Harper, Lorie M. MD, MSCI; Cahill, Alison G. MD, MSCI; Smith, Kylie DO; Macones, George A. MD, MSCE; Odibo, Anthony O. MD, MSCE
Currently, more than one-third of women in the United States are classified as obese1; these women are at significantly increased risk of fetal anomalies.2–4 Unfortunately, maternal obesity adversely affects the sensitivity of ultrasonography for detecting fetal anomalies and minor markers of trisomy.5–8 Because of the increased risk of anomalies and the decreased detection rate, it has been suggested that obese women should consider amniocentesis to aid the detection of trisomies and fetal anomalies such as neural tube defects.9 Additionally, the American College of Obstetrics and Gynecology recommends offering invasive prenatal diagnosis to all women.10 However, although maternal obesity limits ultrasonographic visualization, it may also affect the fetal loss rate associated with invasive diagnostic procedures as a result of technical challenges. To properly counsel obese women regarding the risks and benefits associated with their options for prenatal diagnostic testing, estimates of the procedure-related loss rates specific to this patient population must be estimated. We aimed to estimate the risk of fetal loss in obese and nonobese women undergoing chorionic villus sampling (CVS) and amniocentesis.
MATERIALS AND METHODS
We performed a retrospective cohort study of all consecutive patients undergoing an invasive prenatal diagnostic procedure (CVS or amniocentesis) at a single tertiary center. Institutional review board approval was obtained from Washington University School of Medicine. Data were prospectively collected over a 20-year period (1990–2009) by dedicated research nurses. Each patient seen in our center was given a standardized form requesting information regarding the pregnancy outcome, to be returned after delivery. If a form was not returned within 4 weeks of the expected delivery date, the coordinator called the patient. If the patient could not be contacted, the coordinator contacted the referring physician to obtain outcome data. The follow-up form contains details regarding pregnancy complications, delivery complications, and neonatal outcomes.
Patients were included if they underwent either CVS or second-trimester amniocentesis. They were excluded if they had a fetal demise at the time of presentation for the procedure, if maternal body mass index (BMI, calculated as weight (kg)/[height (m)]2) was unavailable, or if pregnancy outcome information was unavailable. Gestational age was determined by either last menstrual period if known and concordant with ultrasonography (within 7 days of first-trimester ultrasonography or 14 days of second-trimester ultrasonography) or by the earliest ultrasonogram available when the last menstrual period was unknown or discordant with ultrasonography.
The primary outcome was any fetal loss less than 24 weeks of gestation. Because women who did not undergo amniocentesis were not included in this study, this outcome includes the background pregnancy loss rate as well as the loss rate attributable to amniocentesis. This analysis includes termination of pregnancy, because the reason for termination was not recorded, and may have included patients who had a complication of the procedure (ie, rupture of membranes). A secondary analysis was performed examining fetal loss less than 24 weeks of gestation and pregnancy loss within 14 days of the procedure, excluding suspected termination of pregnancy. The attributable risk of the procedure was calculated by comparing obese women undergoing amniocentesis or CVS with all women undergoing ultrasonography at similar gestational ages (15–23 weeks of gestation for amniocentesis and 9–14 weeks of gestation for CVS) who did not undergo a procedure, excluding suspected termination of pregnancy. Pregnancy loss within 14 days of the procedure was chosen as a secondary outcome, because these losses are most commonly related to the procedure itself. Maternal BMI was determined at the time of the procedure based on self-reported maternal height and weight. The exposed (obese) group was defined as maternal BMI 30.0 or higher and the unexposed group was defined as maternal BMI lower than 30.0. A secondary analysis was performed classifying maternal BMI categorically using the World Health Organization categories (underweight less than 18.5, normal weight 18.5–25.0, overweight 25.0–29.9, class I obesity 30.0–34.9, class II obesity 35.0–39.9, class III obesity 40.0 or higher). Additionally, because the largest risk difference would be expected to be between normal and class III obese women, a secondary analysis was performed comparing women with BMIs 40.0 or higher and BMIs less than 25.0.
To assess for selection bias in the women undergoing amniocentesis, we also analyzed the number of amniocentesis procedures performed by BMI category and indication. Using the entire database of women presenting for ultrasound examinations between 15 and 22 weeks of gestation for each common indication (all ultrasonograms, advanced maternal age, abnormal serum screen, and abnormal ultrasonographic findings), the percentage of women undergoing amniocentesis for each indication was assessed by BMI category.
