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Research www.AJOG.org

OBSTETRICS

Ultrasound measurement of fetal adrenal glandenlargement: an accurate predictor of preterm birthOzhan M. Turan, MD, PhD; Sifa Turan, MD, RDMS; Edmund F. Funai, MD; Irina A. Buhimschi, MD;Catherine H. Campbell, MD; Ozan M. Bahtiyar, MD; Chris R. Harman, MD;Joshua A. Copel, MD; Catalin S. Buhimschi, MD; Ahmet A. Baschat, MD

OBJECTIVE: The objective of the study was to test whether ultra-sound-measured fetal adrenal gland volume (AGV) and fetal zoneenlargement (FZE) predicts preterm birth (PTB) better than cervicallength (CL).

STUDY DESIGN: Three-dimensional and 2-dimensional ultrasoundere used prospectively to measure fetal AGV, FZE, and CL in womenith preterm labor symptoms. We corrected AGV for fetal weight

cAGV). The ratio between whole gland depth (D) and central fetal zoneepth (d) (d/D) was used to measure FZE. Ability of cAGV, d/D, and CL to
redict PTB 7 days or less was compared.
Obstet Gynecol 2011;204:311.e1-10.

for prematurity. Thesee Table of Contents

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

CONCLUSION: The 2-dimensional measurement of the adrenal glandFZE is highly effective performing superior to CL in identifying women atrisk for PTB within 7 days.

Key words: cervical length, fetal adrenal gland, preterm birth, 3-
dimensional ultrasound, volume measurement
Cite this article as: Turan OM, Turan S, Funai EF, et al. Ultrasound measurement of fetal adrenal gland enlargement: an accurate predictor of preterm birth. Am J

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Preterm birth (PTB) remains a majorcause of perinatal morbidity and

mortality worldwide. Compared withterm deliveries, early PTB (�34 weeks’

From the Department of Obstetrics,Gynecology and Reproductive SciencesUniversity of Maryland School of Medicine,Baltimore, MD (Drs O. M. Turan, S. Turan,Harman, and Baschat), and the Departmentof Obstetrics, Gynecology, and ReproductiveSciences, Yale University School ofMedicine, New Haven, CT (Drs Funai, I. A.Buhimschi, Campbell, Bahtiyar, Copel, andC. S. Buhimschi).

Presented at the 30th Annual Meeting of theSociety for Maternal-Fetal Medicine, Chicago,IL, Feb. 1-6, 2010.

Received June 16, 2010; revised Sept. 14,2010; accepted Nov. 17, 2010.

Reprints: Ozhan M. Turan, MD, PhD,Department of Obstetrics, Gynecology andReproductive Science, University of MarylandSchool of Medicine, Baltimore, MD [email protected].

0002-9378/freePublished by Mosby, Inc.doi: 10.1016/j.ajog.2010.11.034

For Editors’ Commentary,

gestation) carries a 7-fold increased riskof neonatal death. Following PTB, sur-vivors can experience significant long-term cognitive, behavioral, emotional,sensory, and motor deficits.1 Thus, iden-tification of women at risk for PTB is oneof the critical prerequisites for effectiveintervention and improvement in out-come. For the last several decades, signif-icant effort has been focused toward dis-covery of an accurate method to predictPTB. Traditional predictors such as ob-stetric risk factors and clinical presenta-tion are helpful but seldom completelydefine the population that will truly de-liver preterm.2

Convincing data have shown that2-dimensional (2D) ultrasound mea-surement of cervical length (CL) canidentify women at risk for PTB.3 Accord-ingly, CL is now widely used in clinicalpractice for risk estimation.4 However,as understanding of the mechanisms ofpreterm labor (PTL) have evolved, ob-stetricians have learned that, in somewomen, cervical shortening is a phe-nomenon that carries no increased risk

refore, the search (

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for early and accurate markers that dis-tinguish between physiologic pro-cesses and abnormal activation of thelabor cascade has been ongoing.

