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Ultrasound Obstet Gynecol2003;21: 18Published online in Wiley InterScience (www.interscience.wiley.com).DOI:10.1002/uog.21

Editorial

Integrated fetal testing in growth

restriction: combining multivessel Dopplerand biophysical parameters

A. A. BASCHAT

Center for Advanced Fetal Care, Department of Obstetrics,Gynecology and Reproductive Sciences, University of Maryland,405 West Redwood Street, 4th Floor, Baltimore, MD 21201-1703,USA (e-mail: [email protected])

A N T E N A T A L S U R V E I L L A N C E I N F E T A LG R O W T H R E S T R I C T I O N : A S C R E E N I N GT O O L F O R C O M P R O M I S E

The assessment of fetal growth, development andhealth are considered standard care in most societies.Surveillance has been applied to pregnancies complicatedby intrauterine growth restriction (IUGR) to improvefetal outcome. But antenatal fetal surveillance is evolving.It is no longer adequate to act only at the lastmoment to prevent fetal mortality. Rather, we aim toidentify critical risk factors and improve outcome bydirecting appropriately timed intervention. And it is

the timing of intervention that is perhaps the greatestchallenge. This process is complicated by incompleteknowledge of what actually damages the fetus priorto causing death chronic hypoxemia, acidemia, or acombination of both and the impact of gestationalage on fetal responses to hypoxic stress. Based on ourcurrent understanding of fetal deterioration our focuslies on screening for fetal responses to compromisedoxygenation.

The criteria for a successful screening test are welldefined. The targeted condition must be an importanthealth problem at least 80% of the population shouldbe at risk. The epidemiology, natural history and diseasespectrum must be well delineated. There must be anidentifiable early stage with a sufficiently long latent phaseto allow intervention, which will change outcome. Theemployed tests should be simple, precise and applicable tothe target population. The tests should be well validatedwith a known distribution of results and a suitable cut-offlevel to identify pre-disease. If a screening policy is tobe finalized, there should be evidence from high-qualityrandomized controlled trials that the screening programis clinically, financially, socially and ethically acceptableand is effective in reducing morbidity or mortality. Andthere should be a plan for managing and monitoring the

screening program and an agreed set of quality assurancestandards. These criteria have yet to be fulfilled for anytest of fetal well-being.

Cardiotocography (CTG), Doppler and biophysicalprofile score (BPS) are the principal antenatal testingmodalities. These have predominantly been compared intheir ability to predict fetal compromise and optimize thetiming of intervention1,2. However, the prognostic anddiagnostic information gained in each testing modality isin great part independent of each other. The question thatI will address here is: might it be better to combine, orintegratethese modalities3?

T H E N A T U R A L H I S T O R Y O F F E T A LG R O W T H R E S T R I C T I O N D U E T OP L A C E N T A L I N S U F F I C I E N C Y

We have no accurate estimate of the impact of IUGR sincethe effects of this condition extend from fetal life all theway into adulthood4. The interactions between maternal,placental and fetal factors in the regulation of growthand development are complex. While the impact of thesefactors on long- and short-term outcome is still underinvestigation, considerable insight into natural diseasehistory in fetal life has been gathered.

Abnormal villous development and/or trophoblast

invasion compromises fetal nutrient and waste exchangeand causes disturbed placental blood flow dynamics.This condition may manifest as overt abnormalities of

Copyright 2003 ISUOG. Published by John Wiley & Sons, Ltd. EDITORIAL


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blood flow in fetoplacental and uterine vessels, fetalgrowth restriction, abnormal fetal behavior, abnormalfetal heart rate patterns, a decline in amniotic fluidproduction, or a variable combination of the above.Once a discrepancy between placental supply and fetaldemand is established, there are several possibilities. If

placental disease precludes fetal growth and development,stillbirth occurs. If placental disease is less severe andsurvival is made possible through a series of adaptations,the price may be long-term dysfunction. If placentaldisease is very mild, growth and development may stillbe perceived to be normal but fall short of the geneticallydetermined potential. Decompensation may occur at anytime, triggered by aggravation of the maternal, placentalor fetal condition, or by the stress of labor. Irrespectiveof intervention the fetus remains at risk for additionaldamage and stillbirth. A variety of cardiovascular andcentral nervous system (CNS) responses to placentalinsufficiency have been described.

F E T A L V A S C U L A R A N D B I O P H Y S I C A LR E S P O N S E S I N P L A C E N T A LI N S U F F I C I E N C Y

Evidence of abnormal placentation may be found inthe uterine circulation as elevation of the Dopplerresistance index or persistence of an early diastolicnotch5. In the umbilical circulation, end-diastolic velocitymay be normal, decreased, absent or reversed (A/REDV)proportional to the degree of villous vascular damage6.

