American College of Obstetricians and Gynecologists

Bjorn Winkens

BM Mercer

DJB Barker

DO Mook-Kanamori

GCS Smith

HGK Blaas

J Gardosi

KH Nicolaides

Marc Prudon

NAC Smeets

Nicol AC Smeets

NJ Raine-Fenning

O Falcon

R Aviram

R Bukowski

RE Behrman

S Guid Oei

WP Martins

BMC Pregnancy and Childbirth

English

Crossref

Smeets et al. BMC Pregnancy and Childbirth 2012, 12:38http://www.biomedcentral.com/1471-2393/12/38STUDY PROTOCOL Open AccessFetal volume measurements with threedimensional ultrasound in the first trimester ofpregnancy, related to pregnancy outcome, aprospective cohort studyNicol AC Smeets1*, Marc Prudon2, Bjorn Winkens3 and S Guid Oei4,5AbstractBackground: First trimester growth restriction is associated with an increased risk of adverse birth outcomes (pretermbirth, low birth weight and small for gestational age at birth). The differences between normal and abnormal growth inearly pregnancy are small if the fetal size is measured by the crown-rump-length. Three-dimensional ultrasound volumemeasurements might give more information about fetal development than two-dimensional ultrasound measurements.Detection of the fetus with a small fetal volume might result in earlier detection of high risk pregnancies and a betterselection of high risk pregnancies.Methods: A prospective cohort study, performed at the Máxima Medical Centre, in Eindhoven-Veldhoven, the Netherlands.During the routine first trimester scan with nuchal translucency measurement 500 fetal volumes will be obtained. Thegestational age is based on the first day of the last menstrual period in a regular menstrual cycle and by the crown-rump-length. The acquired datasets are collected and stored on a hard disk for offline processing and volume calculation. Theinvestigator who performs the volume measurements is blinded for the results of the first trimester scan. The manualmode will be used to outline the Region Of Interest, the fetal head and rump, in all cross sections. The fetal volumes arecalculated with a rotational step of 9°.First, the relation between fetal volume and gestational age, for a set of participants with normal pregnancies (training set),will be assessed. This model will then be used to determine expected values of fetal volume for a normal pregnancy,which will be referred to as expected normal values. Secondly, for a new set of participants with normal pregnancies and aset of participants with complicated pregnancies (together defined as validation set), the observed fetal volumes (FVobserved)are compared with their expected normal values (FVexpected) and expressed as a percentage of the expected normal value.The mean difference in percentage error between the set of normal versus complicated pregnancies will then becompared using the independent-samples t-test. Finally, logistic regression analysis will be applied to the validation set ofparticipants to analyze the possibility of predicting the pregnancy outcome after fetal volume calculation in the firsttrimester, using this percentage error.Discussion: After this study it is clear whether FV measurement in the first trimester can detect high risk pregnancies. If it ispossible to detect these pregnancies, more intensive follow up in these pregnancies might result in fewer complicatedpregnancies and fewer fetal morbidities.* Correspondence: n.smeets@atriummc.nl1Department of Gynecology and Obstetrics, Atrium Medical Centre, Parkstad,Henri Dunantstraat 5, Heerlen, 6401 CX, The NetherlandsFull list of author information is available at the end of the article© 2012 Smeets et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.Smeets et al. BMC Pregnancy and Childbirth 2012, 12:38 Page 2 of 4http://www.biomedcentral.com/1471-2393/12/38BackgroundPreterm birth is a growing public health problem that hassignificant consequences for families. Preterm birthaccounts for 12.5% of all births in the United States. Thecosts for society are at least $26 billion dollar a year [1].Low birth weight (<2500 g) and birth weight that is smallfor gestational age (SGA) are associated with increasedmorbidity and mortality perinatal and in later life [2].There is a growing body of evidence that complica-tions in pregnancy are the result of the intra-uterineconditions in the first trimester of pregnancy. Monitor-ing fetal growth during the first trimester of pregnancyis expected to be of significant value in assessing compli-cations in pregnancy. Smith et al. was the first to reportabout the relationship between first trimester fetal two-dimensional ultrasound (2DUS) measurements in rela-tion to an increased risk of preterm birth, a low birthweight or being small for gestational age (SGA) at birth[3]. Bukowski et al. confirmed the relation between slowgrowth in the first trimester of pregnancy and a lowbirth weight [4]. These pregnancies were a result ofassisted reproductive technologies excluding delayedovulation as an explanation for the findings. They alsoreport that a delayed implantation would