Tuuli, Methodius G. MD, MPH; Shanks, Anthony MD; Bernhard, Lisa MD; Odibo, Anthony O. MD, MSCE; Macones, George A. MD, MSCE; Cahill, Alison MD, MSCI
From the Department of Obstetrics and Gynecology, Washington University School of Medicine in St. Louis,, St. Louis, Missouri.
The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of the National Institutes of Health or Robert Wood Johnson Foundation.
Corresponding author: Methodius G. Tuuli, MD, MPH, Department of Obstetrics and Gynecology, Washington University School of Medicine, Campus Box 8064, 4566 Scott Avenue, St Louis, MO 63110; e-mail: email@example.com.
Financial Disclosure Dr. Tuuli is supported by a Women's Reproductive Health Research Career Development grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (National Institutes of Health/National Institute of Child Health and Human Development 1K12HD063086-01). Dr. Cahill is a Robert Wood Johnson Faculty Physician Scholar, which partially supports this work. The other authors did not report any potential conflicts of interest.
OBJECTIVE: Uterine synechiae have generally been considered benign findings in pregnancy. We used a large perinatal database to test the hypothesis that uterine synechiae are associated with pregnancy complications.
METHODS: We performed a retrospective cohort study of women with singleton pregnancies presenting for routine ultrasonographic examinations at 17–22 weeks from 1990–2009. Pregnancies with multiple fetuses, amniotic bands, and congenital uterine anomalies were excluded. We compared pregnancy outcomes between women with and without uterine synechiae. Multivariable logistic regression was used to adjust for confounders.
RESULTS: Of 65,518 pregnancies meeting inclusion criteria, 296 (0.45%) were diagnosed with uterine synechiae. Women with uterine synechiae were significantly more likely to have placental abruption (2.1% compared with 0.6%, adjusted odds ratio [OR] 3.25, 95% confidence interval [CI] 1.43–7.36), preterm premature rupture of membranes (PROM) (5.5% compared with 2.3%, adjusted OR 2.51, 95% CI 1.51–4.18), and cesarean delivery for malpresentation (5.1% compared with 3.0%, adjusted OR 1.75, 95% CI 1.04–2.95). The risks of placenta previa, fetal growth restriction, stillbirth, and preterm delivery were not significantly different.
CONCLUSION: Uterine synechiae are associated with significant increase in the risk of preterm PROM, placental abruption, and cesarean delivery for malpresentation. The notion of uterine synechiae as benign findings in pregnancy should be re-evaluated.
LEVEL OF EVIDENCE: II
Uterine synechiae are intrauterine adhesions around which chorioamniotic membranes wrap during pregnancy to produce amniotic sheets or shelves.1,2 They have a characteristically wide base along the uterine wall and associate with fetal membranes that consist of two layers of amnion and two layers of chorion.3 First described by Asherman in 1950, uterine synechiae are seen in 0.14–0.60% of pregnancies and have generally been considered incidental, benign findings.4–8 Although their exact etiology is unknown, they are believed to be related to intrauterine instrumentation or infection. Early studies suggested a benign course of uterine synechiae in pregnancy but were limited to case reports, case series, and small cohort studies.1,2,7
Recent studies have suggested a link between uterine synechiae and adverse pregnancy outcomes including earlier gestational age at delivery, cesarean delivery for malpresentation, and intrauterine fetal death.6,9 However, the small sample sizes of these studies precluded detailed analysis to control for confounders or necessitated the use of composite outcome measures.6,9
The objective of this study was to use a large perinatal database to test the hypothesis that uterine synechiae are associated with pregnancy complications.
MATERIALS AND METHODS
We conducted a retrospective cohort study of all viable, singleton pregnancies undergoing routine ultrasonographic anatomic survey between 17 and 22 weeks of gestation from 1990–2009 at Washington University in St Louis Medical Center. The Department of Obstetrics and Gynecology created a comprehensive perinatal database in 1990 that is compiled and maintained by dedicated data management staff. Pregnancy and delivery information for all patients who undergo ultrasonographic evaluation at our medical center is entered into the database. Delivery information for patients referred to our center is obtained from the patients, their medical records, and referring physicians using a standardized pregnancy outcome record form.
