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Ultrasound measurement of fetal adrenal gland enlargement: an accurate predictor of preterm birth

Published:February 04, 2011DOI:https://doi.org/10.1016/j.ajog.2010.11.034

      Objective

      The objective of the study was to test whether ultrasound-measured fetal adrenal gland volume (AGV) and fetal zone enlargement (FZE) predicts preterm birth (PTB) better than cervical length (CL).

      Study Design

      Three-dimensional and 2-dimensional ultrasound were used prospectively to measure fetal AGV, FZE, and CL in women with preterm labor symptoms. We corrected AGV for fetal weight (cAGV). The ratio between whole gland depth (D) and central fetal zone depth (d) (d/D) was used to measure FZE. Ability of cAGV, d/D, and CL to predict PTB 7 days or less was compared.

      Results

      Twenty-seven of 74 women (36.5%) presenting between 21 and 34 weeks had PTB of 7 days or less. FZE greater than 49.5% was the single best predictor for PTB (sensitivity/specificity 100%/89%) compared with cAGV (81%/87%) and CL (56%/60%; P < .05). Prediction was independent of obstetrics history and tocolytic use.

      Conclusion

      The 2-dimensional measurement of the adrenal gland FZE is highly effective performing superior to CL in identifying women at risk for PTB within 7 days.

      Key words

      Preterm birth (PTB) remains a major cause of perinatal morbidity and mortality worldwide. Compared with term deliveries, early PTB (<34 weeks' gestation) carries a 7-fold increased risk of neonatal death. Following PTB, survivors can experience significant long-term cognitive, behavioral, emotional, sensory, and motor deficits.
      • Matthews T.
      • MacDorman M.
      2008 National vital statistics. Infant mortality statistics from the 2005 period linked birth/infant death data set.
      Thus, identification of women at risk for PTB is one of the critical prerequisites for effective intervention and improvement in outcome. For the last several decades, significant effort has been focused toward discovery of an accurate method to predict PTB. Traditional predictors such as obstetric risk factors and clinical presentation are helpful but seldom completely define the population that will truly deliver preterm.
      American College of Obstetricians and Gynecologists
      2001 ACOG practice bulletin no. 31. Clinical management guidelines for the obstetrician-gynecologist. Assessment of risk factors for preterm birth.
      For Editors' Commentary, see Table of Contents
      Convincing data have shown that 2-dimensional (2D) ultrasound measurement of cervical length (CL) can identify women at risk for PTB.
      • Crane J.M.
      • Van den Hof M.
      • Armson B.A.
      • Liston R.
      Transvaginal ultrasound in the prediction of preterm delivery: singleton and twin gestations.
      Accordingly, CL is now widely used in clinical practice for risk estimation.
      • Iams J.D.
      • Paraskos J.
      • Landon M.B.
      • Teteris J.N.
      • Johnson F.F.
      Cervical sonography in preterm labor.
      However, as understanding of the mechanisms of preterm labor (PTL) have evolved, obstetricians have learned that, in some women, cervical shortening is a phenomenon that carries no increased risk for prematurity. Therefore, the search for early and accurate markers that distinguish between physiologic processes and abnormal activation of the labor cascade has been ongoing.
      There is evidence to support the view that activation of the fetal hypothalamic-pituitary-adrenal axis, and the cross talk between a variety of placental and fetal adrenal gland endocrine signaling pathways play an important role in initiation of the normal parturition process.
      • Norwitz E.R.
      • Robinson J.N.
      • Challis J.R.
      The control of labor [see comment].
      Biochemical activation causes increased dehydroepinadrosterone-sulfate production in the central zone of the fetal adrenal gland (fetal zone). Accordingly the whole fetal adrenal gland increases in size and this increase is predominantly due to significant enlargement of the central fetal zone.
      • Langlois D.
      • Li J.Y.
      • Saez J.M.
      Development and function of the human fetal adrenal cortex.
      Arguments in support of this process have been provided by an autopsy study, which demonstrated that neonates that delivered in the setting of idiopathic PTB had significantly higher adrenal gland weight than those that delivered secondary to fetal/maternal hemorrhage.
      • Anderson A.B.
      • Laurence K.M.
      • Davies K.
      • Campbell H.
      • Turnbull A.C.
      Fetal adrenal weight and the cause of premature delivery in human pregnancy.
      In a prior study, we were able to show that the 3-dimensional (3D) ultrasound measurement of fetal adrenal gland volume (AGV) allows prenatal identification of this process.
      • Turan O.M.
      • Turan S.
      • Fuani E.F.
      • Buhimschi I.A.
      • Copel J.A.
      • Buhimschi C.S.
      Fetal adrenal gland volume. A novel method for identify women at risk for impending preterm birth.
      In that study the increased volume of the whole fetal adrenal gland significantly correlated with the risk for PTB.
      However, whereas 3D ultrasound studies of the AGV may provide valuable insight in studying the pathophysiology of fetal adaptation to intrauterine stressors and fetal contribution to the preterm labor process, they are technically challenging and have not achieved generalized clinical application. In addition, this method evaluates the whole gland rather than the physiologically relevant fetal zone. In addition, a comparative analysis of the predictive value of AGC vs CL has not yet been performed. Herein we sought to test the hypothesis that ultrasound evaluation of fetal adrenal gland volume and the central fetal zone size are predictive of PTB better than cervical length measurement.

