Stout, Molly J. MD; Odibo, Anthony O. MD, MSCE; Graseck, Anna S. MD; Macones, George A. MD, MSCE; Crane, James P. MD; Cahill, Alison G. MD, MSCI
Leiomyomas originate from clonal proliferation of smooth muscle cells of the uterus and are the most common benign gynecologic tumors. Their exact prevalence is difficult to quantify because the majority of them are asymptomatic. However, postmortem examination prevalence of leiomyomas is often quoted to approach 50%.1 The precise prevalence of leiomyomas in women of reproductive age is similarly difficult to quantify, and estimates in the literature vary widely from less than 1% to 10%.2,3
Published data on obstetric outcomes in women with leiomyomas are conflicting. Some have described an increased risk of cesarean delivery,2,4–7 preterm labor or preterm birth,4,6,8 placental abruption,6,9 malpresentation,2,4,9 and decreased birth weight8,10 in women with leiomyomas, whereas others have reported no increased risk of these adverse outcomes.2,4,6,9,11 These discrepant findings may in part be attributable to lack of control groups, residual confounding, and biases inherent in study designs. More recent studies2,4,5,8,9 have attempted to improve on this knowledge but still report conflicting results and are somewhat limited by small sample sizes.
The objective of this study was to estimate the risk of adverse pregnancy outcomes associated with leiomyomas identified on routine second-trimester ultrasound examination and to characterize risks associated with leiomyomas in pregnancy by considering leiomyoma size, number, and location.
MATERIALS AND METHODS
This study is a retrospective cohort study of all women with consecutive singleton pregnancies from 1990 to 2007 who underwent routine second-trimester fetal anatomic ultrasound survey at a single university institution. Before study initiation, approval by the Washington University School of Medicine human studies review board was obtained. Ultrasound examinations were performed by specialized obstetric and gynecologic sonographers. Final diagnoses and interpretations were determined by attending maternal fetal medicine physicians.
In keeping with American Institute of Ultrasound in Medicine guidelines for obstetric ultrasound examination,12 the presence, location, and size of the largest and potentially clinically relevant leiomyomas were recorded. The practice at our institution is to comment on the six largest leiomyomas. Other routinely documented information includes fetal position, placental location, and details of fetal anatomic survey. In women with leiomyomas, data on leiomyoma number, size, volume, location in the uterus, and location relative to the placenta were collected. Leiomyoma size was quantified using largest mean diameter. Leiomyoma volume was quantified by multiplying measurements in the three standard axes to obtain cubic millimeters. Final diagnoses of fetal, placental, and uterine findings were determined by a dedicated maternal fetal medicine attending.
Maternal demographic data regarding race, tobacco use, alcohol use, and pertinent medical and obstetric history were obtained retrospectively by self-report questionnaire and medical-chart review at the time of ultrasound examination. Gestational diabetes was defined as a result of more than 140 mg/dL on a 1-hour screening glucose tolerance test followed by at least two abnormal values on a 3-hour glucose challenge test using the National Diabetes Data Group cut-offs.13 Pregestational diabetes was defined as either type I or type II diabetes mellitus diagnosed before pregnancy. Chronic hypertension was defined as systolic blood pressure of 140 mm Hg or diastolic blood pressure of 90 mm Hg before 20 weeks of gestation, or the use of antihypertensive medications before pregnancy. Obstetric and delivery outcomes were obtained as the individuals progressed to delivery by designated research nurses and were entered into a database. For women who delivered outside our primary health care system, outcomes were obtained by phone contact with the individual, the referring physician, or both to obtain medical record documentation of obstetric outcomes. Primary outcomes included breech presentation, placenta previa, cesarean delivery, placental abruption, preeclampsia (defined by the American College of Obstetricians and Gynecologists criteria14), intrauterine growth restriction (defined as birth weight less than the 10th percentile according to the Alexander Growth Curve15), and intrauterine fetal death (defined as fetal death beyond 20 weeks of gestational age). Preterm birth-related outcomes of preterm premature rupture of membranes,16 preterm birth at less than 37 weeks, and preterm birth at less than 34 weeks were also evaluated.
Women with at least one leiomyoma noted at routine second-trimester ultrasound examination were compared with women without leiomyomas. Descriptive statistics were used to estimate the frequency of leiomyomas in the study population as a whole and the frequency of each outcome within the two study groups. Baseline demographic and medical characteristics of women with leiomyomas were compared with women without leiomyomas using χ2 and Student t test as appropriate for categorical or continuous variables. Incidences of obstetric and delivery outcomes were compared between groups to obtain unadjusted relative risks (RRs) with 95% confidence intervals (CIs). Stratified analysis was performed to identify potential confounding effects and interactions. Backwards stepwise logistic regression analysis was then performed for each obstetric and delivery outcome to control for baseline demographic characteristics, medical comorbidities, and pertinent confounding diagnoses. Nonsignificant variables were removed from logistic models in a backwards stepwise fashion to obtain adjusted odds ratios (ORs) with 95% CIs (P<.05 was considered significant).