result in alonger duration of pregnancy. However they found theopposite association, confirming that the delayed im-plantation could not explain the observed associations[4]. Mook-Kanamori et al. recently confirmed these earl-ier reports. They reported that fetal growth below the20th percentile in the first trimester of pregnancy is asso-ciated with an increased risk of adverse birth outcomessuch as preterm birth, low birth weight and SGA [5].The differences between normal and abnormal growth inearly pregnancy are small if the fetal size is measured bythe crown-rump-length (CRL). There are several differentdefinitions used in earlier reports for small fetal size in thefirst trimester in relation to complicated pregnancies. Ab-normal growth is calculated as a difference in expected fetalsize (according to the last menstrual period) minus the cal-culated fetal size by ultrasound (CRL/BPD) in days, rangingfrom −1 to −8-10 days [3,6,7]. The weakness of all theseresults is the low positive predictive value, therefore it isnot a good screening test in order to select the high riskpregnancies.Three-dimensional ultrasound (3DUS) volume measure-ments might give more information about fetal developmentthan 2DUS measurements. Fetal volume (FV) measure-ments were subject of earlier studies, where the volumemeasurements proved to be reliable and reproducible [8,9],even in twins [10,11]. A significant correlation between FVand the crown-rump-length (CRL) is already confirmed,with an up to 35-fold increase of the FV and a 4.5-fold in-crease of the CRL in the first trimester of pregnancy [8-10,12,13]. As the FV rises 7 times faster than the CRL, it canbe expected that slight abnormalities in the CRL will bemore obvious in FV measurements. Falcon et al. reportedthat the chromosomal abnormal fetus has a significant smal-ler FV than the chromosomal normal fetus whereas theCRL in trisomy 21 and Turner syndrome were normal[9,13]. These findings suggest that it is possible to detectearly growth impairment with FV measurements, in caseswith a normal CRL. Detection of the fetus with a small FVmight result in earlier detection of high risk pregnanciesA longitudinal follow up study is necessary in order toobtain this knowledge.The objective of this study is to determine whether itis possible to detect a fetus at risk for preterm birth and/or low birth weight for gestational age by measuring thefetal volume with three-dimensional ultrasound in thefirst trimester of pregnancy.MethodsThis is a prospective cohort study, performed at theMáxima Medical Centre, a teaching hospital in Eindho-ven-Veldhoven, the Netherlands.Recruitment500 Participants who have an appointment for the rou-tine first trimester ultrasound scan with nuchal translu-cency measurement are asked to participate in thisstudy. Inclusion criteria: Singleton pregnancy, age> 18years, gestational age between 11+0 and 13+6 weeks. Ex-clusion criteria: Multiple pregnancy and an uncertaingestational age. An uncertain gestational age is definedas an unknown date of the first day of the last menstrualperiod and a varying or unknown length of the men-strual cycle. Participants are included after signing aninformed consent form. Each participant fills out a ques-tionnaire about their general and obstetric history. Theparticipant fills another questionnaire after the delivery.The participants are referred from other surroundinghospitals and midwives for the first trimester ultrasoundscan and the nuchal translucency measurement, there-fore this is a low risk population.Fetal imagingThe Kretz Voluson 730 3D ultrasound scanner (GeneralElectrics Kretz, Zipf, Austria) is used with the RAB4-8Pwide band convex volume probe, a real time 4D-broad-band electronic curved-array transducer with a fre-quency range of 4–8 MHz. The angle sweep is 750. Thethree-dimensional volumes are acquired during thestandard abdominal first trimester scan by an investiga-tor certified for nuchal translucency (NT) measure-ments. The gestational age is established by menstrualdates and confirmed by routine fetal biometry.For volume acquisition the fetus has to be motionlessduring scanning.Smeets et al. BMC Pregnancy and Childbirth 2012, 12:38 Page 3 of 4http://www.biomedcentral.com/1471-2393/12/38Data acquisitionThe routine first trimester (abdominal) ultrasound scanand NT-measurement are performed according to inter-national guidelines [14,15]. 