds during different stages of pregnancy were included in the study. The location, number, and volume of the uterine myomas were followed. In this study, we analyzed the change in uterine myoma volume throughout pregnancy. The approximated uterine myoma volume was calculated by using the formula Volume ⫽ ⌸/6 ⫻ (length) ⫻ (width) ⫻ (height).14 When the patients had multiple uterine myomas, only the largest uterine myoma was followed, and identified throughout the remainder of pregnancy by its specific recorded location. In our practice, pregnant patients have a targeted ultrasound at 16 to 20 weeks of gestation for fetal anatomy scanning. This ultrasound was used as a reference point for the purpose of studying changes in volume of uterine myomas. As a result, we analyzed the change in volume of uterine myomas between three periods: the first study period (up until 19 weeks), second study period (20 –30 weeks), and the third study period (31– 42 weeks). Initially, the volume change was reported as the percentage change in volume of each uterine myoma. We calculated the frequency of increase or decrease in size between the above-mentioned periods of pregnancy. The mean change in volume was reported also in these two groups in the different study periods. If the data were normally distributed, the mean ⫾ SEM were used; and if the distribution were skewed, median and range were used. Previous reports tried to study the influence of myoma size on the direction of the volume change. Different thresholds were used empirically.10,12,13 In our analysis, a receiver operating characteristic (ROC) curve was used to identify a uterine myoma size that can predict
387 the direction of volume change. The area under the curve was calculated. The 2 test was used to compare frequencies. A p value ⬍.05 was considered statistically significant. Bonferroni correction was performed in case of multiple comparisons. All the statistical operations were performed using SPSS for Windows v13.0 (SPSS, Inc., Chicago, IL).
Results During the study period, 107 patients met our inclusion criteria. The mean age of patients was 31 ⫾ 6 years. The racial distribution of our population was as follows: 89.4% African American, 5.7% Caucasian, and 4.9% other races including Hispanic and Middle Eastern. As to the parity, 78.9% of the women were primiparous, and 21.1% were multiparous. The median volume of myomas in different study periods is given in Table 1. Using the formula Myoma volume ⫽ ⌸/6 ⫻ (mean diameter3), we calculated that the mean diameter of 4.8 cm corresponded to the mean volume in the first study period, 4.4 cm in the second study period, and 4.7 cm in the third study period. The volume change of uterine myomas between the different study periods was as follows: between the first and second study periods, the percentage of uterine myomas that decreased in size was 55.1% (95% CI: 43– 66), with a mean decrease in volume of 35% ⫾ 4%; while the percentage of uterine myomas that enlarged was 44.9% (95% CI: 34 –56), with a mean increase in volume of 69% ⫾ 11%. Between the second and third study periods, 75% (95% CI: 56 – 87) became smaller, with a mean decrease in volume of 30% ⫾ 3%; while 25% (95% CI: 13– 43) enlarged, with a mean increase in volume of 102% ⫾ 62%. In Table 2, the volume change was reclassified into three groups: increased in size (an increase of more than 10% in volume), decreased (a decrease of more than 10% in volume), and unchanged (a change of 10% or less in
Table 2 Uterine myoma volume change during pregnancy (when considering a change ⱕ10% as no change) No change Decrease Increase in size in size in size (%) (%) (%) p Change between first 12.9 and second study periods Change between 17.9 second and third study periods *Difference statistically significant.
47.1
40.0
.001*
64.3
17.8
.002*
388
Journal of Minimally Invasive Gynecology, Vol 13, No 5, September/October 2006 Table 3 Volume change between the second and third study periods in relation to myoma size Myoma mean diameter at the second study period ⱕ4 cm (%) ⬎ 4 cm (%) p No change in size Decrease in size Increase in size
40.0 20.0 40.0
5.9 88.2 5.9
.047* .001* .047*
*Difference statistically significant.
Figure 1 The receiver operating characteristic (ROC) curve of the myoma size that predicts a decrease between the first and second study periods. (Area under the curve [AUC] ⫽ 0. 573, p ⫽ .295.)
volume). The distribution reveals that 12.9% of myomas remained unchanged between the first and second study period, and 17.9% of myomas remaining unchanged between the second and third study period. Comparison of percentages within each study period is shown in Table 2. The ROC curves showed that the size of myomas was not useful to predict the direction of volume change between the first and second study periods (Figure 1). However, size was a good predictor for volume change between the second and third periods (Figure 2). The larger the myoma, the more likely it was to decrease in size during pregnancy. A volume corresponding to a
Figure 2 The ROC curve of the myoma size that predicts a decrease between the second and third study periods. A mean diameter of 4 cm had the best sensitivity and specificity to predict a decrease in size. (AUC ⫽ 0.829, p ⫽ .005.)
mean myoma diameter of more than 4 cm had the best trade-off between the sensitivity and specificity to predict a decrease in size between the second and third study periods. Table 3 shows the change in volume between the second and third study periods in myomas measuring 4 cm or less and more then 4 cm. A myoma with mean diameter of more than 4 cm in the second period was associated with a sensitivity of 88% (0.66 – 0.97) and a specificity of 80% (0.49 – 0.94) to predict a decrease in size.
