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EPRODUCTIVE ENDOCRINOLOGY AND INFERTILITY

ibroids and reproductive outcomes: a systematiciterature review from conception to delivery
eter C. Klatsky, MD; Nam D. Tran, MD, PhD; Aaron B. Caughey, MD, PhD; Victor Y. Fujimoto, MD
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n estimated 20-40% of women willhave uterine fibroids develop dur-

ng their reproductive years.1 African-merican women are nearly 3 times as

ikely as white women to have fibroidsevelop, and age is the most commonisk factor for fibroids among all wom-n.2 Nulliparity, a long history of ciga-ette smoking and a prolonged men-trual cycle have also been reported asisk factors in white women.3 The num-er of pregnant women with fibroidsanges from a conservative estimate of.7% in women undergoing routine sec-nd-trimester pregnancy ultrasounds,2.6% in women undergoing in vitroertilization (IVF) treatment, and mayxceed 25% in older women who un-ergo ovum donor recipient IVF.4-6 Theurrent trend of delaying childbearing,long with advances in our ability to pro-ong a woman’s reproductive timeline,nsures that an increasing number ofomen with fibroids will present for in-

ertility, prenatal, and obstetric care.In recent years, a number of small- toedium-sized studies have reported in-

ertility treatment and obstetric out-omes in patients with uterine fibroids.n this article, we reviewed the evidenceegarding an association between fi-roids and the continuum of various re-roductive outcomes. We searched the

rom the Department of Obstetrics,ynecology and Reproductive Science (Drlatsky), Mount Sinai School of Medicineew York, NY; and Department ofbstetrics, Gynecology, and Reproductive

ciences (Drs Tran, Caughey, andujimoto), University of California, Sanrancisco, San Francisco, CA.

eceived July 19, 2007; revised Nov. 29,007; accepted Dec. 31, 2007.

eprints not available from authors.

002-9378/$34.002008 Mosby, Inc. All rights reserved.

uoi: 10.1016/j.ajog.2007.12.039

UBMED databases by using the terms,fibroid,” “leiomyoma,” “infertility,”pregnancy,” and “obstetric complica-ions” and cross-referenced all relevantrticles to find controlled studies com-aring outcomes in women with andithout fibroids. We evaluated each ar-

icle and quantitatively summarized thendings of controlled studies.

IBROIDS AND INFERTILITY:MBRYO IMPLANTATIONhe association between fibroids and

mplantation remains controversial.ome authorities believe that fibroidsave a detrimental effect on implanta-ion, either through impaired transportf gametes, altered uterine contractility,r adverse effects on the endometrium.7

one of these hypotheses have beenroven and few have been rigorouslyested.

The increased use of ultrasonographyas resulted in the increased diagnosis ofterine fibroids in asymptomaticomen with unexplained infertility.ome initial reports noted improvedregnancy rates in asymptomaticomen with primary infertility and who

We examined the published relationshipoutcomes. Submucosal fibroids had thepregnancy rates, odds ratio, 0.5; 95% codecreased implantation. Cumulative pregnawith intramural fibroids 36.9% vs 41.1%however, patients with intramural fibroids a12.9%. Adverse obstetric outcomes are rarfibroid populations. Increased risk of malpr(odds ratio, 3.7; 3.5-3.9), and preterm dehowever, the incidence of labor dystociaevidence that intramural or subserosal fibrotive, controlled trials are needed to assess tneonatal outcomes are expected in pregna

Key words: fibroids, infertility, myomas,

nderwent removal of their fibroids; w

APRIL 2008 Ame

owever, most of these studies lacked ad-quate controls and none were random-zed.8 Unfortunately, in the absence ofontrols, such studies can establish theafety of myomectomy but do not sup-ort a therapeutic benefit for womenith infertility.Recently, researchers studied various

ontrolled populations of patients un-ergoing IVF to assess the effect of fi-roids on implantation. Multiple out-ome variables, including implantation,ngoing pregnancy, and miscarriageates, have been studied. Currently, mostuthorities give greater plausibility to theypothesis that submucosal fibroids aressociated with the greatest adverse ef-ect on implantation and placentation.he role of intramural fibroids is moreontroversial. Subserosal and peduncu-ated fibroids, with greater than 50% ofheir mass outside the myometrialorder are unlikely to cause adverseutcomes.9

mplantation-submucosal fibroidsreview of IVF outcomes that included

4 patients undergoing 86 cycles found a0% decrease in pregnancy rate in

tween uterine fibroids and reproductiverongest association with lower ongoingence interval, 0.3-0.8, primarily throughrates appeared slightly lower in patients

hich may reflect biases in the literature;experienced more miscarriages, 20.4% vsnd may reflect age or other differences inntation (odds ratio, 2.9; 2.6-3.2), cesareanry (odds ratio, 1.5; 1.3-1.7) are reported;s low (7.5%). There was no conclusiveadversely affect fecundity. More prospec-ffects of myomectomy. Good maternal and

es with uterine fibroids.