There is evidence to support the viewthat activation of the fetal hypothalamic-pituitary-adrenal axis, and the cross talkbetween a variety of placental and fetaladrenal gland endocrine signaling path-ways play an important role in initiationof the normal parturition process.5 Bio-hemical activation causes increased de-ydroepinadrosterone-sulfate produc-ion in the central zone of the fetaldrenal gland (fetal zone). Accordinglyhe whole fetal adrenal gland increases inize and this increase is predominantlyue to significant enlargement of theentral fetal zone.6

Arguments in support of this processhave been provided by an autopsy study,which demonstrated that neonates thatdelivered in the setting of idiopathic PTBhad significantly higher adrenal glandweight than those that delivered second-ary to fetal/maternal hemorrhage.7 In a

rior study, we were able to show that the-dimensional (3D) ultrasound mea-urement of fetal adrenal gland volume
AGV) allows prenatal identification of
an Journal of Obstetrics & Gynecology 311.e1

mailto:[email protected]

Research Obstetrics www.AJOG.org

this process.8 In that study the increasedvolume of the whole fetal adrenal glandsignificantly correlated with the risk forPTB.

However, whereas 3D ultrasoundstudies of the AGV may provide valuableinsight in studying the pathophysiologyof fetal adaptation to intrauterine stres-sors and fetal contribution to the pre-term labor process, they are technicallychallenging and have not achieved gen-eralized clinical application. In addition,this method evaluates the whole glandrather than the physiologically relevantfetal zone. In addition, a comparativeanalysis of the predictive value of AGC vsCL has not yet been performed. Hereinwe sought to test the hypothesis that ul-trasound evaluation of fetal adrenalgland volume and the central fetal zonesize are predictive of PTB better than cer-

FIGURE 1Methodology of measurement of th

A, Ultrasound image of transverse, B, coronal, ademonstrated. The adrenal gland, kidney, and sTuran. Fetal zone enlargement. Am J Obstet Gynecol 2011.

vical length measurement.

311.e2 American Journal of Obstetrics & Gynecolo

MATERIALS AND METHODSStudy designThis was a prospective observationalstudy performed at the University ofMaryland School of Medicine and YaleUniversity School of Medicine from2005 to 2009. Consecutive patients withsingleton pregnancies between 21 and 34weeks that presented with signs of pre-term labor or preterm premature rup-ture of membranes (PPROM) were re-cruited for the study. Exclusion criteriaincluded suspected fetal growth restric-tion (sonographically estimated fetalweight �10th percentile), maternalmedical conditions (eg, hypertension,preeclampsia, diabetes, or thyroid or ad-renal diseases), and presence of fetalheart rate abnormalities at enrollment(ie, bradycardia or prolonged variabledecelerations). This study protocol was

hole adrenal gland and the fetal zon

C, saggital planes and corresponding schematiare marked by arrows.

approved by the University of Maryland

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Institutional Review Board and the YaleUniversity Human Investigation Com-mittee. Written informed consent wasobtained from all participants prior toenrolment. The 3D data and outcomesof 32 patients were previously reported.8

Gestational age (GA) was establishedbased on the last menstrual periodand/or an ultrasound evaluation prior to20 weeks. Preterm labor was defined asthe presence of regular uterine contrac-tions with cervical effacement and/oradvancing cervical dilatation. We con-firmed PPROM by visualization of am-niotic fluid vaginal pooling at the time ofthe sterile speculum examination. Posi-tive nitrazine and ferning tests were alsoconsidered diagnostic.

Ultrasound fetal biometry, the CL mea-surement of 3D AGV acquisitions wereperformed for each patient at the time of

pearance of adrenal gland and fetal zone were

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admission. Clinical management was at

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www.AJOG.org Obstetrics Research

the discretion of the obstetric providers.Patients with PPROM were managed ex-pectantly in the absence of signs or symp-toms of clinical chorioamnionitis (fever�38.0°C, abdominal tenderness, fetaltachycardia) and/or abnormalities of fetalheart rate (variable or late decelerations)and/or placental abruption.