      Materials and Methods

      Study design

      This was a prospective observational study performed at the University of Maryland School of Medicine and Yale University School of Medicine from 2005 to 2009. Consecutive patients with singleton pregnancies between 21 and 34 weeks that presented with signs of preterm labor or preterm premature rupture of membranes (PPROM) were recruited for the study. Exclusion criteria included suspected fetal growth restriction (sonographically estimated fetal weight <10th percentile), maternal medical conditions (eg, hypertension, preeclampsia, diabetes, or thyroid or adrenal diseases), and presence of fetal heart rate abnormalities at enrollment (ie, bradycardia or prolonged variable decelerations). This study protocol was approved by the University of Maryland Institutional Review Board and the Yale University Human Investigation Committee. Written informed consent was obtained from all participants prior to enrolment. The 3D data and outcomes of 32 patients were previously reported.
      • Turan O.M.
      • Turan S.
      • Fuani E.F.
      • Buhimschi I.A.
      • Copel J.A.
      • Buhimschi C.S.
      Fetal adrenal gland volume. A novel method for identify women at risk for impending preterm birth.
      Gestational age (GA) was established based on the last menstrual period and/or an ultrasound evaluation prior to 20 weeks. Preterm labor was defined as the presence of regular uterine contractions with cervical effacement and/or advancing cervical dilatation. We confirmed PPROM by visualization of amniotic fluid vaginal pooling at the time of the sterile speculum examination. Positive nitrazine and ferning tests were also considered diagnostic.
      Ultrasound fetal biometry, the CL measurement of 3D AGV acquisitions were performed for each patient at the time of admission. Clinical management was at the discretion of the obstetric providers. Patients with PPROM were managed expectantly in the absence of signs or symptoms of clinical chorioamnionitis (fever >38.0°C, abdominal tenderness, fetal tachycardia) and/or abnormalities of fetal heart rate (variable or late decelerations) and/or placental abruption.
      Following admission, corticosteroid and antibiotic administrations were recommended in accordance with American Congress of Obstetrics and Gynecology recommendations.
      American College of Obstetricians and Gynecologists
      ACOG practice bulletin no. 80. Premature rupture of membranes.
      For most cases (80%), acquisition of the AGV was performed prior to the administration of antenatal steroid. Per institutional protocol, patients were monitored twice daily for fetal heart abnormalities and/or uterine contractions by cardiotocography. Following evaluation the clinical course of each patient was recorded prospectively until birth. The interval (days) was computed from 2D/3D ultrasound examination to delivery of the fetus, and delivery outcomes were recorded.

      Two-dimensional ultrasound and CL measurement

      Ultrasonographic estimated fetal weight was calculated using biparietal diameter, head circumference, abdominal circumference, and femur length.
      • Chien P.F.
      • Owen P.
      • Khan K.S.
      Validity of ultrasound estimation of fetal weight.
      The length of the closed portion of cervix was measured transvaginally in patients with intact membranes
      • Heath V.C.F.
      • Southall T.R.
      • Souka A.P.
      • Novakov A.
      • Nicolaides K.H.
      Cervical length at 23 weeks of gestation: relation to demographic characteristics and previous obstetric history.
      or translabially if PPROM was present.
      • Jeanty P.
      • d'Alton M.
      • Romero R.
      • Hobbind J.C.
      Perineal scanning.