Given that the number of individuals with and without leiomyomas available within the dataset was fixed, a post hoc power calculation was performed based on fetal death, which was the rarest outcome of interest. Assuming a 0.6% background risk for intrauterine fetal death17 and an α of 0.05, we had 80% power to detect a 1.7-fold difference in intrauterine fetal death by presence or absence of leiomyomas.
An additional analysis was performed to further assess the association between specific leiomyoma characteristics and the primary outcomes. Receiver-operating characteristics curves were generated using leiomyoma number, size, and volume, each as continuous variables to identify cut-points for the formation of useful strata for comparisons. Among women with leiomyomas, those with any leiomyoma larger than 5 cm were compared with those with leiomyomas of smaller diameters. A similar analysis was undertaken for those with leiomyoma size larger than 10 cm. Leiomyoma number and volume were stratified (one–three leiomyomas or more than four leiomyomas, volume 1–99 mm3 or more than 100 mm3) and were compared with women without leiomyomas. Last, the influence of placental location was considered regarding whether the leiomyoma and placenta were in a common or separate location and whether any leiomyoma was in the lower uterine segment. All statistical analyses were performed using STATA 10, Special Edition.
Of the 72,373 women who underwent routine second-trimester anatomic survey, complete obstetric follow-up data were available for 64,047 women (8,326 were excluded because no obstetric outcome data were available). The incidence of leiomyomas was 3.2% (n=2,058; Fig. 1).
Women with leiomyomas were older, more likely to be African American, more likely to report bleeding at any time during pregnancy, and less likely to use tobacco. In addition, women with leiomyomas were more likely to have higher body mass indexes, gestational diabetes, pregestational diabetes, and chronic hypertension compared with those without leiomyomas. Gestational age at delivery and neonatal birth weight were statistically lower in women with leiomyomas compared with women without leiomyomas (37.7 weeks compared with 38.2 weeks, P<.01, and 3,005 g compared with 3,106 g, P<.01, respectively; Table 1). Baseline demographic characteristics of women for whom no obstetric outcome data were available are also shown in Table 1. The incidence of leiomyomas was the same between the women with outcome data available compared with women without outcome data (3.2% compared with 2.9%, P=.16).
Of the 2,058 women with leiomyomas, 56 had leiomyomas too small to measure on examination and were included in the subanalysis regarding size, volume, and location with the reference group (women without leiomyomas). The remaining 2,002 women had a number of leiomyomas ranging from 1 to 16, with a median number of one (one: n=1,033, two: n=360, three: n=168, four or more: n=441). Fifty-seven women had leiomyomas larger than 10 cm, 536 women had a largest leiomyoma between 6 cm and 10 cm, and 1,409 women had a largest leiomyoma 5 cm or smaller.
We found that the presence of leiomyomas was associated with an increased risk for breech presentation (5.3% compared with 3.1%, adjusted OR 1.5, 95% CI 1.3–1.9), placenta previa (1.4% compared with 0.5%, adjusted OR 2.2, 95% CI 1.5–3.2), and cesarean delivery, even after excluding pregnancies with breech presentation and placenta previa, which would by routine standard of care require a cesarean delivery (33.1% compared with 24.2%, adjusted OR 1.2, 95% CI 1.1–1.4). Given the potential changes over the long study timeframe regarding physician practice habits, we divided the study time into two groups, early and late. We found no difference in the unadjusted RRs for cesarean deliveries when evaluated separately as early study (1990–1998: RR 1.5, 95% CI 1.3–3.1) or late study (1999–2007: RR 1.6, 95% CI 1.4–1.8). Similarly, when year of study ultrasound examination was included as a covariate in the logistic model, the relationship between leiomyomas and need for cesarean delivery remained the same and year was not significant. We found a twofold increased risk for placental abruption (1.4% compared with 0.7%, adjusted OR 2.1, 95% CI 1.4–3.0), even after controlling for tobacco use, previous preterm birth, and preterm premature rupture of membranes. There was no increased risk of intrauterine growth restriction or preeclampsia in women with leiomyomas compared with women without leiomyomas (Table 2).