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Reviews Reproductive Endocrinology and Infertility www.AJOG.org

3

ared with infertile controls.10 This de-rease was attributable mostly to a 72%ecrease in implantation rate. Most re-roductive endocrinologists have sinceeen recommending resection of sub-ucosal fibroids, before proceedingith assisted reproductive technologies.nfortunately, evidence supporting this

ecommendation remains limited to amall data set, which included a total of4 patients. Table 1 summarizes thendings in controlled studies ofomen with submucosal fibroids. Al-

hough there are no randomized stud-es comparing patients with submuco-al fibroids undergoing hysteroscopicesection to patients managed conser-atively, the safety of hysteroscopicyomectomy has been well demon-

trated. After hysteroscopic myomec-omy, patients achieve pregnancy rateshat are comparable with controlroups without fibroids or prior hys-eroscopic myomectomies.11-13

The routine resection of submucosalbroids in patients with infertility was

TABLE 1Submucosal fibroids

Study design;number of patients

Fm

Farhi et al7d Retrospective cohort.18 IM fibroidpatients, 50 controls

(

...................................................................................................................

Eldar-Geva et al9d Retrospective cohort.6 study patients,249 controls.

4

...................................................................................................................

Cassini et al14 (SM) Prospective,observational.Spontaneousconceptions,following timedintercourse.

(

...................................................................................................................

Cumulative rates

...................................................................................................................

IM, intramuscular; OR, odds ratio; SM, submucosal.a No. of sacs per no. of embryos transferred.b No. of cycles with a gestational sac or living embryo per tc Clinical miscarriage after documented clinical pregnancy.d Included repeat cycles in the same patient.

Klatsky. Fibroids and reproductive outcomes. Am J Obstet

ecently supported by a study comparing m

58 American Journal of Obstetrics & Gynecology

pontaneous pregnancy rates in womenith at least 1 year of infertility and sub-ucosal fibroids.14 Of women who

hose to undergo myomectomy, 40.4%ere successful within 1 year of trying to

onceive spontaneously, vs 21.4% in theohort who declined myomectomy. It isossible that patients who were more ag-ressive about pursuing surgery werelso more aggressive about intercourseiming and frequency, thus possibly in-reasing their chances to conceivepontaneously.

Despite the limitations of each study,everal trends emerge in patients withubmucosal fibroids, with decreases inmplantation rates from 11.5% to 3.0%nd in ongoing pregnancy rates from0% to 14% (Table 1). Similarly, womenith submucosal fibroids show a trend

oward an increased risk of miscarriagerom 22% to 47%.

mplantation: intramural fibroidsn contrast to the limited data on sub-

oid diameter:n (range)

Implantation rateaClinirateb

Fibroids No fibroids Fibro

0 mm) 2.7%5/179

9.8%35/357

9.7%5/55

.........................................................................................................................

m � 26 4.3%1/23

12.3%94/763

10%1/10

.........................................................................................................................

0 mm) 21.4%9/42

.........................................................................................................................

3.0%6/202OR 0.39(0.24-0.65)

11.5%129/1120

14%15/10OR 0(0.28

.........................................................................................................................

er.

ecol 2008.

ucosal fibroids, many recent studies fi

APRIL 2008

eported data for women with asymp-omatic intramural fibroids presentingith infertility for IVF.5-7,9,14-27 Unfor-

unately, results from these studies arenconsistent (Table 2).

In 1998, Elder-Geva et al9 reported andverse effect on ongoing pregnancyates in patients with submucosal (n �) and intramural (n � 46) fibroids, buto difference was observed among pa-

ients with subserosal (n � 33) fibroidshen compared with controls withoutbroids. These findings contrast with

hose of a smaller study that found noifference in pregnancy rates when fi-roids did not distort the endometrialavity.5 Multiple studies have sinceought to investigate the association be-ween intramural fibroids and implanta-ion outcomes.

Hart et al16 reported the largest pro-pective, controlled study to investigatehe effect of small (less than 5 cm) intra-

ural fibroids and found lower implan-ation and ongoing pregnancy rates inatients with fibroids compared with no

pregnancy Spontaneous abortionratec

No fibroids Fibroids No fibroids

25.2%32/127

40%2/5

25%8/32

..................................................................................................................

30.8%98/318

0%0/1

16.3%16/98

..................................................................................................................

40.4%21/52

55.6%5/9

42.9%9/21

..................................................................................................................

0)

30.4%151/497

46.7%7/15OR: 3.85(1.12-13.27)

21.9%33/151

..................................................................................................................

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TABLE 2Intramural fibroids: controlled studies


Fibroid diameter:mean (range)

Implantation ratea Clinical pregnancy ratebSpontaneous abortionratec

Fibroids No fibroids Fibroids No fibroids Fibroids No fibroids

Farhi et al7d Retrospective cohort.28 IM fibroidpatients, 50 controls

(�70 mm) 8.9%26/292

9.8%35/357

29.1%25/86

25.2%32/127

36%9/25

25%8/32

................................................................................................................................................................................................................................................................................................................................................................................

Ramzy et al5d Retrospective cohort.39 fibroid patients,367 controls

32 � 11 mm 12.5%16/128

13.8%165/1192

38.5%15/39

33.5%123/367

16.7%3/18

12.3%19/154

................................................................................................................................................................................................................................................................................................................................................................................

Eldar-Geva et al9d Retrospective cohort.46 fibroid patients,249 controls

24 � 7 mm 6.6%9/137

12.3%94/763

16.4%9/55

30.8%98/318

33.3%3/9

16.3%16/98

................................................................................................................................................................................................................................................................................................................................................................................

Stovall et al15 Retrospective cohort(included both IVFand zygoteintrafallopian transfercycles). 91 fibroidpatients, 91 controls

29 mm (10-54mm)

13.8%46/334

19.7%65/330

37.4%34/91

52.7%48/91

12.5%(4/32)

8.3%(4/48)

................................................................................................................................................................................................................................................................................................................................................................................