      Three-dimensional fetal adrenal gland data acquisition and volume calculation

      Fetal AGV acquisition was performed with the Voluson 730 and E8 systems (Voluson Expert; General Electric Medical Systems, Milwaukee, WI), equipped with a 4-8 MHz curved array transducer as previously described.
      • Turan O.M.
      • Turan S.
      • Fuani E.F.
      • Buhimschi I.A.
      • Copel J.A.
      • Buhimschi C.S.
      Fetal adrenal gland volume. A novel method for identify women at risk for impending preterm birth.
      Three-dimensional blocks were analyzed by a single investigator (O.M.T.) blinded to pregnancy outcome. Calculation of AGV was performed using VOCAL (Virtual Organ Computer-aided AnaLysis, 4D view; General Electric Medical Systems) software package as previously described.
      • Turan O.M.
      • Turan S.
      • Fuani E.F.
      • Buhimschi I.A.
      • Copel J.A.
      • Buhimschi C.S.
      Fetal adrenal gland volume. A novel method for identify women at risk for impending preterm birth.
      The corrected AGV (cAGV) was calculated by using the following formula: cAGV = AGV/estimated fetal weight. As previously described, the cAGV is a GA-independent parameter.
      • Turan O.M.
      • Turan S.
      • Fuani E.F.
      • Buhimschi I.A.
      • Copel J.A.
      • Buhimschi C.S.
      Fetal adrenal gland volume. A novel method for identify women at risk for impending preterm birth.

      Calculation of fetal zone enlargement

      To provide proof of concept regarding our proposed methodology, the whole gland and fetal zone dimensions were determined by using the volumetric blocks used to calculate the AGV. The fetal zone was identified in transverse, sagittal, and coronal planes as an echogenic demarcated area (Figure 1). These 3 planes were used to measure the length (L), width (W), and depth (D) of the whole fetal adrenal gland. Similarly, the fetal zone's length (l), width (w), and depth (d) were also measured. L and l were measured in transverse or sagittal planes. W and w were measured in transverse or coronal planes. D and d were measured in sagittal or coronal planes. Measurements were obtained in those planes that gave the best definition of tissue interfaces.
      Figure thumbnail gr1
      FIGURE 1Methodology of measurement of the whole adrenal gland and the fetal zone
      A, Ultrasound image of transverse, B, coronal, and C, saggital planes and corresponding schematic appearance of adrenal gland and fetal zone were demonstrated. The adrenal gland, kidney, and spine are marked by arrows.
      Turan. Fetal zone enlargement. Am J Obstet Gynecol 2011.
      Three consecutive measurements of fetal adrenal gland and fetal zone were obtained, and the mean of 3 measurements were used for final analysis. The relative size of the fetal zone was calculated for each orthogonal plane by dividing the fetal zone dimension by the gland dimension at the widest point (l/L, w/W, and d/D).
      The intraobserver coefficients of variation for calculation of the cAGV and fetal zone dimensions were 1.5% and 3.5%, respectively.

      Data analysis

      Three ultrasound parameters, the cAGV, relative 2D size of the fetal zone, and the length of the closed portion of the cervix, were related to delivery within 7 days (primary outcome). History of prior PTB, PPROM, tocolytic use, and delivery outcome findings were related to each test variable.
      Normality of data was evaluated with the Kolmogorov-Smirnov test. Categorical variables were analyzed using χ2 or Fisher's exact tests as appropriate. Continuous variables were analyzed using Mann-Whitney or student t test according to their distributions. Pearson correlation was used to measure colinearity between the selected independent variables as well as other relevant relationships between dependent and independent variables. Predictive cutoff levels for each test were calculated by receiver operator characteristics (ROC) curve analysis and curves were compared to assess the predictive value of each. Regression analysis was used for covariate analysis. SPSS 11 (SPSS Inc, Chicago, IL), MedCalc (Broekstraat, Belgium), and Excel 2007 (Microsoft, Richmond, CA) were used for analysis.

