Uterine leiomyomas are benign smooth muscle tumors of the uterus estimated to be present in up to one in five women of reproductive age.1–3 Leiomyomas are commonly implicated by patients and clinicians as a cause of spontaneous abortion. However, a Cochrane systematic review and meta-analysis failed to demonstrate any difference in spontaneous abortion risk between women randomized to myomectomy compared with no leiomyoma surgery before conception.4 Three systematic reviews since 2000 suggest leiomyoma status is associated with spontaneous abortion risk.5–7 These reviews are restricted to or dominated by studies of women seeking reproductive assistance. Because it is understood that women seeking fertility treatment differ in spontaneous abortion risk and rates of successful pregnancy from the average woman, it may not be appropriate to base general understanding of risk associated with leiomyomas on studies of special populations. These considerations provide grounds for reexamining uterine leiomyomas during pregnancy as risk factors for spontaneous abortion in populations more representative of all reproductive-aged women.
The purpose of this review is to quantify the association between leiomyoma presence during pregnancy and the risk of spontaneous abortion with the hypothesis that uterine leiomyomas increase the risk of spontaneous abortion for general obstetric populations. Specifically, we aimed to review studies on which current knowledge is based, calculate a summary effect estimate, and evaluate how leiomyoma location, number, and size modify associated risk.
The plan and protocol for literature search, study selection, data extraction, and analysis were developed by one of the authors (A.C.S.) a priori and adhere to Meta-Analyses and Systematic Reviews of Observational Studies guidelines for reporting meta-analyses and systematic reviews of observational studies.8
All studies published in academic journals were identified through searches of electronic databases (MEDLINE, Web of Science, EMBASE, and ClinicalTrials.gov) using the terms “fibroid,” “leiomyoma,” “leiomyomata,” “myoma,” “miscarriage,” “abortion,” “fertility,” “fetal death,” and “pregnancy loss” (Appendix 1, available online at http://links.lww.com/AOG/B3, for full search strategies). All studies published in English between January 1, 1970, and December 20, 2016, were included in the search. Reference lists of included studies were hand-searched to ensure no eligible reports were missing. A list of all identified studies is available on request.
We included all studies that compared the risk of spontaneous abortion among pregnant women with leiomyomas with pregnant women without leiomyomas. Leiomyoma status had to be determined with imaging for all participants. Because we aim to assess the effect of leiomyomas on spontaneous abortion risk among women of typical reproductive potential, studies limited to women seeking care for recurrent miscarriage, infertility, or assisted reproductive technologies were excluded.
Inclusion screening and data extraction were performed using standardized forms implemented in Research Electronic Data Capture (Appendix 2, available online at http://links.lww.com/AOG/B3).9 The primary outcome was spontaneous abortion (definition varied across studies) among recognized pregnancies. Aspirational coding was completed for factors thought to be associated with both risk of spontaneous abortion among women without leiomyomas and with leiomyoma presence. Potential confounders included maternal age, race, alcohol, body mass index, parity, and prior terminations. Data were abstracted for leiomyoma characteristics (location, size, number) when available. Risk of bias was determined using the Newcastle-Ottawa Scale.10 Scores were converted to Agency for Healthcare Research and Quality classifications of good, fair, or poor quality.11
Study eligibility, data extraction, and risk of bias were determined independently by two reviewers (ACS, SHJ). Percent agreement between authors for these steps was 99.5%, 98.0%, and 95.8%, respectively. Discrepancies between the two reviewers were resolved by a third party blinded to the other reviewers' decisions (SML). Study authors were contacted for missing information.
A random-effects meta-analysis was performed to calculate pooled risk ratios (RRs) and 95% CIs. We limited the meta-analysis to studies evaluating general obstetric populations (excluding studies limited to women undergoing amniocentesis) to arrive at an aggregate estimate most representative of the risk-relationship in women of typical reproductive potential. For the meta-analysis, adjusted point estimates were used when available. Q and I 2 statistics were used to test for heterogeneity between included studies. Begg's and Egger's tests were used to assess publication bias. We evaluated year of publication, study design, and study quality as potential sources of heterogeneity using metaregression. Meta-analyses by leiomyoma location, size, and number were performed if at least three studies presented a measure of association for the characteristic.
Only one study adjusted for confounders. Therefore, we performed a secondary analysis in which we used external estimates of confounding to account for bias attributable to unmeasured confounding in the studies that only reported crude estimates.12,13 This method compares the adjusted and unadjusted estimates from a study that presents both models to quantify U, the multiplicative bias produced from confounding.12 This measure is used to estimate adjusted RRs in studies that do not measure and adjust for confounding factors using the equation: RRadjusted=RRunadjusted/U. We used estimates from the only study that presented adjusted models to estimate U (fully adjusted model included maternal age, race alcohol use, parity, and history of prior terminations). We then corrected the variance of the adjusted measures for the statistical error in the estimate of residual confounding.14 All analyses were performed in Stata 14.1 by one of the authors (A.C.S.).
Of 1,468 studies screened, nine were included in the systematic review and five studies were included in the meta-analysis (Fig. 1). Three of the studies were conducted in the United States, five in Europe, and one in the Middle East and study populations ranged from 200 to 21,219 participants. All publications included were observational cohorts; five enrolled a general obstetric population (Table 1),15–19 whereas four were restricted to women undergoing amniocentesis (Table 2).20–23 Three of the four studies among women undergoing amniocentesis reported leiomyoma presence that increased risk of loss after the procedure by an estimated factor between 2.5 and 8.0 (Table 2). Because these studies were limited to special high-risk populations and required the participant to have an ongoing pregnancy at the time of procedure, we describe these studies in the qualitative synthesis and exclude them in the quantitative analysis. Five studies were classified as good quality 15,17,19,21,23 and four as poor quality 16,18,20,22 based on Agency for Healthcare Research and Quality standards for quality grading (Appendix 3, available online at http://links.lww.com/AOG/B3).