Hart et al16 Prospectiveobservationalcohort.112 fibroidpatients, 322controls

23 � 11 mm(10-50 mm)

12.2%21/172

20.2%123/609

23.3%20/86

34.1%99/290

................................................................................................................................................................................................................................................................................................................................................................................

Surrey et al17d Retrospective cohort.73 fibroid patients,441 controls.

23 � 5 mm 20.2%50/248

23.7%293/1237

50.7%37/73

58.4%191/327

................................................................................................................................................................................................................................................................................................................................................................................

Jun et al18 Retrospective cohort.141 fibroid patients,406 controls.

19 � 13 mm(�70 mm)

30.5%43/141

41.6%169/406

................................................................................................................................................................................................................................................................................................................................................................................

Yarali and Bukulmez19 Retrospective cohort.108 study patients,324 controls

31 � 20 mm(10-80 mm)

9.8%18/183

11.2%102/911

21.9%16/73

27.8%90/324

6.3%1/16

6.7%6/90

................................................................................................................................................................................................................................................................................................................................................................................

Check et al20 Prospectiveobservational cohort.61 study patients,61 controls.

18 � 11 mm(5-51 mm)

34.4%21/61

47.5%29/61

................................................................................................................................................................................................................................................................................................................................................................................

Wang and Check21 Retrospective cohortin ovum donorrecipients. 49 studypatients, 73 controls.

30 mm (�60mm)

29.9%47/157

27.4%60/219

59.2%29/49

46.6%34/73

34.5%10/29

5.9%2/34

................................................................................................................................................................................................................................................................................................................................................................................

Oliveira et al22 Retrospective agematched cohort. 245fibroid patients, 245controls.

19 mm (4-69mm)

47.8%117/245

44.9%110/245

15.9%39/245

13.1%32/245

................................................................................................................................................................................................................................................................................................................................................................................

Bulletti et al23d Patients undergoing1-3 cycles of IVFafter myomectomyor expectantmanagement offibroids

(�50 mm) Nodenominator

Nodenominatorgiven

23.1%3/13

28.6%8/28

................................................................................................................................................................................................................................................................................................................................................................................

Benson et al24 Prospective, age-matched cohort. 143fibroid patients, 715controls.

33 � 21 mm 14.0%20/143

7.6%54/715

................................................................................................................................................................................................................................................................................................................................................................................

Gianaroli et al25 Retrospective age-matched cohort. 75fibroid patients, 127controls.

18 � 14 mm 18%47/261

26.4%73/276

34.9%45/129

41.1%53/129

40%18/45

18.9%10/53

Continued on page 360.

APRIL 2008 American Journal of Obstetrics & Gynecology 359

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8.3%, respectively). Unfortunately, thebroid cohort was significantly older byyears, which may have confounded the

reatment outcomes attributable to pa-ients with fibroids. This same studyroup subsequently reported lowerregnancy rates in the same cohort of pa-ients undergoing repeat cycles of IVF.26

ertainly, they identified a poorer prog-osis group, but whether the difference

s attributable to fibroids, maternal age,r other factors remains unclear, and

TABLE 2Intramural fibroids: controlled studContinued from page 359.


Khalaf et al26d Prospectiveobservational cohort:follow-up outcomesfrom Hart et al16

...................................................................................................................

Feinberg et al27 Retrospective cohort.183 fibroid patients,1044 controls.

...................................................................................................................

Casini et al14 Prospective,observational.Spontaneousconceptions,following timedintercourse. 42fibroid patients, 40“controls” s/pmyomectomy.

...................................................................................................................

Klatsky et al6 Retrospective cohortoocyte donorrecipients. 94 fibroidpatients, 275controls.

...................................................................................................................

Exacoustos and Rosati31

(n � 492)Prospective cohortincludingpregnancies up to20 weeks.

...................................................................................................................

Cumulative rates

...................................................................................................................

IM, intramuscular; IVF, in vitro fertilization; OR, odds ratio.a No. of sacs per no. of embryos transferred.b Most studies defined clinical pregnancy as a cycle resultinc Clinical miscarriage after documented clinical pregnancy.d Included repeat cycles in the same patient.e Limited to patients with early first-trimester ultrasounds.


hese findings have not been consistently t


eproduced by other age-matched co-ort studies.6,17-20,22,27

In 2004, Oliveira et al22 reported lowerregnancy rates in a subgroup of patientsith intramural or subserosal fibroids

arger than 4 cm when compared withatients with fibroids smaller than 4 cm

n maximum diameter. However, thesenvestigators found no significant differ-nce in their primary outcome of liveirth rate in patients with and withoutbroids. These findings are not consis-

s

roid diameter:an (range)

Implantation ratea Clini

Fibroids No fibroids Fibro

t reported

.........................................................................................................................

mm 25.6%103/402

31.1%683/2199

35%64/1

.........................................................................................................................

40 mm) 40.515/3

.........................................................................................................................

mm (10-81)

36.9%75/203

37.0%227/614

48.844/9

.........................................................................................................................

t reported

.........................................................................................................................

18.2%458/2517OR 0.79(0.71-0.88)

22.1%1920/8707

36.9519/OR 0(0.74

.........................................................................................................................

either a living embryo or gestational sac. Hart et al included ch

ecol 2008.

ent with those of Hart et al16 and Fein- r

APRIL 2008

erg et al27 whose study cohorts hadean fibroid diameters of 2.3 cm and 2.6

m. In Oliveira et al,22 the cohort withbroids 1.0-4.0 cm demonstrated a trend

oward higher pregnancy rates than theohort without fibroids (P � NS). Nother study has documented a clear ad-erse relationship between the size of thebroids and poorer implantation orregnancy rates. We recently reportedhat subjects with fibroids ranging from-8 cm had a 67% ongoing pregnancy

pregnancy ratebSpontaneous abortionratec

No fibroids Fibroids No fibroids

36.1%13/36

27.3%44/161

..................................................................................................................