When leiomyoma number was considered categorically (zero leiomyomas, one–three leiomyomas, or four or more leiomyomas), the group with four or more leiomyomas did not exhibit further increased risk for breech presentation, placenta previa, cesarean delivery, abruption, preeclampsia, or intrauterine growth restriction compared with women with fewer leiomyomas. In the analysis to evaluate the influence of leiomyoma size, placenta previa was associated with leiomyoma size larger than 5 cm compared with women with leiomyoma size of 5 cm or smaller (2.4% compared with 0.5%, RR 4.4, 95% CI 2.6–7.5; Table 3). In addition, there was an increased risk for placenta previa if any leiomyoma was in the lower uterine segment (2.7% compared with 1.1%, RR 2.5, 95% CI 1.2–5.3). However, because only 1.9% of the total cohort had placenta previa, no adjusted analysis could be reliably performed. When leiomyoma volume was considered categorically, comparing no leiomyomas, mean leiomyoma volume 1 to 99 mm3, and mean leiomyoma volume more than 100 mm,3 only breech presentation and need for cesarean delivery were significantly associated with increasing leiomyoma volume (Table 4). Leiomyoma location in the lower uterine segment was not associated with an increased risk of breech presentation (6.6% compared with 5.0%, adjusted OR 1.3, 95% CI 0.8–2.0) or for cesarean delivery (35.4% compared with 32.4%, adjusted OR 1.1, 95% CI 0.8–1.4) compared with women with leiomyomas not in the lower uterine segment.
Preterm birth was statistically more likely in women with leiomyomas compared with women without leiomyomas, both at less than 37 weeks (15.1% compared with 10.5%, adjusted OR 1.5, 95% CI 1.3–1.6) and less than 34 weeks (3.9% compared with 2.8%, adjusted OR 1.4, 95% CI 1.0–1.8). This relationship remained even after controlling for confounding variables such as advanced maternal age, African-American race, and medical comorbidities. In addition, women with leiomyomas appeared to have a slightly increased risk for preterm premature rupture of membranes (3.3% compared with 2.4%, adjusted OR 1.3, 95% CI 1.0–1.7; Table 2). There was no relationship between risk for preterm birth and increasing leiomyoma size, increasing leiomyoma volume, or leiomyoma location. In an analysis comparing outcomes in women whose placenta was in the same location as the leiomyoma as opposed to a placental site separate from leiomyoma location, no increased risk of any of the primary outcomes was noted (data available from authors).
We found a twofold increased risk for intrauterine fetal death in women with leiomyomas compared with women without leiomyomas, even after controlling for pertinent risk factors such as advanced maternal age, African-American race, diabetes mellitus, and chronic hypertension, and excluding pregnancies complicated by major fetal anomalies (1.6% compared with 0.7%, adjusted OR 2.1, 95% CI 1.2–3.6, P <.01; Table 2). However, this relationship persisted only in the subgroup of women with leiomyomas who also had a fetus with growth restriction. Among women with leiomyomas who had a fetus without growth restriction, the increased risk of intrauterine fetal death did not remain (Table 5).
Women with four or more leiomyomas were at the greatest risk for intrauterine fetal death (adjusted OR 2.2, 95% CI 1.1–4.6), followed by those with one to three leiomyomas (adjusted OR 1.7, 95% CI 1.1–2.7). The presence of one or more leiomyomas larger than 5 cm in diameter was associated with an increase in risk of intrauterine fetal death (adjusted OR 2.6, 95% CI 1.5–4.5; Table 3), but smaller leiomyoma diameters of 4 cm (adjusted OR 1.7, 95% CI 0.6–4.6), 3 cm (adjusted OR 1.1, 95% CI 0.3–3.1), 2 cm (adjusted OR 1.9, 95% CI 0.9–4.5), or 1 cm (adjusted OR 1.7, 95% CI 0.4–7.1) did not confer a statistically increased risk of intrauterine fetal death. There was no leiomyoma location (fundal, anterior, posterior, right, or left) that conferred a greater risk of intrauterine fetal death relative to the others. Further, there was no statistically significant increased risk for intrauterine fetal death when the location of one or more of the leiomyomas was shared with the placenta compared with women whose leiomyomas were in a location distinct from the placenta (2.2% compared with 1.3%, adjusted OR 2.7, 95% CI 0.8–3.4).
Careful attention was given to the potential confounder of maternal age and the possible association between maternal age and fetal death. Maternal age was considered both dichotomously (advanced maternal age or not) and as a continuous variable, but neither remained significant in the final multivariable model for intrauterine fetal death.
