We tested the hypothesis that the protective effect of parity on fibroids is due to direct pregnancy-related effects by following women from early pregnancy to postpartum period with ultrasound. Of 171 women with one initial fibroid, 36% had no identifiable fibroid at the time of postpartum ultrasound, and 79% of the remaining fibroids decreased in size

Baird, D.D.

Fielding, J.R.

Hartmann, K.E.

Herring, A.H.

Laughlin, S.K.

Olshan, A.F.

Savitz, D.A.

Carolina Digital Repository

Pregnancy-Related Fibroid ReductionShannnon K Laughlin, MD MPH1,2,†, Amy H Herring, ScD3, David A Savitz, PhD4, Andrew FOlshan, PhD2, Julia R Fielding, MD5, Katherine E Hartmann, MD PhD6,7, and Donna D Baird,PhD MPH11Epidemiology Branch, National Institutes of Health, National Institute of Environmental HealthSciences, PO Box 12233, Research Triangle Park, NC 277092Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC275993Biostatistics, University of North Carolina Gillings School of Global Public Health and CarolinaPopulation Center, Chapel Hill, NC 275994Disease Prevention and Public Health Institute, Mount Sinai School of Medicine, New York, NY100295Department of Radiology, University of North Carolina, Chapel Hill 275996Institute for Medicine and Public Health, Vanderbilt University, Nashville, TN 372037Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN 37203AbstractWe tested the hypothesis that the protective effect of parity on fibroids is due to direct pregnancy-related effects by following women from early pregnancy to postpartum period with ultrasound. Of171 women with one initial fibroid, 36% had no identifiable fibroid at the time of postpartumultrasound and 79% of the remaining fibroids decreased in size.Keywordsleiomyoma; postpartum; pregnancy; ultrasound; uterine remodelingUterine leiomyomata, or fibroids, are benign tumors with an estimated prevalence of at least15% in white women and 40% in black women by age 35 (1,2). Higher parity is associatedwith reduced fibroid risk in most epidemiologic studies (3,4,5) and fibroid risk is lower amongwomen with more recent pregnancies (4,5) than with remote pregnancies. Whether theassociation is due to direct protective effects or to fibroid-related infertility is unclear. Bairdand Dunson (6) argued that the parity association is likely due to a pregnancy-related protectiveeffect citing experimental data from the Eker rat, an animal model for fibroids (7).We evaluated pregnancy-related effects on fibroids within a large prospective pregnancy studyusing ultrasound to determine the proportion of tumors that are eliminated or changed in size†Corresponding author: Shannon K. Laughlin, Department of Obstetrics & Gynecology, Mayo Clinic, 200 1st St SW, Rochester MN,55905, Phone: (847) 366-9825, Fax: (507) 266-7953, laughlin.shannon@mayo.edu.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customerswe are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resultingproof before it is published in its final citable form. Please note that during the production process errors may be discovered which couldaffect the content, and all legal disclaimers that apply to the journal pertain.NIH Public AccessAuthor ManuscriptFertil Steril. Author manuscript; available in PMC 2011 November 1.Published in final edited form as:Fertil Steril. 2010 November ; 94(6): 2421–2423. doi:10.1016/j.fertnstert.2010.03.035.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscriptafter pregnancy. This analysis was conducted as part of an ongoing prospective study ofpregnancy, Right from the Start. Methods have been described previously (2,8).The cohort study included an early pregnancy endovaginal ultrasound at radiologic referralfacilities. All sonographers had training in pelvic sonography for a minimum of 3 years andannual study training. Probes for the study were 5-7.5 mHz. The ultrasound systematicallyscreened for uterine fibroids of at least 0.5 cm in largest diameter. Of the 458 first-time studyparticipants with fibroids, 282 participated in the postpartum endovaginal ultrasound, whichwas scheduled between three and six months after the birth. This analysis was limited to womenwho had a single fibroid at early pregnancy screening and who gave birth at ≥ 20 weeksgestation (n = 171).Fibroid characteristics were recorded at each ultrasound. Size of fibroid was based onmeasuring the diameter in each of the three perpendicular planes. Triplicate measures,separated in time by intervening measurements of the gestational sac and fetus, were taken toreduce the chance of focal contractions being misclassified as