43.2%451/1044

25.0%16/64

16.6%75/451

..................................................................................................................

38.5%15/39

..................................................................................................................

54.2%149/275

18.2%8/44

9.4%14/149

..................................................................................................................

7.7%38/492

6.8%829/12,216

..................................................................................................................

5

5)

41.1%1676/4077

15.3%185/1121OR: 1.34(1.04, 1.65)20.4%e

147/719e

OR 1.82(1.43-2.30)

7.7%1121/14,47412.9%e

292/2258e

..................................................................................................................

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......... .........

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igher pregnancy rates than controls andomen with smaller fibroids.6 At thisoint, there is no compelling evidencehat larger intramural fibroids exert aorse impact on ongoing pregnancy

ates. Many studies also excluded pa-ients with fibroids larger than 5 or 7m.7,16,22

With such disparate findings, meta-nalysis can be a useful tool; however, its prone to replicating and amplifying bi-ses in earlier studies and reinforces pub-ication biases favoring studies with pos-tive findings. Table 2 summarizes thendings of individual studies. Each studyas strengths and limitations. Hart et al16

s a well-conducted prospective observa-ional study, but was not age matched.everal larger, age-matched retrospec-ive studies were also well conducted andeported negative findings; however,ach was limited by a lack of power toetect statistically significant out-omes.17-19 Feinberg et al27 conductedn excellent study to assess the role offrican American ethnicity in IVF out-omes and secondarily found a deleteri-us effect of fibroids on delivery rates.e were unable to replicate the findings

f Hart et al or Feinberg et al in an ade-uately powered study of ovum donorVF recipients undergoing embryoransfer.6

We provide cumulative data sum-arizing the findings of these studies

n Table 2, but urge caution when in-erpreting these numbers, as this ap-roach replicates individual study andge biases, as well as a global publica-ion bias favoring positive studies.hat said, when relevant study cohortsre reviewed together, intramural fi-roids appear to be associated with alight decrease in implantation rate,rom 22% to 18%, and an increase inpontaneous abortion rate, from 8% to5%. Although we believe it reasonableo offer hysteroscopic myomectomy toatients with submucosal fibroids,ore prospective studies are needed to

onfirm a deleterious effect indepen-ent of ovarian age, before we wouldecommend removal of intramural fi-
roids for reproductive optimization. m
ISCARRIAGE

he most frequently cited study on theelationship between fibroids and fertil-ty outcomes is a review of published re-orts from 1957-1980, which identified aecrease in miscarriage rates from 41%o 19%, in a cohort of women with symp-omatic fibroids who underwent myo-

ectomy.28 Most of the studies includedere small case series without controls

hat were subject to various method-logic limitations. In addition to the re-all and ascertainment bias associatedith case series, patients in this studyere different because they had symp-

omatic, palpable fibroids. Most infertil-ty patients today are asymptomatic withhe fibroid diagnosis made by ultra-onography. A small, uncontrolled seriesf 19 asymptomatic patients who con-eived with fibroids reported a reductionn spontaneous miscarriages post-

yomectomy compared with the pre-yomectomy rate (24% vs 60%,

espectively).29

A larger, controlled study by Benson etl30 reported a nearly 2-fold increase iniscarriage rate among 143 patientsith sonographically identified fibroids

hat were identified on first-trimester ul-rasound, when compared with morehan 715 age-matched controls withoutbroids (14.0% vs 7.6%, P � .05). Al-

hough fibroid size was not associatedith the spontaneous loss rate, the pres-

nce of multiple fibroids was a signifi-ant predictor of spontaneous loss andmong the 88 patients with only a singlebroid, there was no increased risk ofpontaneous miscarriage compared withontrols. Feinberg et al27 did not reportn the number or size of fibroids butound a trend toward increased miscar-iages in 64 pregnancies with intramuralbroids compared with 451 pregnancies

n patients without fibroids (25.0% vs6.1%, respectively).Many of the previously mentioned

tudies documented trends toward aigher spontaneous abortion rate inomen with intramural fibroids, butere designed to examine pregnancy

ates with IVF and were thus underpow-red to individually address the risk of
iscarriage. When examined together, b
APRIL 2008 Ame

hese trends begin to look significant. Incontrolled studies that reported spon-

aneous abortions in pregnancies result-ng from IVF, women with intramuralbroids had a spontaneous abortion ratef 22.0%, compared with 15.4% in con-rols (Table 2). After including data fromhe study by Benson et al,30 women un-ergoing first-trimester ultrasoundsith intramural fibroids appear signifi-

antly more likely to experience a spon-aneous miscarriage, 20.4% vs 12.9%odds ratio [OR], 1.6; 95% confidencenterval [CI], 1.3-2.0). Of note, the studyy Exacoustos et al31 is unique because ofxclusion criteria with a maximum fi-roid diameter of less than 3.0 cm and

nclusion criteria of screening ultra-ounds up to 20 weeks’ gestation. Thistudy was excluded from our cumulativeata set and found a lower miscarriageate with fibroids, when compared withtudies that included only subjects witharly first-trimester ultrasounds.