3D ViewTM (General Electron-ics, Sonoview II) is used to receive, store digitally andmeasure the fetal volumes from the 3DUS-datasets. Afterobtaining the ideal (midsagittal) plane for NT-measure-ment, an automatic 3DUS sweep is performed, which con-sists of multiplanar and surface reconstruction modes.The acquired datasets are collected and stored on a harddisk for offline processing and volume calculation. The in-vestigator who performs the volume measurements isblinded for the results of the first trimester scan.The VOCAL imaging software (an extension of 3DViewTM) consists of several available modes for volume cal-culations, the “manual mode” is most frequently used. Thismode is more flexible as it employs to manually define thecontours of the object of interest with a computer mouse.As the human embryo has an irregular shape, the manualmode will be used to outline the Region Of Interest (ROI),the fetal head and rump, in all cross sections. It is not pos-sible to include the fetal extremities in these measurements,because the software does not allow to define separatestructures in one cross section. Therefore the ROI has toconsist of one continuous object in every cross section.This method was also used by Falcon et al. [9,13].With VOCAL it is possible to use four different rota-tional steps that define the angle through which the ob-ject of interest is rotated. These steps are 6°, 9°, 15° or30°, which results in respectively 30, 20, 12 or 6 crosssections for each volume measurement, as the dataset isrotated 1800 to complete one volume measurement.The fetal volumes are calculated with a rotational stepof 9° in the A(axial)-plane, which is a longitudinal plane.Figure 1 An image of a fetal volume reconstruction.This 9° rotation is to be preferred in irregular objects, asit is as reliable as the 6° rotation, but significantly fasterto perform [16].The 9° rotational step results in a sequence of 20 lon-gitudinal sections of the fetus around a fixed axis. Ineach of these planes the two-dimensional (2D) contourof the fetus (excluding the limbs) is defined manually, asdescribed by others [10,11,13]. The VOCAL programthen calculates the volume of the defined contour. Aftercalculation the computed reconstruction of the fetus isdisplayed together with the fetal volume (Figure 1).There can be an undulating surface of the 3D image,which is caused by the rotational steps and representsthe ROI’s in each measured plane. We have previouslyreported that the inter- and intraobserver agreement offetal volume measurements by 3DUS is very high [17].Statistical analysisFirst, for a set of participants with normal pregnancies(training set), the relation between fetal volume and gesta-tional age (GA) will be assessed using multiple linear re-gression. The influence of fetal gender and parity will beobserved, if needed different training sets will be generated.This model will then be used to determine expected valuesof fetal volume for a normal pregnancy, which will be re-ferred to as expected normal values. Secondly, for a new setof participants with normal pregnancies and a set of partici-pants with complicated pregnancies (together defined asvalidation set), the observed fetal volumes (FVobserved) arecompared with their expected normal values (FVexpected)and expressed as a percentage of the expected normalvalue, i.e. percentage error = 100% * (FVobserved –FVexpected)/FVexpected. The mean difference in percentageerror between the set of normal versus complicatedSmeets et al. BMC Pregnancy and Childbirth 2012, 12:38 Page 4 of 4http://www.biomedcentral.com/1471-2393/12/38pregnancies will then be compared using the independent-samples t-test. Finally, logistic regression analysis will beapplied to the validation set of participants to analyze thepossibility of predicting the pregnancy outcome after fetalvolume calculation in the first trimester, using this percent-age error. For the statistical analysis SPSSTM (ChicagoIllinois, USA) version 18.0 for Windows will be used. Atwo-sided p-value≤0.05 is considered statistically signifi-cant. As we use a smaller rotational angle, there might be adifference with the results of Falcon et al. [9].Sample sizeAt the routine first trimester scan with nuchal translucencymeasurement, 500 fetal volumes will be measured. 50% ofthese volumes (n=250) will be used as the training set andthe other 50% as the validation set. Since it was expectedthat at least 10% of all pregnancies will be complicated bypre-term delivery or a low birth weight for gestational age,the validation set consists of 50 complicated pregnanciesand 200 normal pregnancies. Based on the independent-samples t-test to compare the mean percentage error be-tween complicated and normal pregnancies, these samplesizes are sufficient to detect a medium standardized effectsize (Cohen’s d=0.5) with sufficient power (80%) using asignificance level of 5% and accounting for 10-20% lost tofollow up.The protocol is approved by the hospital’s medical eth-ics committee and informed consent will be obtainedprior to inclusion in this study.DiscussionAfter this study it is clear whether FV measurement inthe first trimester can detect high risk pregnancies. If itis possible to detect these pregnancies, more intensivefollow up in these pregnancies might result in less com-plicated pregnancies and less fetal morbidity.We expect to perform measurements in a normalpopulation. Based on the definition of SGA, it is to beexpected that 50 fetuses will be SGA (10%), and 62 de-liveries will be preterm (12,5%).SummaryThis study is designed to provide information onwhether FV volume measurements with three-dimen-sional ultrasound in the first trimester of pregnancy canbe helpful in selecting high risk pregnancies.Competing interestThe authors declare that they have no competing interests.Author details1Department of Gynecology and Obstetrics, Atrium Medical Centre, Parkstad,Henri Dunantstraat 5, Heerlen, 6401 CX, The Netherlands. 