Discussion A review of three commonly used textbooks demonstrates that the classic teaching is uterine myomas increase in size during pregnancy. Williams Obstetrics states that, “Normal rapid uterine (myoma) expansion during pregnancy results from a complex mechanism mediated not only by estrogen and progesterone but also by growth factors.”5 In Comprehensive Gynecology, the author states that, “Myomas often enlarge during pregnancy.”6 And in Current Obstetrics & Gynecology, the behavior of myomas during pregnancy was described as follows: “During the second and third trimesters of pregnancy, myomas may rapidly increase in size.”7 These statements were challenged by many reports that showed a tendency for many myomas to remain unchanged or to decrease in size during pregnancy. LevToaff et al found that 58% and 55.3% of the small uterine myomas (⬍6 cm) did not change in size during the first and second trimesters, respectively. In the third trimester, 60.9% of the small uterine myomas did not change in size, and 34.8% decreased in size. Of large uterine myomas (ⱖ6 cm), 80% increased in size during first trimester, and 48.3% decreased in size in the second trimester. Finally, in the third trimester, 58.8% of the large uterine myomas increased in size, while 29.4% did not change in size.10 Aharoni et al reported that only 22% of uterine myomas increased in size, 59% changed less than 10% of the initial volume, and 19% decreased in size.11 Rosati et al found that 31.6% of uterine myomas increased in size, 60.6% had no change in size, and 7.8% decreased in size.12 Strobelt et al showed that 62.7% of uterine myomas disappeared during pregnancy.13
Hammoud et al
Volume change of myomas during pregnancy
The notion that uterine myomas increase in size in pregnancy stems from literature that antedates the era of ultrasound. The clinical diagnosis of myomas in pregnancy proved to be inaccurate. Muram et al found that in pregnant patients who had myomas, only 42% of the myomas were diagnosed by physical examination. In most instances, the clinical diagnosis was made when the neoplasm was large. When the myoma was 3 to 5 cm in diameter, the rate of detection on physical examination was only 12.5%.3 This controversy regarding the change in volume of uterine myomas probably was first questioned in 1959 by Lamb and Greene, long before the ultrasound era.15 They proposed three mechanisms for what they called “the apparent growth” of uterine myomas in pregnancy. First, the apparent increase is an increase in the palpable area without increase in mass.15 The second mechanism is the hypertrophy and/or hyperplasia of smooth muscle and connective tissue. Lamb and Greene showed that late in pregnancy, the mean diameter of the leiomyoma cell remained approximately the same as in early pregnancy, but the mean diameter of the myometrial cell increased by 50%.15 The third mechanism is the swelling due to degenerative changes. This theory was not supported by LevToaff et al who found that out of 10 patients who had degeneration none had a significant change in myomas size.10 On the contrary, degeneration was used to explain the decrease in size of myomas. Strobelt et al postulated that stretching of the myometrium due to progressive expansion of the amniotic cavity and degenerative changes related to ischemia may lead to shrinkage or disappearance of the tumor.13 This later assumption is supported in part by the early works of Sampson16 and Faulkner17 who suggested that arterial supply of leiomyomas is from one or more arteries entering from the periphery and encircling the tumor. Sampson was the first to postulate that degeneration occurs when the myoma migrates upward and loses its blood supply.16 Faulkner also demonstrated that red degeneration is due to a vascular accident.18 A fourth mechanism, not mentioned by Lamb and Greene, is the growth in response to increased estrogen and progesterone levels during pregnancy. The hormonal dependence of uterine myomas was first explained by Tamaya et al who found that estrogen- and progesteronereceptor levels were higher in the myoma cells compared with the myometrium.19 However, the relationship between estrogen and progesterone levels and myomas growth proved later to be more complex. Maruo et al20 showed that progesterone has a dual role, stimulatory and inhibitory on myoma cell growth and survival, depending on the local growth factor environment.20 In support of the dual effect of progesterone on myomas, Maruo et al reported that during use of levonorgestrel- releasing intrauterine devices, uterine myomas can increase in size, stay the same, or shrink. These latter findings explain
389 why in our study as well as in other reports, myomas remained unchanged, decreased in size, or enlarged.20
Conclusion Our findings showed that, contrary to common belief, a substantial percentage of myomas decrease in volume during the course of pregnancy. This study serves as an “eye opener” to the literature regarding the volume change of uterine myomas during pregnancy. The limitations of our study are common to many of the previously reported studies. Its retrospective nature dictated the inclusion of patients who had two or more ultrasounds and imposed also the choice of the anatomy scan as a reference point. By doing this, we missed any volume change that might happen in the first trimester and early second trimester. Another limitation is that the ultrasound examinations of the patients were performed in similar pregnancy periods but not always at the same gestational age. The different intervals between ultrasound examinations should not affect the frequencies of increase or decrease in size that we reported; however, they might affect the mean increase or decrease in size.
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