Data are unavailable to evaluate theisk of miscarriage in women with sub-ucosal fibroids. Casini et al14 reportediscarriages in 5 of 9 (53%) pregnantomen with submucosal fibroids andiscarriages in 9 of 21 (43%) womenho underwent prior myomectomy andnly 1 patient in the Benson et al24 studyad a submucosal fibroid.

IBROIDS IN PREGNANCYhe effects of fibroids on pregnancy out-omes and complications are even morembiguous. Most reports use retrospec-ive cohort or case-control study designs,hich are subject to ascertainment bi-

ses, identifying fibroids after patientsave pain develop, undergo cesarean de-

ivery, or develop other complications ofregnancy. The most commonly re-orted complaint associated with uter-

ne fibroids during pregnancy is pain.32

cute pain episodes can be severenough to warrant hospitalization fornalgesia. A review of antepartum ad-issions for fibroid-related pain exacer-

ations found ibuprofen to be the mostffective analgesic. However, nonsteroi-al antiinflammatory drugs (NSAIDs)re usually avoided in the third trimester
ecause of the associated fetal and neo-

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atal risks of early closure of the fetaluctus arteriosus, pulmonary hyperten-ion, decreased fetal renal function,ligohydramnios, necrotizing enteroco-

itis, intracranial hemorrhage, and a con-ern for maternal platelet dysfunction.33

Although initial hypotheses suggestedhat pain was secondary to fibroidrowth during pregnancy, painful epi-odes appear to be unrelated to absolutebroid size or growth.32 Prospective,

ongitudinal studies have also failed toocument significant change in fibroidize during pregnancy.34-37 Edema andocal areas of infarction are other com-

only proposed mechanisms for pain.he strong analgesic effect of NSAIDS

uggests that symptoms are due to pros-aglandins released from cellular damagen fibroids. When pain is severe, it is

ore often accompanied by sono-raphic findings of anechoic or cysticpaces in the fibroids; however, this find-ng is nonspecific and can be seen insymptomatic lesions as well.31,32

BSTETRIC OUTCOMESeveral investigators have reported on

TABLE 3Labor and delivery complicationsStudy (n � patientswith fibroids) Cesarean

Vergani et al41 (n � 183) �...................................................................................................................

Davis et al43 (n � 85) N/A...................................................................................................................

Rice et al38 (n � 93) �

...................................................................................................................


(n � 492)�

...................................................................................................................

Qidwai et al39 (n � 401) �b

...................................................................................................................

Sheiner et al44 (n � 690) �...................................................................................................................

Benson et al30 �...................................................................................................................

Coronado et al40

(n � 2065)�

...................................................................................................................

Roberts et al45 (n � 51) �...................................................................................................................

Vergani et al42 (n � 251) �...................................................................................................................

PP, postpartum.(�) positive association with P � .05.(�) negative association, P � .05.(N/A) not examined/reported.a Reported increased malpresentation associated with the sizb Reported no difference in rate of operative vaginal deliverie


bstetric outcomes in patients with fi- d


roids. Although the studies are incon-istent and use different methodologiesor retrospectively ascertaining the pres-nce of fibroids with subsequent con-icting findings, several preliminaryonclusions can be described. Tables 3nd 4 describe studies assessing antepar-um and peripartum complications inomen with fibroids. Unfortunately, a

ack of power to evaluate uncommonutcomes together with a risk of ascer-ainment bias in positive studies prohib-ts more definitive conclusions. We re-ort the cumulative data from each ofhe studies reviewed (Table 5). We cau-ion the reader because these data do notccount for confounding variables inomen with fibroids and may amplifyias related to advanced maternal agend a higher likelihood to diagnose fi-roids in complicated pregnancies.

ode of deliveryhe weight of the evidence supports aausative role for fibroids in higher ratesf cesarean delivery, particularly inomen with larger fibroids (Table 3).espite its adequate size and prospective

Malpresentation Labor dystociaPohe

N/A N/A �.........................................................................................................................

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.........................................................................................................................

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.........................................................................................................................

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the largest fibroid.

ecol 2008.

ocumentation, Exacoustos et al31 did a

APRIL 2008

ot find a higher incidence of operativeeliveries; however, every other studyhat assessed mode of delivery found aigher cesarean rate among women withbroids, 48.8% compared with 13.3%Table 3). The most common cause ofhe higher cesarean rates appears to be

alpresentation.38-42 When studies pro-pectively examine labor curves inomen with documented fibroids, noifference was seen in patients with fi-roids. Coronado et al40 reported higherates of labor dystocia; however, theydentified fibroid patients from Interna-ional Classification of Diseases (ICD)odes charted retrospectively at dis-harge. These data likely reflect a signif-cant ascertainment bias because manyatients may have had fibroids diag-osed at the time of cesarean, which wasore likely to occur in patients with ab-

ormal labor curves.40 Conversely, bothergani et al42 and Qidwai et al39 re-orted high vaginal delivery rates among

abor-eligible women with very large fi-roids and concluded that women with

arge fibroids should not be counseled

artumrrhage

Retainedplacenta

Chorio orendometritis

� N/A..................................................................................................................

N/A N/A..................................................................................................................

ectomy)N/A N/A

..................................................................................................................

ectomy)N/A �(endometritis)

..................................................................................................................

N/A �..................................................................................................................

N/A N/A..................................................................................................................

N/A N/A..................................................................................................................

N/A N/A

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N/A N/A..................................................................................................................