Pregnancies were dated by the women's last menstrual periods and confirmed with first- or second-trimester ultrasonography using standard criteria. At the time of anatomic survey, the intrauterine cavity is routinely surveyed for abnormalities.10 All ultrasonograms were performed by Registry of Diagnostic Medical Sonographers-certified ultrasonographers credentialed in obstetrics and gynecology. Final diagnostic interpretations were made by experienced sonologists and maternal-fetal medicine attending physicians. Uterine synechiae were identified as thick bands associated with fetal membranes stretching across the uterus without involvement of any fetal structure (Fig., 1A and B). Presence of uterine synechiae of any size and location was included in this analysis.
All women with complete follow-up data were eligible for this study. We excluded pregnancies with multiple fetuses and congenital uterine anomalies. We also specifically excluded pregnancies with amniotic bands, which are disrupted amniotic membranes associated with fetal deformity.11 All women in the database who met inclusion criteria were included and no a priori sample size calculation was performed. The presence or absence of uterine synechiae defined the two groups. We compared pregnancy complications (preterm premature rupture of membranes (PROM), placental abruption, intrauterine growth restriction, stillbirth, preterm birth, placenta previa, and cesarean delivery for malpresentation) between women with and without uterine synechiae. Placental abruption was defined clinically by the attending physician at the time of delivery. Fetal growth restriction was defined as birth weight less than the tenth percentile on the Alexander growth standard.12 Stillbirth was defined as fetal death after 20 weeks of gestation. Preterm PROM was defined as rupture of membranes before 37 weeks of gestation and preterm delivery was defined as birth before 37 or 34 weeks of gestation.
We compared baseline characteristics of pregnancies with and without uterine synechiae. Continuous variables were compared using the Student's t test, whereas categorical variables were compared using the χ2 or Fisher's exact test as appropriate. We calculated rates and unadjusted odds ratios (ORs) with 95% confidence intervals (CIs) for each pregnancy complication. Multivariable logistic regression was used to calculate adjusted ORs. Candidate variables for the logistic regression models were selected on the basis of biologic plausibility, risk factors that have been identified in the literature for the various outcomes, and results of univariable and stratified analyses. Backward elimination was used to reduce the number of variables in each model. Differences between hierarchical explanatory models were assessed using the likelihood ratio test or Wald test. Model fit for each final model was assessed with the Hosmer-Lemeshow goodness-of-fit test.13 All tests were two-tailed with P<.05 considered significant. All statistical analyses were completed using STATA 11 software. The study was approved by our institutional human studies review board.
Of 65,518 pregnancies meeting inclusion criteria, 296 (0.45%) were diagnosed with uterine synechiae (Fig. 2). The mean gestational age at diagnosis was similar in the two groups. Women with uterine synechiae had a lower body mass index on average and were significantly more likely to be white, smoke cigarettes, and have a history of spontaneous or induced abortion (Table 1).
Women with uterine synechiae were significantly more likely to experience pregnancy complications. They were more than threefold more likely to have placental abruption (2.1% compared with 0.6%, adjusted OR 3.25, 95% CI 1.43–7.36) and more than twofold more likely to have preterm PROM (5.5% compared with 2.3%, adjusted OR 2.51, 95% CI 1.51–4.18) when compared with women without uterine synechiae. They were also nearly twofold more likely to have cesarean delivery for malpresentation (5.1% compared with 3.0%, adjusted OR 1.75, 95% CI 1.04–2.95]) (Table 2). In contrast, rates of placenta previa, fetal growth restriction, stillbirth, and preterm delivery before 37 or 34 weeks of gestation were not significantly different in women with and without uterine synechiae.
To estimate whether improvement in ultrasonographic technology has had a significant influence on the detection of uterine synechiae and their association with pregnancy complications, we calculated the incidence of uterine synechiae and their association with pregnancy complications among women evaluated before (1990–2000) and after (2001–2009) 2001. The incidence of uterine synechiae was higher among women who underwent ultrasonographic evaluation in the earlier time period compared with those evaluated in the later period (0.52% compared with 0.38%, P=.005). Risks for placental abruption, preterm PROM, and cesarean delivery for malpresentation were similar in the two time periods (Table 3).