      Results

      Seventy-four patients at high risk for PTB were recruited for the study. Demographics and clinical and outcome characteristics are presented in Table 1. Of the women evaluated in this study, 27 (36.5%) delivered within 7 days from the time of our evaluation. As expected, women who gave birth longer than 7 days from the time of our evaluation more frequently had intact membranes, were delivered at a higher GA, and had babies of greater birthweight. The majority of women who delivered less than 34 weeks GA had a delivery interval less than 7 days.
      TABLE 1Distribution of demographic and outcome characteristics according to delivery interval
      CharacteristicsAll cases (n = 74)Delivery ≤7 d (n = 27)Delivery >7 d (n = 47)P value
      Comparisons performed between delivery of groups 7 days or less and delivery longer than 7 days.
      Demographic
       Age, y, mean (SD)26.0 (6.38)25.7 (5.63)26.2 (6.83)NS
       Parity, median (range)1 (0–4)0 (0–3)1 (0–4)NS
       Race (n, %)NS
        Black39 (53)15 (56)24 (51)
        White25 (34)8 (31)17 (36)
        Hispanic7 (9)3 (11)4 (9)
        Other3 (4)1 (2)2 (4)
       Gestational age at enrollment, wks, mean (SD)27.6 (3.49)27.6 (3.71)27.4 (3.38)NS
       History of prior preterm birth, n (%)26 (35)8 (31)18 (39)NS
       Presence of PPROM, n (%)21 (28)12 (46)9 (19).03
      Outcome
       Gestational age at delivery, wks, mean (SD)32.1 (4.87)28.1 (3.40)34.5 (3.96)< .0001
       Delivery weight, g, mean (SD)1779 (864.59)1098.7 (504.27)2225 (786.22)< .0001
       Cesarean section, n (%)22 (30)8 (30)14 (30)NS
       Delivery <37 wks, n (%)58 (78)27 (100)33 (70)NS
       Delivery <34 wks, n (%)44 (59)26 (96)18 (38)< .0001
      NS, not significant; PPROM, preterm premature rupture of membranes.
      Turan. Fetal zone enlargement. Am J Obstet Gynecol 2011.
      a Comparisons performed between delivery of groups 7 days or less and delivery longer than 7 days.
      There was a significant correlation between GA and all 3 dimensions of the adrenal gland fetal zone (l, w, and d) (Pearson correlation R = 0.42, 0.50, and 0.54, respectively; P < .001 for all). Similarly, we observed a significant correlation between GA and the total gland measurements (L, W, and D) (R= 0.56, 0.52, and 0.41, respectively; P < .0001 for all). However, there was no relationship between GA and the relative dimension of the adrenal gland fetal zone (R= −0.04 for the l/L ratio, 0.07 for the w/W ratio, and 0.12 for the d/D ratio, respectively; P > .05 for all).
      To determine the best indicator of fetal zone enlargement, we first correlated the cAGV individually with l/L, w/W, and d/D ratios. All 3 ratios correlated significantly with the cAGV (R = 0.53, 053, and 0.60, respectively; P < .0001 for all) (Figure 2). Next, using ROC curve analysis, we calculated the predictive performance of the different ratios for PTB within 7 days of delivery (Table 2). By using ROC curve comparative analysis, we determined that the d/D ratio showed superior predictive value compared with the l/L and w/W ratios (z = 2.49, P = .013 and z = 2.08, P = .037, respectively). Accordingly, the d/D ratio was used as a measure of fetal zone enlargement (FZE) and for the remainder of the analysis.
      Figure thumbnail gr2
      FIGURE 2Correlation analysis between cAGV and percent change of fetal zone
      Correlation analysis between cAGV and percent change of fetal zone in A, length, B, width, and C, depth. Red central line represents ideal correlation. Dotted lines show 95% confidence intervals. Black lines represent SDs. Level of statistical significance of each tests were given.
      cAGV, corrected adrenal gland volume for fetal weight.
      Turan. Fetal zone enlargement. Am J Obstet Gynecol 2011.
      TABLE 2Predictive value of fetal zone dimension ratios for prediction preterm birth within 7 days
      VariableSensitivity (95% CI)Specificity (95% CI)+LR (95% CI)−LR (95% CI)
      l/L >63.8%85 (66–96)68 (53–81)2.7 (2.1–3.4)0.22 (0.1–0.6)
      w/W >51.9%74 (54–89)85 (72–94)5 (3.9–6.4)0.3 (0.1–0.8)
      d/D >49.7%100 (87–100)89 (77–97)9.4 (8.5–10.4)0
      CI, confidence interval; d/D, depth of fetal zone/depth of whole gland; l/L, length of fetal zone/length of whole gland; w/W, width of fetal zone/width of whole gland; +LR, positive likelihood ratio; -LR, negative likelihood ratio.
      Turan. Fetal zone enlargement. Am J Obstet Gynecol 2011.