Obese and nonobese patients were compared with univariable and bivariate statistics using unpaired Student's t tests or Mann-Whitney U tests, as appropriate, for continuous variables and χ2 tests or Fisher's exact test, as appropriate, for categorical variables. Potentially confounding variables of the exposure–outcome association were identified in the stratified analyses. Multivariable logistic regression models for fetal loss were then developed to better estimate the effect of maternal obesity while adjusting for potentially confounding effects. Clinically relevant covariates for initial inclusion in multivariable statistical models were selected using results of the stratified analyses, and factors were removed in a backward stepwise fashion based on significant changes (more than 10%) in the exposure-adjusted odds ratio or significant differences between hierarchical models using the likelihood ratio test. Covariates considered in the analysis were maternal age, gestational age at the time of the procedure, race, hypertension, diabetes, tobacco use, conception by in vitro fertilization, and the diagnosis of anomalies on ultrasonography. Because the data set covers a long time period (20 years), the effect of the year of the procedure on loss was examined. Time-to-event analyses were performed to estimate the fetal loss rate by BMI while accounting for time, in days, from the procedure; time zero was defined as the time of the procedure. Kaplan-Meier graphs were created for time to delivery stratified by maternal obesity and compared using the log-rank test. A post hoc power analysis was performed to determine this retrospective study's ability to detect a difference between groups using the prevalence of the outcome in the nonobese group and assuming a univariable analysis. The statistical analysis was performed using STATA 11 Special Edition.
Of 17,935 women who underwent an invasive diagnostic procedure, 1,538 (8.5%) were excluded for lack of BMI information and 638 (3.6%) were excluded for lack of outcomes data, leaving 15,759 (87.9%) available for the analysis. Of the 10,779 patients who underwent amniocentesis, 2,742 (25.4%) were obese (Table 1). Among the 4,980 patients who underwent CVS, 855 (17.2%) were obese. Maternal age and gravidity were similar between the obese and nonobese groups. Obese patients were more likely to be African American, use tobacco, and have hypertension or pregestational diabetes. Obese patients were less likely to conceive using in vitro fertilization. Women who were obese were more likely to have an amniocentesis than a CVS and underwent both procedures at a slightly later gestational age than nonobese women. The most common indication for procedure was advanced maternal age, and obese women were slightly more likely to have a procedure for abnormal serum screening than nonobese women.
To investigate for selection bias, the percentage of women undergoing amniocentesis was examined by BMI and indication (Table 2). As BMI category increased, the percentage of women undergoing amniocentesis for any indication decreased (P<.01). The percentage of women undergoing amniocentesis for advanced maternal age and ultrasonographic findings remained constant across BMI categories (P=.41 and P=.17, respectively), but the number of women undergoing amniocentesis for abnormal serum screening decreased as BMI increased (P<.01).
Between obese and nonobese women undergoing amniocentesis, no difference existed in the risk of any fetal loss before 24 weeks of gestation (4.7% compared with 4.2%, adjusted odds ratio [OR] 1.1, 95% confidence interval [CI] 0.8–1.5) (Table 3). For women undergoing CVS, no difference in the risk of any pregnancy loss was seen between obese and nonobese women (6.4% compared with 6.3%, adjusted OR 1.0, 95% CI 0.7–1.3). When excluding pregnancies ending in termination, the risk of pregnancy loss was similar between obese and nonobese women undergoing amniocentesis (1.9% compared with 1.3%, adjusted OR 1.2, 95% CI 0.9–1.8) or CVS (3.5% compared with 3.0%, adjusted OR 1.1, 95% CI 0.7–1.7). The loss rate for pregnancies between 15 and 23 weeks of gestation not undergoing an amniocentesis was 1.6% when excluding terminations, resulting in an attributable risk for obese women undergoing amniocentesis of 0.3% (95% CI −0.2 to 0.9). The loss rate for women undergoing ultrasound examinations but not CVS between 9 and 14 weeks of gestation was 3.4%. Therefore, for obese women undergoing CVS, the attributable risk was 0.1% (95% CI −0.1 to 0.2). The risk of pregnancy loss within 14 days of the procedure was similar for both amniocentesis and CVS between obese and nonobese women. Figure 1 displays the time to pregnancy loss after amniocentesis for obese and nonobese women (log-rank P=.51). After adjusting for maternal age, maternal obesity remained insignificant in the Cox model (P=.67).
Because so few patients had BMIs less than 18.5, the underweight and normal weight categories were combined. Although higher fetal loss rates were noted for amniocentesis and CVS as BMI increased, this observation was not statistically significant when all fetal losses were considered (Table 4). For amniocentesis, when pregnancies ending in termination were excluded, the trend toward higher loss rates as BMI increased was statistically significant (P=.03).
Because we expected the greatest difference to exist between women with BMIs 40.0 or higher and BMIs less than 25.0, these two groups were compared directly. The difference in fetal loss after amniocentesis was significant after adjusting for maternal age (adjusted OR 2.2, 95% CI 1.2–3.9).
To explain the difference in fetal loss rates by BMI category in amniocentesis, we investigated the number of needle insertions per amniocentesis by BMI category (Table 5). Women in higher BMI categories were more likely to require a second needle insertion (P=.02).