We found that uterine synechiae are associated with a threefold increased risk of placental abruption and a twofold increased risk of preterm PROM and cesarean delivery for malpresentation. In contrast, we did not find increased risks of placenta previa, fetal growth restriction, stillbirth, or preterm delivery.
Our findings contradict those of several small prior studies that suggested no association between uterine synechiae and pregnancy complications.1,2,7 This is likely attributable to the reduced statistical power associated with the small sample sizes of those studies. On the other hand, our findings are consistent with those of Nelson and Grobman who recently reported increased risk of a composite obstetric morbidity.9 Notably, the increased risk of the composite outcome in that study was largely driven by higher rates of preterm PROM and placental abruption. They also found an increased risk of cesarean delivery. Our analysis improves on that study by assessing individual pregnancy complications and more adequately adjusting for confounders.
This is a large study dedicated to evaluating the association between uterine synechiae and pregnancy complications. The comprehensive database and large sample size allowed us to assess relatively infrequent pregnancy complications. Importantly, it permitted adjustment for multiple confounders. Despite these strengths, there are limitations that should be considered when interpreting our results. The retrospective nature of our study makes it vulnerable to inaccuracies in data collection, selection bias, and confounding. However, our database has been well-validated in several studies and inaccuracies were found to be infrequent.14–19 Nearly 11% of the potential participants in the database lacked outcome data and could not be included in this study. This has the potential to introduce selection bias. However, analysis of the baseline characteristics of those patients showed that they were similar to patients with outcome data, suggesting that any effect on our results is likely small. Although we controlled for multiple confounders, there is the potential for residual confounding. Although all examinations were performed by Registry of Diagnostic Medical Sonographers-certified ultrasonographers and final diagnostic interpretations were made by experienced sonologists and maternal-fetal medicine attending physicians, there is the potential for misclassification. If pregnancies with uterine synechiae were missed and they are included in the nonexposed group for this analysis, it would tend to bias our results toward the null hypothesis of no difference rather than produce spurious associations. It is also reassuring that the incidence of uterine synechiae in our cohort (0.45%) is remarkably similar to those of prior studies.4–8
We did not have information on the orientation of the uterine synechiae and their relation to the placenta. Therefore, we were unable to assess the effect of these characteristics, which may be possibly related to the risk of pregnancy complications.5 Another important consideration for a study of this nature that spans a long period of time is whether improving ultrasonographic technology significantly influenced the detection of uterine synechiae. In sensitivity analysis comparing the incidence of uterine synechiae and the association with pregnancy complications among women evaluated before and after 2001, a higher rate of uterine synechiae was noted in the earlier time period with no differences in the risks of pregnancy complications.
Despite the significant association we found between uterine synechiae and adverse pregnancy complications, a study of this nature cannot establish a causal relationship. It is possible that uterine synechiae may be simply markers of underlying factors that cause pregnancy complications. However, a causal link between uterine synechiae and placental abruption, PROM, and malpresentation is biologically plausible. Placental implantation near the poorly vascularized synechiae may predispose to placental abruption and the wrapping of fetal membranes around synechiae may lead to premature rupture as the uterus enlarges. The presence of synechiae, especially when large, may distort the uterine cavity, resulting in malpresentation and the need for cesarean delivery.3,20
In conclusion, this large cohort study showed a twofold to threefold increased risk of pregnancy complications, including placental abruption, PROM, and cesarean delivery malpresentation when uterine synechiae are noted at routine second-trimester ultrasonography. This challenges the notion of uterine synechiae as benign incidental findings in pregnancy. Although there are currently no proven interventions to prevent these complications, our results are useful for counseling women diagnosed with uterine synechiae. The finding of uterine synechiae should also trigger increased vigilance on the part of patients and their physicians. Further research will help determine if there is indeed a causal relationship between uterine synechiae and pregnancy complications and whether adhesiolysis before pregnancy in women known to have uterine synechiae is beneficial.
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