      There was a significant correlation between measurement-to-delivery interval and cAGV & FZE. On the other hand, CL was not correlated (Figure 3). Cervical length measurement were similar among the group of women who delivered within or longer than 7 days from the time of enrollment (17.2 ± 10.12 mm vs 16.6 ±12.0 mm, P > .05). Analysis of the 3D and 2D shows both AGV and d/D ratio were significantly increased in babies born less than 7 days from the time of evaluation (Table 3).
      Figure thumbnail gr3
      FIGURE 3Correlation analysis between measurement-to-delivery interval and ultrasound examination findings
      Correlation analysis between measurement-to-delivery interval and A, cervical length, B, cAGV, and C, fetal zone depth. Red central line represents ideal correlation. Dotted lines show 95% confidence intervals. Black lines represent SDs. Measurement-to-delivery interval was transferred to logarithmic scale. Level of statistical significance of each tests were given.
      cAGV, corrected adrenal gland volume for fetal weight.
      Turan. Fetal zone enlargement. Am J Obstet Gynecol 2011.
      TABLE 3Ultrasound examination findings according to delivery interval
      VariableDelivery ≤7 d (n = 27)Delivery >7 d (n = 47)P value
      Cervical length, mm, mean (SD)17.2 (10.12)16.6 (12.0)NS
      Corrected adrenal gland volume, mm3/kg, mean (SD)561.3 (214.93)329.2 (129.17)< .0001
      Fetal zone enlargement, %, mean (SD)59.9 (7.12)40.6 (10.44)< .0001
      NS, not significant.
      Turan. Fetal zone enlargement. Am J Obstet Gynecol 2011.
      Next, we evaluated the relationships between CL, cAGV, FZE, and the measurement-to-delivery interval. The best cutoffs for predicting birth within 7 days of evaluation were identified using ROC curve analysis (Figure 4). The sensitivity, specificity, +LR, −LR, and relative risk of CL, cAGV, and FZE are listed in Table 4. A key finding of our analysis was that the cAGV and FZE were superior to CL measurement in prediction of PTB (z = 3.40, P = .001 and z = 5.22, P < .0001). There was no significant difference between 3D gland volumes and 2D d/D ratio (z = 1.87, P > .05). The comparative analysis for the CL, cAGV, and FZE according to the scan to delivery interval is shown in Figure 5.
      Figure thumbnail gr4
      FIGURE 4Receiver operating characteristic curves
      Receiver operating characteristic curve for the ability of cervical length, cAGV, and fetal zone depth enlargement to predict a delivery within 7 days of the initial ultrasound evaluation.
      cAGV, corrected adrenal gland volume for fetal weight.
      Turan. Fetal zone enlargement. Am J Obstet Gynecol 2011.
      TABLE 4Predictive value of ultrasound parameters for identification of women at risk for preterm birth
      VariableSensitivity (95% CI)Specificity (95% CI)+LR (95% CI)1LR (95% CI)
      Cervical length ≤16 mm56 (35–75)60 (44–74)1.4 (0.9–2.1)0.8 (0.4–1.3)
      Corrected adrenal gland volume ≥420 mm3/kg81 (62–94)87 (74–95)6.4 (5.2–7.9)0.2 (0.07–0.6)
      Fetal zone enlargement ≥49.7%100 (87–100)89 (77–97)9.4 (8.5–10.4)0
      CI, confidence interval; +LR, positive likelihood ratio; −LR, negative likelihood ratio.
      Turan. Fetal zone enlargement. Am J Obstet Gynecol 2011.
      Figure thumbnail gr5
      FIGURE 5Graphic representation of the performance of individual test in predicting preterm birth
      Graphic representation of the performance of A, cervical length, B, cAGV, and C, fetal zone depth in predicting preterm birth within 7 days from the time of evaluation. Level of statistical significance of each tests were given. Red dotted lines represents ROC-derived cutoffs. Cervical length was not different in patients who delivered within 7 days or after 7 days. Fetal zone depth was above the cutoff in all patients who were delivered within 7 days.
      cAGV, corrected adrenal gland volume for fetal weight; ROC, receiver operator characteristics.
      Turan. Fetal zone enlargement. Am J Obstet Gynecol 2011.
      Finally, we used multiple regression analysis to evaluate relationship between FZE, measurement-to-delivery interval, and clinical variables such as history of PTB, PPROM, and tocolytic use. These show that the cAGV (P < .0001) and the d/D ratio (P < .0001) were independent predictors of PTB within 7 days of evaluation. All the listed variables were excluded from the model (P > .05 for all).