Following admission, corticosteroidand antibiotic administrations were rec-ommended in accordance with Ameri-can Congress of Obstetrics and Gynecol-ogy recommendations.9 For most cases(80%), acquisition of the AGV was per-formed prior to the administration ofantenatal steroid. Per institutional pro-tocol, patients were monitored twicedaily for fetal heart abnormalities and/oruterine contractions by cardiotocogra-phy. Following evaluation the clinicalcourse of each patient was recorded pro-spectively until birth. The interval (days)was computed from 2D/3D ultrasoundexamination to delivery of the fetus, and

TABLE 1Distribution of demographic and ou

Characteristics

Demographic..........................................................................................................

Age, y, mean (SD)..........................................................................................................

Parity, median (range)..........................................................................................................

Race (n, %).................................................................................................

Black.................................................................................................

White.................................................................................................

Hispanic.................................................................................................

Other..........................................................................................................

Gestational age at enrollment, wks, mean..........................................................................................................

History of prior preterm birth, n (%)..........................................................................................................

Presence of PPROM, n (%)...................................................................................................................

Outcome..........................................................................................................

Gestational age at delivery, wks, mean (SD..........................................................................................................

Delivery weight, g, mean (SD)..........................................................................................................

Cesarean section, n (%)..........................................................................................................

Delivery �37 wks, n (%)..........................................................................................................

Delivery �34 wks, n (%)...................................................................................................................

NS, not significant; PPROM, preterm premature rupture of mea Comparisons performed between delivery of groups 7 days

Turan. Fetal zone enlargement. Am J Obstet Gynecol 201

delivery outcomes were recorded. g

Two-dimensional ultrasoundand CL measurementUltrasonographic estimated fetal weightwas calculated using biparietal diameter,head circumference, abdominal circum-ference, and femur length.10 The lengthof the closed portion of cervix wasmeasured transvaginally in patients withintact membranes11 or translabially ifPPROM was present.12

Three-dimensional fetal adrenalgland data acquisitionand volume calculationFetal AGV acquisition was performedwith the Voluson 730 and E8 systems(Voluson Expert; General Electric Med-ical Systems, Milwaukee, WI), equippedwith a 4-8 MHz curved array transduceras previously described.8 Three-dimen-ional blocks were analyzed by a singlenvestigator (O.M.T.) blinded to preg-ancy outcome. Calculation of AGV waserformed using VOCAL (Virtual Or-

ome characteristics according to del

All cases(n � 74)

Delivery <(n � 27)

.........................................................................................................................

26.0 (6.38) 25.7 (5.6.........................................................................................................................

1 (0–4) 0 (0–3).........................................................................................................................

.........................................................................................................................

39 (53) 15 (56).........................................................................................................................

25 (34) 8 (31).........................................................................................................................

7 (9) 3 (11).........................................................................................................................

3 (4) 1 (2).........................................................................................................................

) 27.6 (3.49) 27.6 (3.7.........................................................................................................................

26 (35) 8 (31).........................................................................................................................

21 (28) 12 (46).........................................................................................................................

.........................................................................................................................

32.1 (4.87) 28.1 (3.4.........................................................................................................................

1779 (864.59) 1098.7 (504.........................................................................................................................

22 (30) 8 (30).........................................................................................................................

58 (78) 27 (100).........................................................................................................................