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(PPster

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TABLE 4Antepartum complicationsStudy (n � patientswith fibroids) IUGR

Preterm laboror deliverya

Placentaprevia

First-trimesterbleeding Abruption PPROM

Vergani et al41 (n � 183) � � � N/A � �................................................................................................................................................................................................................................................................................................................................................................................

Davis et al43 (n � 85) � � N/A N/A N/A �................................................................................................................................................................................................................................................................................................................................................................................

Rice et al38 (n � 93) � � N/A N/A � N/A................................................................................................................................................................................................................................................................................................................................................................................


(n � 492)� �PTD �PTL N/A � � �

................................................................................................................................................................................................................................................................................................................................................................................

Qidwai et al39 (n � 401) N/A � � N/A � �................................................................................................................................................................................................................................................................................................................................................................................

Sheiner et al44 (n � 690) N/A � N/A N/A � N/A................................................................................................................................................................................................................................................................................................................................................................................

Coronado et al40

(n � 2065)�b �c � � � N/A (�PROM)

................................................................................................................................................................................................................................................................................................................................................................................

Roberts et al45 (n � 51) � � N/A � N/A �................................................................................................................................................................................................................................................................................................................................................................................

Vergani et al42 (n � 251) � � � N/A � �................................................................................................................................................................................................................................................................................................................................................................................

IUGR, intrauterine growth rate; PPROM, preterm premature rupture of membranes; PROM, premature rupture of membranes.(�) positive association with P � .05.(�) negative association, P � .05.(N/A) not examined/reported.a Preterm labor required hospitalization and tocolysis.b Reported more infants �2500 g but did not control for preterm deliveries/gestational age.c Reported increased deliveries before 38 weeks.

Klatsky. Fibroids and reproductive outcomes. Am J Obstet Gynecol 2008.

TABLE 5Cumulative obstetric outcomes from included studies

Fibroids No fibroids P valueUnadjusted OR(95% CI)

Cesarean 48.8% (2098/4322) 13.3% (22,989/173,052) �.001 3.7 (3.5-3.9)................................................................................................................................................................................................................................................................................................................................................................................

Malpresentation 13.0% (466/3585) 4.5% (5864/130,932) �.001 2.9 (2.6-3.2)................................................................................................................................................................................................................................................................................................................................................................................

Labor dystocia 7.5% (260/3471) 3.1% (4703/148,778) �.001 2.4 (2.1-2.7)................................................................................................................................................................................................................................................................................................................................................................................

Postpartumhemorrhage

2.5% (87/3535) 1.4% (2130/153,631) �.001 1.8 (1.4-2.2)

................................................................................................................................................................................................................................................................................................................................................................................

Peripartumhysterectomy

3.3% (18/554) 0.2% (27/18,000) �.001 13.4 (9.3-19.3)

................................................................................................................................................................................................................................................................................................................................................................................

Retained placenta 1.4% (15/1069) 0.6% (839/134,685) .001 2.3 (1.3-3.7)................................................................................................................................................................................................................................................................................................................................................................................

Chorio or endometritis 8.7% (78/893) 8.2% (2149/26,090) .63 1.06 (0.8-1.3)................................................................................................................................................................................................................................................................................................................................................................................

IUGR 11.2% (112/961) 8.6% (3575/41,630) �.001 1.4 (1.1-1.7)................................................................................................................................................................................................................................................................................................................................................................................

Preterm labor 16.1% (116/721) 8.7% (1577/18,187) �.001 1.9 (1.5-2.3)................................................................................................................................................................................................................................................................................................................................................................................

Preterm delivery 16.0% (183/1145) 10.8% (3433/31,770) �.001 1.5 (1.3-1.7)................................................................................................................................................................................................................................................................................................................................................................................

Placenta previa 1.4% (50/3608) 0.6% (924/154,334) �.001 2.3 (1.7-3.1)................................................................................................................................................................................................................................................................................................................................................................................

First-trimester bleeding 4.7% (120/2550) 7.6% (1193/15,732) �.001 0.6 (0.5-0.7)................................................................................................................................................................................................................................................................................................................................................................................

Abruption 3.0% (115/4159) 0.9% (517/60,474) �.001 3.2 (2.6-4.0)................................................................................................................................................................................................................................................................................................................................................................................

PPROM 9.9% (123/1247) 13.0% (7319/56,418) .003 0.8 (0.6-0.9)................................................................................................................................................................................................................................................................................................................................................................................

PPROM or PROM 6.2% (217/3512) 12.2% (7425/60,661) �.001 0.5 (0.4-0.6)................................................................................................................................................................................................................................................................................................................................................................................

CI, confidence interval; IUGR, intrauterine growth rate; OR, odds ratio; PPROM, preterm premature rupture of membranes; PROM, premature rupture of membranes.

Klatsky. Fibroids and reproductive outcomes. Am J Obstet Gynecol 2008.

APRIL 2008 American Journal of Obstetrics & Gynecology 363

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3

Placenta previa is a less common out-ome and was positively associated withbroids in 2 studies.39,42 Two other stud-

es found no association with placentarevia, making this association difficulto ascribe to fibroids as advanced mater-al age and prior uterine surgery wereot considered40,41 (Table 4).

etal/neonatal morbidityhe most common cause of neonatalorbidity reported in any of these stud-

es was preterm delivery. Five studiesave reported earlier gestational ages atelivery in women with fibroids with andditional study reporting a higher inci-ence of hospitalization for threatenedreterm labor in patients with fibroidsTable 4).31,38-40,43,44 Delivery and hos-italization may have been secondary to

ncreased incidence of pain syndromesn women with fibroids, resulting in a de-ision to proceed with an early delivery.