      Comment

      Our results suggest that ultrasound examination of fetal adrenal gland and assessment of FZE at time of evaluation for symptoms of PTL may be clinically beneficial. High sensitivity and specificity of this method will help to accurately define the actual population at risk. This will allow us to implement better therapeutic and preventive interventions. For example, in the absence of intraamniotic infection and enlargement of fetal adrenal gland zone, unnecessary therapies (steroid, tocolytics, cervical cerclage) may be withheld. However, more research is still necessary.
      One of the aims of this study was to provide the proof of concept that 3D and 2D evaluation of the fetal adrenal gland are equivalent in their ability to predict PTB. As a result, several limitations were inherent. For example, the measurements of the fetal adrenal gland and that of the fetal zone were performed in the already-acquired 3D blocks. Further studies remain to determine whether the multiplanar evaluation of the fetal adrenal gland is possible and retains its high accuracy when the regular ultrasound equipment is used. Lastly, our findings need to be confirmed in a larger cohort of patients at low and high risk of PTB.
      It is not unusual for women to present with symptoms of PTL. Still, their outcome is frequently normal.
      • Honest H.
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      Prediction and early detection of preterm labor.
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      • et al.
      Cervicovaginal fibronectin improves the prediction of preterm delivery based on sonographic cervical length in patients with preterm uterine contractions and intact membranes.
      In the absence of a reliable and accurate biomarker of PTB, a lot of attention was focused on CL. This is because significant shortening of the cervix is associated with an increased risk of PTB in both nulliparous and parous women.
      • Iams J.D.
      • Goldenberg R.L.
      • Meis P.J.
      • et al.
      The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal Fetal Medicine Unit Network.
      Given the easiness of the ultrasound technique, evaluation of the uterine cervix has been widely incorporated into our routine clinical practice. Yet CL measurement before 15
      • Berghella V.
      • Talucci M.
      • Desai A.
      Does transvaginal sonographic measurement of cervical length before 14 weeks predict preterm delivery in high-risk pregnancies?.
      or after 32 weeks
      • Tongsong T.
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      • Piyamongkol W.
      • Sirichotiyakul S.
      Single transvaginal sonographic measurement of cervical length early in the third trimester as a predictor of preterm delivery.
      do not appear to be an accurate predictor of PTB because they are poor indicators. Nevertheless, although a short cervix suggests an increased risk of PTB, this clinical marker is not a good predictor of the measurement-to-delivery interval.
      • Volumenie J.L.
      • Luton D.
      • De Spirlet M.
      • Sibony O.
      • Blot P.
      • Oury J.F.
      Ultrasonographic cervical length measurement is not a better predictor of preterm delivery than digital examination in a population of patients with idiopathic preterm labor.
      The functional role of the fetal zone is to synthesize steroid precursors that are transformed by the placenta to produce estrogens.
      • Elliot J.R.
      • Armour R.G.
      The development of the cortex in the human suprarenal gland and its condition in hemicephaly.
      Therefore, it makes sense to propose that the relationship between PTB and an enlarged fetal zone may be related to the important role played by this organ in the endocrine regulation of parturition.
      • Rainey W.E.
      • Carr B.R.
      • Wang Z.N.
      • Parker Jr, C.R.
      Gene profiling of human fetal and adult adrenals.
      • Gravett M.G.
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      • Hess D.L.
      • Eschenbach D.A.
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      • Rainey W.E.
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      • Carr B.R.
      The human fetal adrenal: making adrenal androgens for placental estrogens.
      • Challis J.R.
      • Bloomfield F.H.
      • Bocking A.D.
      • et al.
      Fetal signals and parturition.
      Evaluation of the fetal AGV and size is a unique departure from prior clinical approaches because it focuses on the fetus rather than on the mother.
      • Smith R.
      Parturition.