44 (59) 26 (96).........................................................................................................................

nes.

s and delivery longer than 7 days.

an Computer-aided AnaLysis, 4D view;

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eneral Electric Medical Systems) soft-are package as previously described.8

The corrected AGV (cAGV) was calcu-lated by using the following formula:cAGV � AGV/estimated fetal weight. Aspreviously described, the cAGV is a GA-independent parameter.8

Calculation of fetal zone enlargementTo provide proof of concept regardingour proposed methodology, the wholegland and fetal zone dimensions weredetermined by using the volumetricblocks used to calculate the AGV. Thefetal zone was identified in transverse,sagittal, and coronal planes as an echo-genic demarcated area (Figure 1). These3 planes were used to measure the length(L), width (W), and depth (D) of thewhole fetal adrenal gland. Similarly, thefetal zone’s length (l), width (w), anddepth (d) were also measured. L and lwere measured in transverse or sagittalplanes. W and w were measured in trans-

ry interval

Delivery >7 d(n � 47) P valuea

..................................................................................................................

26.2 (6.83) NS..................................................................................................................

1 (0–4) NS..................................................................................................................

NS..................................................................................................................

24 (51)..................................................................................................................

17 (36)..................................................................................................................

4 (9)..................................................................................................................

2 (4)..................................................................................................................

27.4 (3.38) NS..................................................................................................................

18 (39) NS..................................................................................................................

9 (19) .03..................................................................................................................

..................................................................................................................

34.5 (3.96) � .0001..................................................................................................................

) 2225 (786.22) � .0001..................................................................................................................

14 (30) NS..................................................................................................................

33 (70) NS..................................................................................................................

18 (38) � .0001..................................................................................................................

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verse or coronal planes. D and d were


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measured in sagittal or coronal planes.Measurements were obtained in thoseplanes that gave the best definition of tis-sue interfaces.

Three consecutive measurements offetal adrenal gland and fetal zone wereobtained, and the mean of 3 measure-ments were used for final analysis. Therelative size of the fetal zone was calcu-lated for each orthogonal plane by divid-ing the fetal zone dimension by the glanddimension at the widest point (l/L, w/W,and d/D).

The intraobserver coefficients of vari-ation for calculation of the cAGV andfetal zone dimensions were 1.5% and3.5%, respectively.

FIGURE 2Correlation analysis between cAGV

Correlation analysis between cAGV and percentotted lines show 95% confidence intervals. Bla

cAGV, corrected adrenal gland volume for fetal weight.

Turan. Fetal zone enlargement. Am J Obstet Gynecol 2011.

TABLE 2Predictive value of fetal zone dimefor prediction preterm birth within

VariableSensitivity(95% CI)

Spec(95%

l/L �63.8% 85 (66–96) 68 (5...................................................................................................................

w/W �51.9% 74 (54–89) 85 (7...................................................................................................................

d/D �49.7% 100 (87–100) 89 (7...................................................................................................................

CI, confidence interval; d/D, depth of fetal zone/depth of whole gof fetal zone/width of whole gland; �LR, positive likelihood ra



Data analysisThree ultrasound parameters, the cAGV,relative 2D size of the fetal zone, and thelength of the closed portion of the cervix,were related to delivery within 7 days(primary outcome). History of priorPTB, PPROM, tocolytic use, and deliveryoutcome findings were related to eachtest variable.

Normality of data was evaluated withthe Kolmogorov-Smirnov test. Categor-ical variables were analyzed using �2 orFisher’s exact tests as appropriate. Con-tinuous variables were analyzed usingMann-Whitney or student t test accord-ing to their distributions. Pearson corre-lation was used to measure colinearity

d percent change of fetal zone

nge of fetal zone in A, length, B, width, and C,lines represent SDs. Level of statistical significan

on ratiosays

ity�LR (95% CI) �LR (95% CI)

1) 2.7 (2.1–3.4) 0.22 (0.1–0.6)..................................................................................................................

4) 5 (3.9–6.4) 0.3 (0.1–0.8)..................................................................................................................

7) 9.4 (8.5–10.4) 0..................................................................................................................

; l/L, length of fetal zone/length of whole gland; w/W, widthLR, negative likelihood ratio.