fibroids. We averaged acrossplanes to provide a single mean diameter per fibroid.Using mutually exclusive categories, fibroid type was defined as: 1) submucous – anyleiomyoma in contact with or distorting the uterine cavity; 2) subserous – distorting the externalcontour of the uterus; 3) intramural – within the myometrium, neither distorting contour norcavity; and 4) pedunculated – attached to the uterus with an identifiable stalk. Location (fundus,corpus, lower uterine segment) was also mutually exclusive and position was marked asanterior, posterior or both. Fibroid images were saved initially as still photos and later as digitalimages on CD-ROM for review by study physicians (KH, SL).We performed a validation study using magnetic resonance imaging (MRI) to evaluate theelimination of fibroids seen on postpartum ultrasounds. A subset of women who completedthe postpartum ultrasound in the preceding 18 months was invited for pelvic MRI. Elevenwomen participated, four with ultrasound-documented postpartum fibroids (positive controls)and seven with no fibroid seen at postpartum ultrasound (validation sample). Participation ratewas 26% (11/42 eligible). Of those who gave reasons for non-participation the major reasonswere time restrictions and breastfeeding. MRI was performed using a 3.0T unit using a standardprotocol. T2-weighted and contrast enhanced images were reviewed in the sagittal and axialplanes. Radiologists had no prior knowledge of fibroid status.Chi-squared and the Kolmogorov-Smirnov tests were used to compare fibroids that resolvedto below detectable size with those that remained. We evaluated resolution by fibroidcharacteristics and by timing of the early pregnancy ultrasounds. The sign test was used tocompare diameter change in a matched analysis of the persisting fibroids. We used linearregression to evaluate fibroid size change by fibroid characteristics using the differencebetween post-partum and early pregnancy fibroid diameter for remaining fibroids. Data wereanalyzed with STATA10.0 (Stata Corporation, College Station, TX).Mean age of the women was 31.2 years (SD 4.8), 62% were white, and nearly half werenulliparous at enrollment. Median gestational age was 8 weeks (25th, 75th percentiles 7, 10)for early pregnancy ultrasound and 3.6 months (25th, 75th percentiles 3.2, 4.4) after deliveryfor postpartum ultrasounds. Most fibroids were either intramural or subserous and were locatedin the uterine corpus. Mean diameter of the fibroids ranged from 0.4 cm to 8.0 cm with a medianof 1.9 cm (25th, 75th percentiles 1.1, 3.2).Of the 171 women, 54% (95% confidence interval (CI) 46, 61) had one fibroid at the time ofpostpartum ultrasound and 10% had more than one, leaving 36% of fibroids that were resolvedbeyond the ability to detect them (Figure 1). Fibroid type, location and position were notLaughlin et al. Page 2Fertil Steril. Author manuscript; available in PMC 2011 November 1.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscriptassociated with fibroid resolution (p>0.2). Initial tumor size was also not related to fibroidresolution (p>0.4); one third of fibroids >3 cm in diameter resolved.Fibroids seen at the postpartum ultrasound were generally smaller than at initial ultrasound.Among the 109 single fibroids detected at the postpartum ultrasound, 79% (95% CI 70, 86)were smaller than the initially-measured size. The median diameter on early pregnancyultrasound was 1.9 cm (25th, 75th percentile 1.2, 3.3) and the postpartum diameter wassignificant smaller (p<0.001) with a median change in diameter of 0.5 cm (25th, 75th percentiles0.1, 1.4). The reduction in diameter associated with submucous fibroids was greater (1.8 cmchange) than the reduction associated with intramural (0.2 cm), subserous (0.6 cm) orpedunculated (0.5 cm) fibroids (p<0.002). Fibroids in the lower segment were associated witha greater change in fibroid diameter (1.4cm) when compared to fibroids in the corpus (0.5cm)or fundus (0.4cm, p=0.003). The reduction in fibroid size did not differ by position (left orright).Our results were supported by the MRI. The four women who had fibroids on the postpartumultrasound also had fibroids on MRI and measured fibroid sizes were consistent. Of the sevenwomen with no fibroids on postpartum ultrasound, three had no fibroids on MRI and two hadfibroids on MRI that were at or below the level of detection by ultrasound. The remaining twowomen had fibroids on MRI large enough that they could have been detected by ultrasound(mean diameters of 0.6 and 0.7 cm); however, these MRIs occurred more than 13 weeks afterthe