      Our group provided the first evidence that 3D ultrasound volumetry of the fetal adrenal gland accurately predicts impending PTB.
      • Turan O.M.
      • Turan S.
      • Fuani E.F.
      • Buhimschi I.A.
      • Copel J.A.
      • Buhimschi C.S.
      Fetal adrenal gland volume. A novel method for identify women at risk for impending preterm birth.
      However, the expertise required for 3D ultrasonographic technique and the focus of our research on the entire adrenal gland rather than on the functionally relevant fetal zone were important drawbacks for implementation of this methodology in the routine clinical practice.
      This study provides a simpler alternative. That is, the 2D measurement of the fetal adrenal gland zone is as reliable as the cAGV and better than CL in predicting PTB within 7 days of the onset of symptoms. Measurement of our adrenal gland parameters was possible within acceptable variability. This finding is encouraging and argues for the clinical applicability of the method.
      In our high-risk study population, almost 80% of the women delivered less than 37 weeks of gestation. The depth of the fetal zone appeared to contribute most to the increase in the AGV. The high predictive value of the FZE seems to be independent of traditional risk factors such as a history of prior PTB and PPROM. In addition, because it can be concluded from our multivariate analysis, tocolytic therapy appears to be ineffective in the presence of an enlarged fetal zone.
      The structure of the human fetal adrenal gland is significantly different from its adult counterpart. In utero the fetal zone is the most prominent and distinctive portion of the adrenal gland. Consequently, the fetal zone occupies the majority of the adrenal gland size. The fetal adrenal gland undergoes significant growth because of an increase in the fetal zone size so that by 18 weeks of gestation, the gland is almost as large as the kidney. The fetal zone continues to enlarge, particularly during the last 6 weeks of gestation.
      • Rainey W.E.
      • Rehman K.S.
      • Carr B.R.
      Fetal and maternal adrenals in human pregnancy.
      Our study confirms that the dimensions of the fetal adrenal gland and fetal zone increases with GA as a part of the physiological development. However, despite this increase, the proportion of the gland occupied by the fetal zone remains constant throughout gestation in all dimensions. This facilitates the distinction between an abnormal hypertrophy of fetal zone and a physiologic increase in its size that is in linear relationship with the remainder of the gland. Therefore, it is reasonable to propose that a disproportionate increase in size of the adrenal gland enables for recognition of the premature activation of the parturition cascade in a noninvasive fashion.
      The American Congress of Obstetrician and Gynecologists is currently recommending 2 tests for the prediction of PTB, ultrasound measurement of the CL, and fetal fibronectin.
      American College of Obstetricians and Gynecologists
      ACOG practice bulletin no. 43. Clinical management guidelines for the obstetrician-gynecologist. Management of preterm labor.
      However, the use of fetal fibronectin in PPROM patients is problematic, given the high false-positive rate of this test in this particular clinical setting.
      • Nisell H.
      • Hagskog K.
      • Westgren M.
      Assessment of fetal fibronectin in cervical secretion in cases of equivocal rupture of the membranes at term.
      In our study population, one-third of the patients had PPROM. Therefore, for our analysis, the results of the fetal fibronectin tests were not used.
      Cervical length did not correlate with the measurement-to-delivery interval. These findings were compatible with a recent Cochrane systematic review.
      • Berghella V.
      • Baxter J.K.
      • Hendrix N.W.
      Cochrane Pregnancy and Childbirth Group.
      A key finding of this analysis was that there is insufficient evidence to recommend routine screening of asymptomatic or symptomatic pregnant women with CL measurement. The authors also concluded that there is a nonsignificant association between knowledge of CL results and a lower incidence of PTB at less than 37 weeks in symptomatic women.
      An important finding of our study was that FZE predicted PTB independent of well-recognized risk factors of prematurity. It is well known that a history of prior PTB is a risk factor for a premature delivery.
      • Boyd H.A.
      • Poulsen G.
      • Wohlfahrt J.
      • Murray J.C.