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between the selected independent vari-ables as well as other relevant relation-ships between dependent and indepen-dent variables. Predictive cutoff levels foreach test were calculated by receiver op-erator characteristics (ROC) curve anal-ysis and curves were compared to assessthe predictive value of each. Regressionanalysis was used for covariate analysis.SPSS 11 (SPSS Inc, Chicago, IL), Med-Calc (Broekstraat, Belgium), and Excel2007 (Microsoft, Richmond, CA) wereused for analysis.

RESULTSSeventy-four patients at high risk forPTB were recruited for the study. Demo-graphics and clinical and outcome char-acteristics are presented in Table 1. Ofthe women evaluated in this study, 27(36.5%) delivered within 7 days from thetime of our evaluation. As expected,women who gave birth longer than 7days from the time of our evaluationmore frequently had intact membranes,were delivered at a higher GA, and hadbabies of greater birthweight. The ma-jority of women who delivered less than34 weeks GA had a delivery interval less

th. Red central line represents ideal correlation.of each tests were given.

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There was a significant correlation be-tween GA and all 3 dimensions of theadrenal gland fetal zone (l, w, and d)(Pearson correlation R � 0.42, 0.50, and0.54, respectively; P � .001 for all). Sim-larly, we observed a significant correla-ion between GA and the total gland

easurements (L, W, and D) (R� 0.56,.52, and 0.41, respectively; P � .0001 forll). However, there was no relationshipetween GA and the relative dimensionf the adrenal gland fetal zone (R�0.04 for the l/L ratio, 0.07 for the w/W

atio, and 0.12 for the d/D ratio, respec-ively; P � .05 for all).

To determine the best indicator of fe-al zone enlargement, we first correlated

FIGURE 3Correlation analysis between meas

Correlation analysis between measurement-to-dcorrelation. Dotted lines show 95% confidence inevel of statistical significance of each tests wer

cAGV, corrected adrenal gland volume for fetal weight.


TABLE 3Ultrasound examination findings ac

VariableD(

Cervical length, mm, mean (SD)...................................................................................................................

Corrected adrenal gland volume, mm3/kg, mean (SD)

5

...................................................................................................................

Fetal zone enlargement, %, mean (SD)...................................................................................................................

NS, not significant.


he cAGV individually with l/L, w/W,nd d/D ratios. All 3 ratios correlated sig-ificantly with the cAGV (R � 0.53, 053,nd 0.60, respectively; P � .0001 for all)Figure 2). Next, using ROC curve anal-sis, we calculated the predictive perfor-ance of the different ratios for PTBithin 7 days of delivery (Table 2). Bysing ROC curve comparative analysis,e determined that the d/D ratio showed

uperior predictive value compared withhe l/L and w/W ratios (z � 2.49, P �013 and z � 2.08, P � .037, respec-ively). Accordingly, the d/D ratio wassed as a measure of fetal zone enlarge-ent (FZE) and for the remainder of the

nalysis.

ement-to-delivery interval and ultras

ry interval and A, cervical length, B, cAGV, and Cals. Black lines represent SDs. Measurement-to-iven.

rding to delivery interval

ery <7 d27)

Delivery >7 d(n � 47) P value

2 (10.12) 16.6 (12.0) NS..................................................................................................................

3 (214.93) 329.2 (129.17) � .0001

..................................................................................................................

9 (7.12) 40.6 (10.44) � .0001..................................................................................................................