Our meta-analysis included five studies with 21,829 participants from general obstetric populations (1,394 women with leiomyomas and 20,435 without).15–19 The meta-estimate does not suggest uterine leiomyomas are associated with an increased risk of spontaneous abortion (RR 1.16, 95% CI 0.80–1.52) (Fig. 2A). Heterogeneity of included studies was low (Q statistic 8.01, P value .09, τ2 0.07) with some true between-study variation (I 2 50.0%). Year of publication, study design (retrospective cohort compared with prospective cohort), and study quality did not explain any additional between-study heterogeneity (analysis not shown). There were too few studies for the Begg's and Egger's tests to detect evidence of publication bias (P=.21 and P=.08). A trim-and-fill analysis predicted two missing studies pulling the corrected point estimate towards the null (RR 1.04, 95% CI 0.74–1.48).
Only one of the five studies in the meta-analysis adjusted for confounders of the relationship between leiomyomas and spontaneous abortion risk. We approximated adjusted point estimates for the four studies that reported crude results using the data from Hartmann and colleagues as an external estimate of confounding.19 The meta-analysis with the adjusted estimates demonstrated leiomyoma status is not associated with increased spontaneous abortion risk (RR 0.83, 95% CI 0.68–0.98) (Fig. 2B). Two studies reported risk of spontaneous abortion by leiomyoma number or size: one presented crude results that suggest risk of loss increases with leiomyoma size and number 15 and the other presented adjusted results that do not indicate a dose-dependent trend by either leiomyoma characteristic (Table 3).19
This meta-analysis, including 21,829 pregnancies from five cohort studies, indicates uterine leiomyoma presence is not associated with increased risk of spontaneous abortion among general obstetric populations. Strikingly few studies rigorously examine the association between uterine leiomyomas and spontaneous abortion risk. Many neglect common confounders such as maternal age and race, which are known to be related to spontaneous abortion risk and leiomyoma presence.1,24 This is the first review on the association between leiomyoma presence and spontaneous abortion that specifically evaluates studies of general obstetric populations and the only review that quantitatively accounts for bias resulting from potential confounders. Our findings challenge common clinical belief and should cause us to reconsider understanding of uterine leiomyomas as a risk factor for spontaneous abortion in women of typical reproductive potential. The misconception that leiomyomas increase risk of spontaneous abortion in the general population may lead to undue anxiety for patients with leiomyomas, inappropriate risk counseling, or the recommendation of unnecessary surgeries.
Three past reviews on this association estimate uterine leiomyomas increase risk of spontaneous abortion by between 24% and 75%.5–7 These reviews are either intentionally 7 or incidentally 5,6 dominated by studies of special populations such as women seeking fertility treatment or with a history of recurrent miscarriage. None of these reviews quantitatively address possible bias resulting from maternal age or race in their main summary estimates.5–7
Women in this review were already pregnant or had to achieve pregnancy to be enrolled in the included cohorts and are a distinct population from women who are unable to conceive naturally. Submucosal or large intramural leiomyomas may decrease fertility by impeding implantation,5 and leiomyomas contributing to this phenotype may affect risk of loss differently from those characterized in this review. Therefore, the women in this review are different from those included in past reviews and the risk association described here more likely characterizes the relationship between leiomyomas and spontaneous abortion risk in a population of women of average reproductive potential.
The methods for the execution of this meta-analysis were rigorous and quantitatively strong. We are the first to present all relevant studies conducted in general obstetric populations on this association. Although several of the original studies do not present adjusted analyses, we use a method considered to be an effective tool for minimizing bias from unmeasured confounders.12 Application of this method indicates crude estimates are biased and the fact that all studies describing a significant association between leiomyomas and spontaneous abortion risk are unadjusted should provide an impetus for reevaluating prior beliefs.
This meta-analysis should be interpreted in light of the following considerations. To optimally determine case status and capture spontaneous abortion events, participants should be enrolled before conception or in early pregnancy and undergo standardized imaging for leiomyoma assessment. This design is resource-intensive and difficult to implement on a large scale, and accordingly, four of the five studies included in the meta-analysis were retrospective analyses.15–18 These studies are subject to selection bias because they depend on care utilization, rely on availability of imaging data, and recruit participants solely from academic medical centers. Methods for defining exposure and outcome status varied between studies. One study only counted women as exposed if they had a leiomyoma with a dimension greater than 3 cm 17 and three studies did not provide a minimum measurement threshold in their exposure definition.15,16,18 Variation in exposure definitions may introduce heterogeneity secondary to differential exposure classification. The gestational age cutoff for spontaneous abortion definitions ranged from 20 to 25 weeks of gestation.25 Because losses are concentrated in early pregnancy with very few occurring beyond 20 weeks of gestation, we do not anticipate these differences to materially affect the summary estimate. Because four of the five studies fail to adjust for pertinent confounders, we attempted to account for bias using external estimates of unmeasured confounding.15–18 Our ability to estimate a bias-free summary measure using this method is dependent on how well the bias present in Hartmann et al reflects confounding present in other studies.12,13
In conclusion, this systematic review and meta-analysis does not indicate that leiomyoma presence, location, number, or size is related to spontaneous abortion risk in general obstetric populations.
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