Conversely, the weight of the evidenceuggests that these patients are not atigher risk for preterm premature rupturef the membranes (PPROM).31,39,41-43,45

nly 1 small study suggested an increase inPROM rates43 and a second study re-orted an increase in PPROM at term.owever, this latter study was subject to

he earlier described ascertainment biasnd may have selected for patients with ab-ormal labor curves.40 In fact, the cumula-

ive data suggest a mild ameliorative effectf fibroids on rates of PPROM.Despite concerns about placentation,

o single study has been able to demon-trate a higher rate of intrauterine fetalrowth restriction among women withbroids. Birthweights were similar in 6tudies (Table 4).31,38,41-43,45 Only 1tudy reported a higher incidence ofirthweights under 2500 g in pregnan-ies with fibroids; however, the analysesid not adjust for gestational age at de-

ivery, which was lower in patients withbroids.40 Our cumulative data suggest

hat these women may be at slightly in-reased risk of delivering small-for-ges-ational-age infants; however, these datao not control for maternal or gesta-ional age and there is no evidence that

yomectomy would ameliorate this
isk. r

Placental abruption is a rare but po-entially devastating outcome that haseen inconsistently associated with fi-roids (3 negative and 4 positive stud-

es). In studies that found a positive as-ociation, the strongest correlation wasocumented in patients with submuco-al or retroplacental fibroids.31,38,44,40

roviders should be aware that these pa-ients may be at higher risk for abrup-ion; however, myomectomy has noteen shown to decrease this risk and theackground risk remains low.

ostpartum complicationshe most common postpartum compli-ation with fibroids is postpartum hem-rrhage (PPH), likely caused by de-reased uterine contractility in womenith fibroids. Although the data are con-icting, 4 studies demonstrated a posi-

ive association with bleeding or severetony,31,38,39,42 whereas 2 studies did notnd a difference (Table 3).40,45 The in-reased requirement for emergency hys-erectomy in women with fibroids re-orted in 2 studies supports theypothesis that the altered contractilityf a uterus with fibroids renders it morerone to hemorrhage.31,38 In addition,n increased rate in endomyometritis re-orted by Qidwai et al39 ceased to be sig-ificant after controlling for PPH. Ex-coustos et al31 also reported an increasen postpartum infection rates, but didot control for PPH. Retained placenta isnother rare complication that has beenxamined and does not appear related tobroid status (Table 4).

YOMECTOMYespite the lack of consensus on the ben-

fits of intramural fibroid resection,here is a wealth of evidence demonstrat-ng that myometrial tissue heals well af-er myomectomy and that infertilityreatments after myomectomy are notompromised by the surgery.13 Never-heless, myomectomy should not be per-ormed without a clear indication andvidence of benefit.

As with any surgical procedure, myo-ectomy carries morbidity and risk for

omplication. Abdominal and transmu-
al myomectomies often necessitate fu- o
APRIL 2008

ure cesarean sections and may generateelvic adhesions that might contributeo subsequent infertility. The economicosts associated with myomectomy asell as the delayed time to infertility

reatment initiation must be consideredhen identifying patients for whomyomectomy could be beneficial.In complicated pregnancies, myomec-

omy can be successfully performed inatients with intractable pain from rap-

dly growing or degenerating subserosalr pedunculated fibroids. In a series of 13uch patients with myomectomy per-ormed before 26 weeks, all delivered ateast 7 weeks out from surgery with goodeonatal outcomes.31

TERINE ARTERYMBOLIZATIONyomectomy remains the standard of

are for treating symptomatic fibroids inomen desiring fertility preservation;owever, many women are now choos-

ng to undergo uterine artery emboliza-ion (UAE) as an alternative to hysterec-omy for symptomatic fibroids. Theommittee on Gynecologic Practice ofmerican College of Obstetrics and Gy-ecology considers the desire for future

ertility to be a relative contraindicationo UAE and many authorities recom-

end use of contraception for womenfter the procedure.46 Nevertheless, suc-essful pregnancies have been reported.wo retrospective studies recently docu-ented 80 pregnancies in 1755 womenho underwent UAE.47,48 An additional

eport compared outcomes in 53 preg-ancies after UAE with women undergo-

ng laparoscopic myomectomy.49 Al-hough fertility rates cannot be inferredrom these data, the outcomes of preg-ancies suggest a modest trend toward

ncreasing risk of preterm delivery, post-artum hemorrhage, and abnormal pla-entation. None of these studies in-luded age-matched controls or cohortsith untreated fibroids. The majority ofregnancies in both studies were carriedo term without complication. Sixty-ight percent of the patients underwentesarean deliveries; however, the major-ty of these cesareans were elective with-
ut a trial of labor.

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UMMARY

espite the relatively small number ofatients studied, the evidence for hyster-scopic myomectomy of submucosal fi-roids in patients undergoing assistedeproductive technologies is compelling.hat said, controlled trials would help toetter assess the benefit of routine pre-onception hysteroscopic resection ofubmucosal fibroids.