ultrasound, so it is unclear whether the fibroids were missed or below the level of detectionat the time of the ultrasound. Of the eight fibroids present on the MRI, one showed 100% non-enhancement and two showed central lack of enhancement after contrast indicating there maybe central ischemia for some of the fibroids.Our study was designed to test for a direct protective effect of pregnancy on fibroids. We foundthat 36% of fibroids were resolved below our ability to detect them. Fibroids that remainedwere reduced in diameter by a median of 0.5 cm. Previous studies that tracked fibroids duringpregnancy were based on clinically identified fibroids rather than those detected by systematicultrasound screening. Three studies included postpartum ultrasounds (9-11) and reportedinstances of fibroid elimination or shrinkage. The largest included 34 postpartum assessmentsand these were at four weeks postpartum when uterine involution may not be complete (12);they found up to an 18% reduction in fibroid size for small fibroids. A study of 262 tumors innon-pregnant premenopausal women showed that most fibroids grow over time (13). Thoughspontaneous regression occurred it was infrequent and shrinkage was limited; only 7% had ashrinkage rate of more than 20% per six months (13). This suggests that observed pregnancy-related regression is much more common than would be expected among non-pregnant women.Additionally, though breastfeeding creates a hypoestrogenic state that could confound ourfindings, prior studies have found no association of breastfeeding and fibroids (4,6,14,15),especially after controlling for parity (14). A limitation of our study is that the fibroid screeningwas done in early pregnancy rather than before pregnancy. Fibroids may grow during the firsttrimester, as noted in 12 women from a prior study (11) that showed 8% increase at 10 weeksand 3% at 12 weeks over the pre-pregnancy size. Given the large size reduction in our study(median percent change in diameter of 30%), early first trimester growth is not likely to accountfor much of the volume loss. Furthermore, if early-pregnancy growth followed by latershrinkage back to prepregnancy size were an important contributor to our observed results, thefibroids measured toward the end of the first trimester would be expected to show the biggestchange. However, we found no association of higher gestational age at first ultrasound andfibroid resolution (p=0.4). An additional limitation is that our sample included only eighttumors greater than 5 cm in diameter (5%), so we were unable to adequately evaluatepregnancy-related effects on very large tumors.Laughlin et al. Page 3Fertil Steril. Author manuscript; available in PMC 2011 November 1.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptThe mechanism by which fibroids resolve is of great interest. Ischemia of the myometrium andmyomas at the time of delivery has been proposed as a mechanism (16). Studies on fibroidvasculature show abnormal vessels which are reduced in density compared to adjacentmyometrium making fibroids more susceptible to ischemia (17,18). Additionally, clot formsin both myometrial and fibroid tissue after delivery, but a decrease in fibrinolytic activity infibroids compared to myometrium leads to more sustained ischemia in fibroids (16). Ischemiamay continue during postpartum uterine involution which involves major remodeling of thevasculature (19). It is notable that MRI revealed decreased blood flow in three of eightpostpartum fibroids. Further investigation of the natural mechanisms of pregnancy-relatedfibroid resolution may identify future directions for developing therapies that could limit theneed for highly invasive treatments.AcknowledgmentsThe authors would like to thank the staff and participants of the Right from the Start study for making our researchpossible. Special thanks to Allen Wilcox and Reem Hasan for reviewing earlier versions of this manuscript.Financial support: The work was conducted as part of the Right from the Start study. The parent study received supportfrom the American Water Works Association Research Foundation under Contract #2579 (Savitz); Pfizer ScholarsGrants for Faculty Development in Clinical Epidemiology (Hartmann) and NICHD RO1 HD043883-04 andHD049675: “Consequences and Course of Uterine Fibroids in Pregnancy” (Hartmann). Laughlin was supported bythe NIH Women's Health Fellowships in Intramural Women's Health Research. The postpartum data collectionresearch was supported in part by the Intramural Research Program of the NIH and the National Institute ofEnvironmental Health Sciences (P30ES10126).References1. Baird D, Dunson DB, Hill MC, Cousins D, Schectman JM. High cumulative incidence of uterineleiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol 2003;188:100–7.