a

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There was a significant correlation be-ween measurement-to-delivery intervalnd cAGV & FZE. On the other hand, CLas not correlated (Figure 3). Cervical

ength measurement were similar amonghe group of women who deliveredithin or longer than 7 days from the

ime of enrollment (17.2 � 10.12 mm vs6.6 �12.0 mm, P � .05). Analysis of theD and 2D shows both AGV and d/Datio were significantly increased in ba-ies born less than 7 days from the timef evaluation (Table 3).Next, we evaluated the relationships

etween CL, cAGV, FZE, and the mea-urement-to-delivery interval. The bestutoffs for predicting birth within 7 daysf evaluation were identified using ROCurve analysis (Figure 4). The sensitivity,pecificity, �LR, �LR, and relative riskf CL, cAGV, and FZE are listed in Table. A key finding of our analysis was thathe cAGV and FZE were superior to CL

easurement in prediction of PTB (z �.40, P � .001 and z � 5.22, P � .0001).here was no significant difference be-

ween 3D gland volumes and 2D d/D ra-io (z � 1.87, P � .05). The comparative

nd examination findings

tal zone depth. Red central line represents idealery interval was transferred to logarithmic scale.

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elive , feterv delive g

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nalysis for the CL, cAGV, and FZE ac-


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cording to the scan to delivery interval isshown in Figure 5.

Finally, we used multiple regressionanalysis to evaluate relationship betweenFZE, measurement-to-delivery interval,and clinical variables such as history ofPTB, PPROM, and tocolytic use. Theseshow that the cAGV (P � .0001) and thed/D ratio (P � .0001) were independent

redictors of PTB within 7 days of eval-ation. All the listed variables were ex-luded from the model (P � .05 for all).

COMMENTOur results suggest that ultrasound ex-amination of fetal adrenal gland and as-

FIGURE 4Receiver operating characteristic c

Receiver operating characteristic curve for the aenlargement to predict a delivery within 7 days ocAGV, corrected adrenal gland volume for fetal weight.


sessment of FZE at time of evaluation for


symptoms of PTL may be clinically ben-eficial. High sensitivity and specificity ofthis method will help to accurately definethe actual population at risk. This willallow us to implement better therapeuticand preventive interventions. For exam-ple, in the absence of intraamniotic in-fection and enlargement of fetal adrenalgland zone, unnecessary therapies (ste-roid, tocolytics, cervical cerclage) may bewithheld. However, more research is stillnecessary.

One of the aims of this study was toprovide the proof of concept that 3D and2D evaluation of the fetal adrenal glandare equivalent in their ability to predict

es

y of cervical length, cAGV, and fetal zone depthe initial ultrasound evaluation.

PTB. As a result, several limitations were r

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inherent. For example, the measure-ments of the fetal adrenal gland and thatof the fetal zone were performed in thealready-acquired 3D blocks. Furtherstudies remain to determine whether themultiplanar evaluation of the fetal adre-nal gland is possible and retains its highaccuracy when the regular ultrasoundequipment is used. Lastly, our findingsneed to be confirmed in a larger cohortof patients at low and high risk of PTB.

It is not unusual for women to presentwith symptoms of PTL. Still, their out-come is frequently normal.13-16 In thebsence of a reliable and accurate bio-arker of PTB, a lot of attention was

ocused on CL. This is because signifi-ant shortening of the cervix is associ-ted with an increased risk of PTB inoth nulliparous and parous women.17

Given the easiness of the ultrasoundtechnique, evaluation of the uterine cer-vix has been widely incorporated intoour routine clinical practice. Yet CLmeasurement before 1518 or after 32

eeks19 do not appear to be an accuratepredictor of PTB because they are poorindicators. Nevertheless, although ashort cervix suggests an increased risk ofPTB, this clinical marker is not a goodpredictor of the measurement-to-deliv-ery interval.20

The functional role of the fetal zone isto synthesize steroid precursors that aretransformed by the placenta to produceestrogens.21 Therefore, it makes sense to

ropose that the relationship betweenTB and an enlarged fetal zone may beelated to the important role played byhis organ in the endocrine regulation ofarturition.22-25 Evaluation of the fetal

AGV and size is a unique departure fromprior clinical approaches because it fo-cuses on the fetus rather than on themother.26 Our group provided the firstvidence that 3D ultrasound volumetryf the fetal adrenal gland accurately pre-icts impending PTB.8 However, the ex-ertise required for 3D ultrasonographicechnique and the focus of our researchn the entire adrenal gland rather thann the functionally relevant fetal zoneere important drawbacks for imple-entation of this methodology in the

urv

bilitf th

outine clinical practice.