The effect of intramural fibroids on fe-undity is less clear. Intramural fibroidsay have a small detrimental affect on

ngoing pregnancy rates, likely attribut-ble to a modest decrease in implanta-ion rate and an increase in the risk ofpontaneous abortion in implantedregnancies. However, the modest, ifny, clinical impact of these fibroidsust be weighed against the cost, mor-

idity, and treatment delay of myomec-omy before pursuing IVF if the lesionsre not symptomatic or cavity distorting.he cumulative effects reported herein

hould be interpreted cautiously, be-ause of the inherent publication biashat is believed to favor positive results,hich can have a 3- to 6-fold higherrobability of being published.46,47 Fur-hermore, the cumulative analysis doesot control for confounding factors suchs age and number of embryos trans-erred. Larger, prospective studies areeeded to better quantify any risk posedy intramural fibroids based on size, lo-ation and number.

In counseling patients with fibroidsreconceptually, it is important to rec-gnize that most patients with asymp-omatic fibroids can conceive spontane-usly. In patients presenting with

nfertility, submucosal fibroids haveeen associated with markedly lower on-oing pregnancy rates in small studies,ut no randomized, controlled trialsvaluating the benefit of hysteroscopicyomectomy have been reported.omen with intramural fibroids should

e counseled that there is conflicting ev-dence on the effect that these fibroidsave on infertility, with the cumulativeffect of such lesions unlikely to be large.ubserosal fibroids appear to have no ef-
ect on fecundity. r
The most commonly experienced ad-erse obstetric outcome in women withbroids is an increase in cesarean deliv-ry, which is mostly attributable to mal-resentation. The risk of preterm labornd delivery also appears to be slightlylevated in these patients. Very large fi-roids located near the placenta maylace obstetric patients at slightly in-reased risk during labor, particularly forysterectomy and postpartum hemor-hage. The association with placental ab-uption is weak and inconsistent withreat variation from study to study. Neo-atal outcomes do not appear different

rom pregnancies in women with fi-roids compared with controls.In addition, patients should be coun-

eled that obstetric risks are usually out-eighed by the morbidity, cost, and riskf a major abdominal surgery to removehem before pregnancy. When womenith large fibroids present in cephalicresentation and in labor, their likeli-ood of having a successful vaginal de-

ivery remains high. Most other out-omes influenced by fibroids are rarenough that the absolute risk of having aomplication attributable to fibroids isutweighed by the morbidity and risksssociated with preconceptual prophy-actic myomectomy. In addition, myo-

ectomy is unlikely to reduce the in-reased risk of cesarean delivery, becausehe possibility of extensive myometrialissection or transmural incisions couldompel obstetricians to perform electiveesarean deliveries.

Surgery remains best suited for pa-ients with symptomatic fibroids who areood operative candidates and desirereservation of their fertility. Althoughyomectomy is effective at relieving re-

ated pelvic pressure and menorrhagia,ts role in fertility enhancement has yet toe well demonstrated.50,51 f

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ace. Obstet Gynecol 1997;90:967-73. t
APRIL 2008 Ame

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eiomyomata on in-vitro fertilization treatment.um Reprod 1995;10:2576-8.. Rosenfeld DL. Abdominal myomectomy fortherwise unexplained infertility. Fertil Steril986;46:328-30.. Elder-Geva T, Meagher S, Healy DL, Ma-lachlan V, Breheny S, Wood C. Effect of intra-ural, subserosal, and submucosal uterine fi-roids on the outcome of assisted reproductiveechnology treatment Fertil Steril 1998;70:87-91.0. Pritts EA. Fibroids and Infertility: a system-tic review. Obstet Gynecol Surv 2001;6:483-91.1. Shokeir TA. Hysteroscopic management inubmucous fibroids to improve fertility. Archynecol Obstet 2005;273:504.2. Narayan R, Rajat?, Goswamy K. Treatmentf submucous fibroids, and outcome of as-isted conception. J Am Assoc Gynecol Lapa-osc 1994;1:307-11.3. Surrey ES, Minjarez DA, Stevens JM,choolcraft WB. Effect of myomectomy on theutcome of assisted reproductive technologies.ertil Steril 2005;83:1473-9.4. Casini ML, Rossi F, Agostini R, Unfer V. Ef-

ects of the position of fibroids on fertility. Gy-ecol Endocrinol 2006;22:106-9.5. Stovall DW, Parrish SB, Van Voorhis BJ,ahn SJ, Sparks AET, Syrop CH. Uterine

eiomyomas reduce the efficacy of assisted re-roduction cycles. Hum Reprod 1998;3:192-7.6. Hart R, Khalaf Y, Yeong CT, Seed P, Taylor, Braude P. A prospective controlled study of

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ion-embryo. Fertil Steril 2001;75:405-10.8. Jun SH, Ginsurg ES, Racowsky C, Wise LA,ornstein MD. Uterine leiomyomas and their ef-

ect on in vitro fertilization outcome. J Assisteprod Genet 2001;18:139-43.9. Yarali H, Bukulmez O. The effect of intramu-al and subserous uterine fibroids on implanta-
ion and clinical pregnancy rates in patients hav-

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3

ng intracytoplasmic sperm injection. Archynecol Obstet 2002;266:30-3.0. Check JH, Choe JK, Lee G, Dietterich C.he effect on IVF outcome of small intramuralbroids not compressing the uterine cavity asetermined by a prospective matched controltudy. Hum Reprod 2002;17:1244-8.1. Wang W, Check JH. Effect of corporal fi-roids on outcome following embryo transfer inonor embryo recipients. Clin Exp Obstet Gy-ecol 2004;31:263-4.2. Oliveira FG, Abdelmassih VG, Diamond MP,ozortsey D, Melo NR, Abdelmassih R. Impactf subserosal and intramural fibroids that do notistort the endometrial cavity on the outcome of

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fibromas y fertilidad

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