2Department ofGeneral Practice, University of Maastricht, Maastricht, The Netherlands.3Department of Methodology and Statistics, University of Maastricht,Maastricht, The Netherlands. 4Department of Gynecology and Obstetrics,Máxima Medical Centre, Eindhoven-Veldhoven, The Netherlands.5Department of Electrical Engineering, Eindhoven University of Technology,Eindhoven, The Netherlands.Authors’ contributionsNS and SO designed the study with input from MP and BW. NS, MP, BW andSO drafted the manuscript. NS, MP, BW and SO produced the detailedworking protocol. All authors read and approved the final manuscript.Received: 3 May 2011 Accepted: 28 May 2012Published: 28 May 2012References1. Behrman RE, Stith Butler A: Committee on Understanding Premature Birth andAssuring Healthy Outcomes. Preterm birth: Causes, consequences, andprevention. Washington, D.C: National Academies Press; 2007.2. Barker DJB: Adult consequences of fetal growht restriction. Clin ObstetGynecol 2006, 49:270–283.3. Smith GCS, Smith MFS, McNay MB, Fleming JEE: First-trimester growth andthe risk of low birth weight. N Engl J Med 1998, 339:1817–1822.4. Bukowski R, Smith GCS, Malone FD, Ball RH, Nyberg DA, Comstock CH,Hankins GDV, Berkowitz RL, Gross SJ, Dugoff L, Craigo SD, Timor-Tritsch IE,Carr SR, Wolfe HM, D’Alton ME: Fetal growth in early pregnancy and riskof delivering low birth weight infant: prospective cohort study. BMJ 2007,doi:10.1136/bmj.39129.637917. AE.5. Mook-Kanamori DO, Steegers EAP, Eilers PH, Raat H, Hofman A, JaddoeVWV: Risk factors and outcomes associated with first-trimester fetalgrowth restriction. JAMA 2010, 303:527–534.6. Gardosi J, Francis A: Early pregnancy predictors of preterm birth: the role ofa prolonged menstruation-conception interval. BJOG 2000, 107:228–237.7. Mercer BM, Merlino AA, Milluzzi CJ, Moore JJ: Small fetal size before 20weeks’ gestation: associations with maternal tobacco use, early pretermbirth, and low birthweight. Am J Obstet Gynecol 2008, 198:673. e1-673.e8.8. Blaas HGK, Taipale P, Torp H, Eik-Nes SH: Three-dimensional ultrasoundvolume calculations of human embryos and young fetuses: a study onthe volumetry of compound structures and its reproducibility. UltrasoundObstet Gynecol 2006, 27:640–646.9. Falcon O, Peralta CFA, Cavoretto P, Auer M, Nicolaides KH: Fetal trunk andhead volume in chromosomally abnormal fetuses at 11+0 to 13+6weeks of gestation. Ultrasound Obstet Gynecol 2005, 26:517–520.10. Martins WP, Ferriani RA, Nastri CO, Filho FM: First trimester fetal volumeand crown-rump length: Comparison betweens singletons and twinsconceived by in vitro fertilization. Ultrasound Med Biol 2008, 34:1360–1364.11. Martins WP, Nastri CO, Barra DA, Navarro PAAS, Filho FM, Ferriani RA: Fetalvolume and crown-rump length from 7 to 10 weeks of gestational agein singletons and twins. Eur J Obstet Gynecol Reprod Biol 2009, 145:32–35.12. Aviram R, Kamar Shpan D, Markovitch O, Fisherman A, Tepper R: Three-dimensional first trimester fetal volumetry; comparison with crown rumplength. Early Hum Dev 2004, 80:1–5.13. Falcon O, Peralta CF, Cavoretto P, Faiola S, Nicolaides KH: Fetal trunk andhead volume measured by three-dimensional ultrasound at 11+0 to 13+6 weeks of gestation in chromosomally normal pregnancies. UltrasoundObstet Gynecol 2005, 26:263–266.14. Nicolaides KH: The 11-13+6 weeks scan. London: The Fetal MedicineFoundation; 2004.15. American College of Obstetricians and Gynecologists: ACOG PracticeBulletin No. 101: Ultrasonography in pregnancy. Obstet Gynecol 2009,113:451–461.16. Raine-Fenning NJ, Clewes JS, Kendall NR, Bunkheila AK, Campbell BK,Johnson IR: The interobserver reliability and validity of volumecalculation from three-dimensional ultrasounds datasets in the in vitrosetting. Ultrasound Obstet Gynecol 2003, 21:283–291.17. Smeets NAC, van de Ven J, Oei SG: Inter- and intraobserver variation offetal volume measurements with three-dimensional ultrasound in thefirst trimester of pregnancy. J Perinat Med 2011, 39:539–543.doi:10.1186/1471-2393-12-38Cite this article as: Smeets et al.: Fetal volume measurements with threedimensional ultrasound in the first trimester of pregnancy, related topregnancy outcome, a prospective cohort study. BMC Pregnancy andChildbirth 2012 12:38.

Fetal volume measurements with three dimensional ultrasound in the first trimester of pregnancy, related to pregnancy outcome, a prospective cohort study

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Fetal volume measurements with three dimensional ultrasound in the first trimester of pregnancy, related to pregnancy outcome, a prospective cohort study

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