1.


This study provides a simpler alterna-tive. That is, the 2D measurement of thefetal adrenal gland zone is as reliable asthe cAGV and better than CL in predict-ing PTB within 7 days of the onset ofsymptoms. Measurement of our adrenalgland parameters was possible within ac-ceptable variability. This finding is en-couraging and argues for the clinical ap-plicability of the method.

In our high-risk study population, al-most 80% of the women delivered lessthan 37 weeks of gestation. The depth ofthe fetal zone appeared to contributemost to the increase in the AGV. Thehigh predictive value of the FZE seems tobe independent of traditional risk factorssuch as a history of prior PTB and

FIGURE 5Graphic representation of the perfo

Graphic representation of the performance of A,of evaluation. Level of statistical significance of ein patients who delivered within 7 days or after 7cAGV, corrected adrenal gland volume for fetal weight; ROC, rece


TABLE 4Predictive value of ultrasound para

Variable

Cervical length �16 mm...................................................................................................................

Corrected adrenal gland volume �420 mm3/k...................................................................................................................

Fetal zone enlargement �49.7%...................................................................................................................

CI, confidence interval; �LR, positive likelihood ratio; �LR, n

Turan. Fetal zone enlargement. Am J Obstet Gynecol 201

PPROM. In addition, because it can beconcluded from our multivariate analy-sis, tocolytic therapy appears to be inef-fective in the presence of an enlarged fe-tal zone.

The structure of the human fetal adrenalgland is significantly different from itsadult counterpart. In utero the fetal zone isthe most prominent and distinctive por-tion of the adrenal gland. Consequently,the fetal zone occupies the majority of theadrenal gland size. The fetal adrenal glandundergoes significant growth because ofan increase in the fetal zone size so that by18 weeks of gestation, the gland is almost aslarge as the kidney. The fetal zone contin-ues to enlarge, particularly during the last 6weeks of gestation.27

ance of individual test in predicting

ical length, B, cAGV, and C, fetal zone depth intests were given. Red dotted lines represents ROys. Fetal zone depth was above the cutoff in all

operator characteristics.

ters for identification of women at r

Sensitivity (95% CI) Specificity (95

56 (35–75) 60 (44–74).........................................................................................................................

81 (62–94) 87 (74–95).........................................................................................................................

100 (87–100) 89 (77–97).........................................................................................................................

ve likelihood ratio.

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Our study confirms that the dimen-sions of the fetal adrenal gland and fe-tal zone increases with GA as a part ofthe physiological development. How-ever, despite this increase, the propor-tion of the gland occupied by the fetalzone remains constant throughoutgestation in all dimensions. This facil-itates the distinction between an ab-normal hypertrophy of fetal zone and aphysiologic increase in its size that is inlinear relationship with the remainderof the gland. Therefore, it is reasonableto propose that a disproportionate in-crease in size of the adrenal gland en-ables for recognition of the prematureactivation of the parturition cascade ina noninvasive fashion.

term birth

icting preterm birth within 7 days from the timederived cutoffs. Cervical length was not differentients who were delivered within 7 days.

for preterm birth

I) �LR (95% CI) 1LR (95% CI)

1.4 (0.9–2.1) 0.8 (0.4–1.3)..................................................................................................................

6.4 (5.2–7.9) 0.2 (0.07–0.6)..................................................................................................................

9.4 (8.5–10.4) 0..................................................................................................................

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The American Congress of Obstetricianand Gynecologists is currently recom-mending 2 tests for the prediction of PTB,ultrasound measurement of the CL, andfetal fibronectin.28 However, the use of fe-al fibronectin in PPROM patients is prob-ematic, given the high false-positive rate ofhis test in this particular clinical setting.29

In our study population, one-third of thepatients had PPROM. Therefore, for ouranalysis, the results of the fetal fibronectintests were not used.