In this study of more than 64,000 pregnancies, we found the presence of leiomyomas increased the risk of important obstetric sequelae. The high prevalence of leiomyomas in the general population makes their effect on pregnancy noteworthy. The incidence of leiomyomas in our study population was 3.2%, which is similar to the incidence of leiomyomas reported in previous studies.4,9
Previous studies have included only live births and thus have not been able to comment on a relationship between leiomyomas and intrauterine fetal death. In our study, women with leiomyomas had a twofold increased risk of intrauterine fetal death, even after excluding fetal anomalies and controlling for pertinent risk factors for intrauterine fetal death. On examination of the relationship between leiomyomas and intrauterine fetal death stratified by the presence or lack of growth restriction, an important relationship emerged. The data of this study suggest that the increased risk of fetal death persists only in the population of women who have both leiomyomas and intrauterine growth restriction. Given the observational nature of these data, causality cannot be confidently concluded. Notably, there was no increased risk for fetal death in women with a leiomyoma in a shared location with the placenta compared with women whose leiomyomas were separate from the placenta. The absolute risk for intrauterine fetal death within the cohort was approximately 0.9%. Even with a twofold increased risk found in women with leiomyomas, the absolute risk for intrauterine fetal death remains small. However, given the gravity of the outcome of fetal death, a twofold increased risk remains an important finding.
In this study, women with leiomyomas were more likely to require cesarean deliveries, even after excluding diagnoses such as placenta previa and breech presentation. Previous data regarding these outcomes had been conflicting with those of Qidwai et al4 describing an increased risk for cesarean delivery, malpresentation, and placenta previa; however, Exacostos and Rosati9,18 in a cohort of 12,000 women showed no increased risk of these outcomes. Qidwai et al4 evaluated the subgroup of women with leiomyomas larger than 10 cm and found an increased risk for malpresentation among women with large leiomyomas. We found no increase for breech presentation in women with leiomyoma size larger than 5 cm. However, in our study, increasing leiomyoma volume was associated with an increased risk for breech presentation. Women with a leiomyoma in the lower uterine segment were no more likely to require cesarean delivery than those with leiomyomas in other uterine locations.
We also found that women with leiomyomas have an increased risk of preterm premature rupture of membranes and an increased risk of preterm birth at less than 37 weeks and at less than 34 weeks. However, our data do not suggest a specific leiomyoma number, size, volume, or location specifically associated with this risk. Data regarding preterm birth and premature rupture of membranes have been conflicting in previous published data, with some suggesting an increased risk for preterm delivery4,8 and others suggesting no increase in risk for preterm delivery among women with leiomyomas.9
The strengths of this study include the large population available for our study, thereby allowing a detailed and robust analysis of the relationship between leiomyomas and rare outcomes such as fetal death and placental abruption. Importantly, because we did not limit our analysis to live births we were able to evaluate the risk between leiomyomas and intrauterine fetal death. In addition, the diagnosis of leiomyomas made on second-trimester ultrasound examination, as opposed to the use International Classification of Diseases, 9th Revision, Clinical Modification codes or medical record reviews, decreases overrepresentation of those women with overtly symptomatic disease and underrepresentation of those with clinically “insignificant” or overlooked leiomyoma disease.
Limitations of our study include that 11% of the study population was lost to follow-up and thus no outcome data were available. However, a sensitivity analysis was performed, and the patients lost to follow-up did not differ with respect to the incidence of leiomyomas from our study population. In addition, although there were some demographic characteristics that differed slightly between the groups, those differences were not consistent in classifying the group as being at low or high risk. The effects of those differences are therefore likely to bias our results toward the null. This study population is derived from an urban referral hospital and high-risk behaviors, such as an almost 20% incidence of self-reported alcohol use, is notable. However, our cohort included individuals at high-risk and at lower risk and encompassed a wide range of sociodemographic characteristics, offering generalizability to similar centers.
Mechanisms by which leiomyomas increase the risk of adverse obstetric outcomes are unknown, but speculations as to distensibility of the uterus, physical obstruction, efficacy of contraction patterns, inflammation, and alterations in the endometrial structure and molecular signaling all have been postulated. The findings of the analysis regarding leiomyoma size, number, and location suggest that some of the increased risk for adverse obstetric outcomes may be attributable to a global effect on the uterus or placenta and not via a direct physical interaction between the placenta and the leiomyoma.
As women of reproductive age delay child-bearing, the incidence of leiomyomas increases and their clinical effect may be important for individual counseling. Women with leiomyomas are at slightly higher risk for needing cesarean delivery. However, these data suggest that except for the common obstetric indications of breech presentation or placenta previa, a leiomyoma in the lower uterine segment should not preclude a trial of labor. The finding of increased risk of fetal death is notable as an outcome that may be altered by our clinical interventions. More than 50% of the fetal deaths occurring in this cohort occurred at more than 32 weeks of gestation, suggesting that the practice of performing growth ultrasound examinations with antenatal testing may be clinically useful tools. Based on this large cohort of women, it appears that although leiomyomas are cytologically benign, they may not be clinically benign, and particular attention to individual counseling and appropriate clinical interventions may be beneficial in women with this common uterine pathology.