      • Feenstra B.
      • Melbye M.
      Maternal contributions to preterm delivery.
      Evidence in support of our assertion comes from studies that showed that the probability of PTB before 37 weeks increases up to 64% if the patient has a history of prior PTB.
      • Iams J.D.
      • Goldenberg R.L.
      • Mercer B.M.
      • et al.
      The Preterm Prediction Study: recurrence risk of spontaneous preterm birth. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.
      In that analysis, a positive fetal fibronectin result and a CL less than 25 mm had significant additive predictive value. In our high-risk study population, a prior PTB history did not predict the patients who will deliver within 7 days. This was in contrast to the increase in fetal zone, which successfully stratified risk (Figure 6, A). Such findings should be expected, given that enlargement of the fetal zone reflects an acute activation of the parturition machinery. In contrast, the role of genetic risk factors in prematurity is highly dependent on gene-gene and gene-environment interactions, which may not occur.
      Figure thumbnail gr6
      FIGURE 6Graphic representation of the relation between secondary outcomes and FZE
      The X axis represents fetal zone enlargement for each graph. Red dotted line shows ROC curve derived cutoff levels for FZE (49.7%). Fetal zone depth more than 49.7% labeled as high risk for PTB and less than 49.7% showed as low risk for PTB. The Y axis shows measurement to delivery interval in weeks. Yellow vertical box represents delivery within 7 days. A, Patients with a history of prior PTB were marked as black-filled circles. B, Presence of PPROM was represented with black-filled circles. C, Patients who received tocolytic treatment were shown with black-filled circles.
      FZE, fetal zone enlargement; PPROM, preterm premature rupture of membranes; PTB, preterm birth; ROC, receiver operator characteristics.
      Turan. Fetal zone enlargement. Am J Obstet Gynecol 2011.
      Prediction of latency period in patients with PPROM continues to be a clinical dilemma in the absence of overt intrauterine infection. Reports in the literature regarding CL measurement and correlation with duration of latency period show conflicting results.
      • Fischer R.L.
      • Austin J.D.
      Cervical length measurement by translabial sonography in women with preterm premature rupture of membranes: can it be used to predict the latency period or peripartum maternal infection?.
      • Tsoi E.
      • Fuchs I.
      • Henrich W.
      • Dudenhausen J.W.
      • Nicolaides K.H.
      Sonographic preterm prelabor amniorrhexis.
      Different inflammation markers in amniotic fluid were used for prediction of delivery, but these tests requires invasive testing.
      • Romero R.
      • Yoon B.H.
      • Mazor M.
      • et al.
      A comparative study of the diagnostic performance of amniotic fluid glucose, white blood cell count, interleukin-6, and Gram stain in the detection of microbial invasion in patients with preterm premature rupture of membranes.
      • Buhimschi C.S.
      • Bhandari V.
      • Hamar B.D.
      • et al.
      Proteomic profiling of the amniotic fluid to detect inflammation, infection, and neonatal sepsis.
      In our PPROM group, all patients who had an enlarged fetal zone delivered within 7 days. The latency period was prolonged to as long as 14 weeks if the fetal zone was within the normal limits (Figure 6, B).
      The role of tocolytic treatment in prolonging pregnancy is at best controversial. Despite significant research efforts, clinicians cannot predict in which patients therapy is going to succeed or fail. In our high-risk population, we found that patients delivered within 7 days if the fetal zone is enlarged despite tocolytic treatment (Figure 6, C). These observations confirm that the predictive value of the FZE is independent from that of the clinical circumstances associated with PTB.
      In conclusion, 2D ultrasound evaluation of the fetal zone is a noninvasive clinical tool, which holds promise to change the clinical practice and management of PTB. Two-dimensional measurement of the depth of the adrenal fetal zone offers the potential to accurately predict PTB within 7 days. This prediction is equal to the more complex 3D volume measurement. Enlargement of the fetal zone appears to be superior to the CL measurement for prediction of PTB, and its value seems to be independent of several major clinical circumstances.

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