Elevated placental blood flow resistance favors redis-tribution of cardiac output towards vital organs7. Thismay be apparent through increased aortic blood flowimpedance8, a decrease in the ratio of cerebral to placen-tal Doppler indices (cerebroplacental ratio = CPR)9 or adecline in amniotic fluid volume10 as a sign of decreasedrenal perfusion. With fetal perception of hypoxemia addi-tional vascular responses such as brain sparing may beinvoked to enhance local perfusion11,12. Although oftenused interchangeably, redistribution (umbilical arteryA/REDV), centralization (low CPR) and brain sparingappear to be different vascular responses. While the CPRis almost always abnormal in fetuses with overtly abnor-mal umbilical artery flow, brain sparing may developindependently of the umbilical artery waveform1315.

A number of changes in fetal biophysical variablesare observed with chronic placental dysfunction. Thesemay reflect abnormal maturation of brainstem reflexes,chronic hypoxemia, redistribution of cardiac output or acombination of these. Autonomic reflexes superimposedon the intrinsic cardiac activity determine fetal heart rate.These reflexes originate from the brainstem and may bemodulated through incorporation of signals from highercenters, the reticular activating system and peripheralsensory inputs. Variations of the heart rate and episodic

accelerations coupled to fetal movement are indicativeof normal functioning of these connections. Conversely,lack of normalheart rate mayrepresenthypoxia-mediated

effects on the regulatory centers, decreased overall globalfetal activity or delayed development of reactivity1620.

When the physiological responses to hypoxia becomeexhaustedthefetus cannotadapt anyfurther. Fetal decom-pensation may be associated with several findings. Thereis a decline in forward cardiac function21, associated with

an increase in venous Doppler indices

2224

. Deregulationof cardiovascular homeostasis may be seen (normaliza-tion of cerebral Doppler indices25,26) and assessment ofthe arterial circulation becomes a less reliable index ofcompromise. Following a decline in global fetal activity,fetal breathing movement, body movements and tone maybe lost18,27. The development of overtly abnormal fetalheart rate patterns appears to be related to a significantworsening of cardiac dysfunction as a result of worseninghypoxemia2830.

It is apparent that the clinical presentation and diseasespectrum of IUGR is variable reflecting the diverse patho-physiology. Several authors have suggested a sequence of

deterioration that is evident on various antenatal surveil-lance tests. Abnormal umbilical artery flow, CPR andbrain sparing are early circulatory abnormalities10,31,32.Oligohydramnios, loss of fetal tone and or movement,abnormal venous flow and overt heart rate decelera-tions are typically late changes10,26,27,33. Yet such arigid classification does not take into account individ-ual variations in responses, the impact of gestationalage, inconsistent relationships between circulatory andbiophysical deterioration and the differential effects thatsudden alterations in maternal status may have on fetaltesting variables3,27,3436. There is no uniform agreement

on the relationship between computerized fetal heart ratechanges and venous Doppler abnormalities33,37. Stud-ies by Hecher and Ferrazzi suggest that only 50% offetuses with abnormal computerized CTG (cCTG) maydevelop abnormal venous indices10,33. It is apparent,however, that arterial Doppler abnormalities identify aprodrome of fetal disease when the decline in biophys-ical variables is subtle and predominantly evident oncomputerized analysis. In the preterm fetus, deteriorationof circulatory and biophysical status occurs in a closetemporal relationship27. Because subtle Doppler findingsare more common this relationship may not hold nearterm10,3840. In contrast, the loss in biophysical variableswith metabolic deterioration is largely independent of thegestational age41.

RELATIONSHIP BETWEEN NON-INVASIVEA N T E N A T A L T E S T S A N D F E T A L A C I D B A S E B A L A N C E

Absence of umbilical artery end-diastolic velocitiesindicates a significant villous abnormality. However,the relationship between placental pathology and fetalacidemia is inconsistent both at cordocentesis and

birth28,4245. Brain sparing, elevation in thoracic andabdominal aortic pulsatility index (PI) and an abnormalCPR are all associated with a decrease in fetal pO2and

Copyright 2003 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol2003;21: 18.


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a median decrease of the pH of two standard deviations(2 SD)4648.

An elevation in precordial venous indices (inferiorvena cava and ductus venosus) has to date providedthe most consistent relationship with a significant declinein umbilical venous pH (4 SD) in IUGR fetuses4850.Based on receiveroperating curve (ROC) statistics with abackground acidemia rateof41.5% and 52.8%,use of theinferior vena cava percentage reverse flow or the preloadindex provides sensitivities for the prediction of fetalacidemia ranging from 73.5% to 95% and specificities of72.3% to 75%49,50. And while the Doppler findings ineach of the vascular beds correlate with fetal acidbasestatus, there is a wide variation of fetal pH with abnormalresults (Figure 1).