Because experience and advances in ultrasonographic technology may affect the fetal loss rate over time, the effect of year of procedure was examined. When the data set was divided into 5-year increments, no difference in fetal loss rates by procedure and obesity was found (data not shown).
A BMI 30.0 or higher does not appear to significantly increase the risk for fetal loss after invasive prenatal diagnostic procedures compared with nonobese women. A higher loss rate with class III obesity (BMI 40.0 or higher) was noted to be only statistically significant for amniocentesis but may have been limited by the small number of morbidly obese women undergoing CVS.
The loss rates presented are all fetal losses before 24 weeks of gestation, not necessarily only losses attributable to the amniocentesis. At our institution, the fetal loss rate attributable to amniocentesis is one in 76911; the loss rates between women who undergo CVS is comparable to those who do not.12 We chose to primarily present all fetal losses rather than only those attributable to the procedure for both clarity and transparency, particularly because this analysis was focused only on women undergoing a procedure rather than including all women who presented to the ultrasonographic unit. The secondary analysis of losses within 14 days of the procedure most closely reflects losses attributable directly to the procedure, because this is the timeframe for the majority of procedure-related losses. The attributable loss rates of 0.3% for amniocentesis and 0.1% for CVS determined for obese women compared with women not undergoing a procedure are similar to prior reported loss rates.
A higher rate of fetal loss after amniocentesis in morbidly obese women is biologically plausible. This may be the result of decreased visualization generally and inability to visualize entry of the needle into the amniotic cavity specifically. Additionally, the increased distance between the abdominal wall and amniotic cavity may increase the risk that the needle is misdirected and require redirection or repeated attempts.
We did not detect a difference in fetal loss after CVS as BMI increased. The majority of CVSs at our institution are performed transcervically; as a result, the effect of maternal abdominal wall thickness on the procedure may be less than with a transabdominal approach.
To examine for selection bias, we evaluated the number of amniocenteses performed in each BMI category for common indications. The number of amniocenteses performed for abnormal serum screening decreases as BMI increases, suggesting a possible selection bias. Health care providers may discourage women from undergoing amniocentesis when they suspect that the procedure will be difficult, which could falsely decrease the loss rates in higher BMI categories. However, the number of procedures performed is stable across BMI category when the indication was advanced maternal age or ultrasonographic abnormalities, suggesting perhaps another reason for the difference. One possible explanation is that obese women with abnormal serum screening undergo fewer diagnostic procedures because fewer abnormalities (both anomalies and minor markers) are discovered on ultrasonography. Additional studies are needed to confirm these hypotheses-generating findings.
Minimal published data exist on the risk of pregnancy loss by maternal BMI after invasive prenatal diagnostic procedures. One of the strengths of our study is its relatively large sample size, which included more than 2,000 amniocentesis procedures and more than 800 CVS procedures in obese patients. A post hoc power analysis with an α error 0.05 was performed to determine the power of this study to detect a difference between groups. Our sample size enabled us to examine a fairly rare outcome (pregnancy loss) with a greater than 90% power to detect a 50% increase in the risk of pregnancy loss after both amniocentesis and CVS (with an α error of 0.05). Additionally, the prospectively collected patient-level information allowed us to examine confounding factors such as maternal age and gestational age at procedure as well as to consider losses within 14 days of the procedure and exclude elective terminations.
One weakness of the study is that patient height and weight were self-reported. However, it has been shown that maternal reporting of weight can be accurate within 1–2 kg13; therefore, the use of patient report is unlikely to result in significant misclassification. Importantly, women reported this information before their procedure, and thus any misclassification would have been nondifferential with respect to our study question. The relatively small number of women with BMIs 40 or higher undergoing CVS limits our ability to detect an increase in the risk of fetal loss with approximately 70% power to detect a twofold increased risk. We excluded 10% of the population from the analysis as a result of either missing BMI information (approximately 70%) or missing outcomes data (approximately 30%), thus creating the potential for a possible selection bias. The women with missing BMI data were not more likely to experience pregnancy loss than those whose BMI was recorded (6% compared with 5%, P=.16); women with missing outcome data were more likely to be African American or use tobacco but were similar to the included population in all other respects (data available on request). Given the small number of patients excluded and their largely similar characteristics to the study population, this is unlikely to represent a large source of bias. Lastly, the fact that all of our procedures are performed by Maternal-Fetal Medicine subspecialists and that the majority of CVS is performed transcervically should be kept in mind when considering the generalizability of our results.
In conclusion, the risk of fetal loss after amniocentesis and CVS appears to be similar in obese women (BMI 30.0 or higher) compared with nonobese women. As BMI increases greater than 40, the risk of pregnancy loss after amniocentesis appears to be increased. When counseling women regarding the risk of fetal loss after an invasive prenatal diagnostic procedure, it may be appropriate to use BMI-specific risks, particularly in morbidly obese women.
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