[PubMed: 12548202]2. Laughlin SK, Baird DD, Savitz DA, Herring AH, Hartmann KE. Prevalence of uterine leiomyomas inthe first trimester of pregnancy: an ultrasound-screening study. Obstet Gynecol 2009;113:630–5.[PubMed: 19300327]3. Okolo S. Incidence, aetiology and epidemiology of uterine fibroids. Best Pract Res Clin ObstetGynaecol 2008;22:571–88. [PubMed: 18534913]4. Wise LA, Palmer JR, Harlow BL, Spiegelman D, Stewart EA, Adams-Campbell LL, et al. Reproductivefactors, hormonal contraception, and risk of uterine leiomyomata in African-American women: aprospective study. Am J Epidemiol 2004;159:113–23. [PubMed: 14718211]5. Marshall LM, Spiegelman D, Goldman MB, Manson JE, Colditz GA, Barbieri RL, et al. A prospectivestudy of reproductive factors and oral contraceptive use in relation to the risk of uterine leiomyomata.Fertil Steril 1998;70:432–9. [PubMed: 9757871]6. Baird DD, Dunson DB. Why is parity protective for uterine fibroids? Epidemiology 2003;14:247–50.[PubMed: 12606893]7. Walker CL, Cesen-Cummings K, Houle C, Baird D, Barrett JC, Davis B. Protective effect of pregnancyfor development of uterine leiomyoma. Carcinogenesis 2001;22:2049–52. [PubMed: 11751438]8. Promislow JH, Makarushka CM, Gorman JR, Howards PP, Savitz DA, Hartmann KE. Recruitmentfor a community-based study of early pregnancy: the Right From The Start study. Paediatr PerinatEpidemiol 2004;18:143–52. [PubMed: 14996255]9. Neiger R, Sonek JD, Croom CS, Ventolini G. Pregnancy-related changes in the size of uterineleiomyomas. J Reprod Med 2006;51:671–4. [PubMed: 17039693]10. Aharoni A, Reiter A, Golan D, Paltiely Y, Sharf M. Patterns of growth of uterine leiomyomas duringpregnancy. A prospective longitudinal study. Br J Obstet Gynaecol 1988;95:510–3. [PubMed:3042016]11. Rosati P, Exacoustos C, Mancuso S. Longitudinal evaluation of uterine myoma growth duringpregnancy. A sonographic study J Ultrasound Med 1992;11:511–5.Laughlin et al. Page 4Fertil Steril. Author manuscript; available in PMC 2011 November 1.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript12. Negishi H, Kishida T, Yamada H, Hirayama E, Mikuni M, Fujimoto S. Changes in uterine size aftervaginal delivery and cesarean section determined by vaginal sonography in the puerperium. ArchGynecol Obstet 1999;263:13–6. [PubMed: 10728621]13. Peddada SD, Laughlin SK, Miner K, Guyon JP, Haneke K, Vahdat HL, et al. Growth of uterineleiomyomata among premenopausal black and white women. Proc Natl Acad Sci U S A2008;105:19887–92. [PubMed: 19047643]14. Lumbiganon P, Rugpao S, Phandhu-fung S, Laopaiboon M, Vudhikamraksa N, Werawatakul Y.Protective effect of depot-medroxyprogesterone acetate on surgically treated uterine leiomyomas: amulticentre case--control study. Br J Obstet Gynaecol 1996;103:909–14. [PubMed: 8813312]15. Samadi AR, Lee NC, Flanders WD, Boring JR 3rd, Parris EB. Risk factors for self-reported uterinefibroids: a case-control study. Am J Public Health 1996;86:858–62. [PubMed: 8659663]16. Burbank F. Childbirth and myoma treatment by uterine artery occlusion: do they share a commonbiology? J Am Assoc Gynecol Laparosc 2004;11:138–52. [PubMed: 15200765]17. Walocha JA, Litwin JA, Miodonski AJ. Vascular system of intramural leiomyomata revealed bycorrosion casting and scanning electron microscopy. Hum Reprod 2003;18:1088–93. [PubMed:12721189]18. Wei JJ, Zhang XM, Chiriboga L, Yee H, Perle MA, Mittal K. Spatial differences in biologic activityof large uterine leiomyomata. Fertil Steril 2006;85:179–87. [PubMed: 16412751]19. Wakasa T, Wakasa K, Nakayama M, Kuwae Y, Matsuoka K, Takeuchi M, et al. Change inMorphology and Oxytocin Receptor Expression in the Uterine Blood Vessels during the InvolutionProcess. Gynecol Obstet Invest 2008;67:137–44. [PubMed: 19005262]Laughlin et al. Page 5Fertil Steril. Author manuscript; available in PMC 2011 November 1.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptFigure 1.Distribution of initial fibroid size for 171 solitary fibroids, and proportion of each group thatwere no longer detected on the postpartum ultrasound.Laughlin et al. Page 6Fertil Steril. Author manuscript; available in PMC 2011 November 1.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript

Pregnancy-related fibroid reduction

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Pregnancy-related fibroid reduction

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