Cervical length did not correlate with

FIGURE 6Graphic representation of the relat

The X axis represents fetal zone enlargement for ehan 49.7% labeled as high risk for PTB and lessellow vertical box represents delivery within 7 das represented with black-filled circles. C, Pati

FZE, fetal zone enlargement; PPROM, preterm premature rupture


the measurement-to-delivery interval. w


These findings were compatible with arecent Cochrane systematic review.30 A

ey finding of this analysis was that theres insufficient evidence to recommendoutine screening of asymptomatic orymptomatic pregnant women with CL

easurement. The authors also con-luded that there is a nonsignificant as-ociation between knowledge of CL re-ults and a lower incidence of PTB at lesshan 37 weeks in symptomatic women.

An important finding of our study washat FZE predicted PTB independent of

between secondary outcomes and F

graph. Red dotted line shows ROC curve derivedn 49.7% showed as low risk for PTB. The Y axi. A, Patients with a history of prior PTB were mas who received tocolytic treatment were shown wembranes; PTB, preterm birth; ROC, receiver operator character

ell-recognized risk factors of prematu- t

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ity. It is well known that a history ofrior PTB is a risk factor for a prematureelivery.31 Evidence in support of our as-

sertion comes from studies that showedthat the probability of PTB before 37weeks increases up to 64% if the patienthas a history of prior PTB.32 In that anal-sis, a positive fetal fibronectin result andCL less than 25 mm had significant ad-itive predictive value. In our high-risktudy population, a prior PTB historyid not predict the patients who will de-

iver within 7 days. This was in contrast

off levels for FZE (49.7%). Fetal zone depth moreows measurement to delivery interval in weeks.d as black-filled circles. B, Presence of PPROMblack-filled circles.

.

ion ZE

ach cuttha s sh

ays rkeent ithof m istics

o the increase in fetal zone, which suc-

efleitdril

lsctIttlsvta

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cessfully stratified risk (Figure 6, A).Such findings should be expected, giventhat enlargement of the fetal zone reflectsan acute activation of the parturitionmachinery. In contrast, the role of ge-netic risk factors in prematurity is highlydependent on gene-gene and gene-envi-ronment interactions, which may notoccur.

Prediction of latency period in pa-tients with PPROM continues to be aclinical dilemma in the absence of overtintrauterine infection. Reports in the lit-erature regarding CL measurement andcorrelation with duration of latency pe-riod show conflicting results.33,34 Differ-nt inflammation markers in amnioticuid were used for prediction of deliv-ry, but these tests requires invasive test-ng.35, 36 In our PPROM group, all pa-ients who had an enlarged fetal zoneelivered within 7 days. The latency pe-iod was prolonged to as long as 14 weeksf the fetal zone was within the normalimits (Figure 6, B).

The role of tocolytic treatment in pro-onging pregnancy is at best controver-ial. Despite significant research efforts,linicians cannot predict in which pa-ients therapy is going to succeed or fail.n our high-risk population, we foundhat patients delivered within 7 days ifhe fetal zone is enlarged despite toco-ytic treatment (Figure 6, C). These ob-ervations confirm that the predictivealue of the FZE is independent fromhat of the clinical circumstances associ-ted with PTB.

In conclusion, 2D ultrasound evalua-ion of the fetal zone is a noninvasive clin-cal tool, which holds promise to changehe clinical practice and management ofTB. Two-dimensional measurement of

he depth of the adrenal fetal zone offershe potential to accurately predict PTBithin 7 days. This prediction is equal to

he more complex 3D volume measure-ent. Enlargement of the fetal zone ap-

ears to be superior to the CL measure-ent for prediction of PTB, and its value

eems to be independent of several majorlinical circumstances. f

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