Similar observations have been made for fetal heartrate analysis, breathing, tone, gross body movementand amniotic fluid volume. While a reactive CTG evenby criteria graded for gestational age virtually excludes

hypoxemia, a non-reactive CTG is associated with a widerange of pH values41,51,52. The accuracy for the predictionof acidemia can be enhanced by computerized fetal heartrate analysis. All computerized variables such as short-term, long-term mean minute variation and episodic orperiodic changes are related to a range of normal andabnormal fetal pH values29,53,54. In IUGR fetuses, ashort-term variation of 3.5 ms due to prolonged episodesof low variation appears to be the best predictor of acord artery pH < 7.20 at birth by ROC analysis witha background acidemia rate of 21%55. Though clearlyabnormal in the non-laboring patient, lost in this analysis

react +dec

NST

AFV

Tone

FBM

FGM

AEDV

MCA

CPR

DV

TAO

DAO

cCTG

+acc

FHR analysis

0

p

H

10

8

6

4

2

Biophysicalvariables

Dopplervelocimetry

Figure 1A diagrammatic representation of pH deviation from thegestational age mean ( pH) with abnormal test results in variousantenatal tests. These include fetal heart rate (FHR) analysis usingtraditional non-stress testing (NST; react, non-reactive)52 and thecomputerized cardiotocogram (cCTG; + acc, accelerations present;+ dec, obvious decelerations present)29. Biophysical variables(AFV, amniotic fluid volume; FBM, fetal body movement; FGM,fetal gross movement)52. The same relationships are expressed forumbilical artery absent end-diastolic velocity (AEDV) and deviationof the arterial or venous Doppler index > 2SD from the gestationalage mean for the thoracic aorta (TAO), descending aorta (DAO),the middle cerebral artery (MCA), cerebroplacental ratio (CPR)and the ductus venosus (DV)28,4548.

is the clinical relevance of a pH < 7.20 at delivery.Loss of fetal breathing movements is associated with amoderate decrease in pO2 and a wide range of pH inboth cordocentesis samples and at birth. In contrast, theabsence of fetal tone and gross body movement is almostalways associated with acidemia41,51,52.

T H E E F F E C T S O F G E S T A T I O N A L A G E

Gestational age has a profound impact on all aspectsof IUGR. The degree of placental pathology determinesuteroplacental blood flow patterns, gestational age andspectrum of manifestation as well as the overall risk foradverse outcome.

Mild placental dysfunction with minimal or noumbilical artery blood flow abnormality is more commonamong fetuses presenting with IUGR in the thirdtrimester, and an abnormal CPR or brain sparing maybe the only Doppler evidence of placental dysfunction.

In contrast, umbilical artery A/REDV is rarely seenbeyond 3234 weeks since it is associated with earlygrowth failure (second and early third trimester)marked fetal vascular and behavioral responses andearly decompensation6,10,15,40,56. Abnormal venous flowsare therefore almost exclusively reported in fetuseswith markedly abnormal umbilical artery blood flowand early-onset IUGR. In the third trimester subtleDoppler findings in the arterial circulation are morecharacteristic10,34,39,40,57.

There is a physiological change in the reference rangefor almost all Doppler indices with gestational age. To

account for this, measurements need to be transformedto Z-scores for statistical analysis. An index deviation>2 SD from the gestational age mean provides a widelyaccepted statistical cut-off for an abnormal result. Thethree arterial Doppler indices (S/D ratio, resistance indexand PI) appear to vary little clinically58. It has not beenresolved whether there are relevant differences betweenthe numerous venous indices currently in use49.

The establishment of fetal behavioral states andmaturation of fetal heart rate control with couplingto fetal behavior is achieved at various gestationalepochs. Delayed maturation of biophysical milestonesis a feature of IUGR. The physiologic decline ofthe baseline heart rate and maturation of reactivityare delayed while short- and long-term variability isdecreased59,60. Similarly, development of behavioralstates and integration of behavior patterns may bedelayed61. These developmental abnormalities couldinfluence the reliability of computerized, as well astraditional, fetal heart rate analysis.

In addition to fetal manifestations, gestational age hasa significant impact on short- and long-term outcomes.A/REDV is associated with an increased risk for stillbirthand premature delivery due to fetal decompensation36,62.Fetal acidemia, poor transition to extrauterine life,

condition of the neonate after delivery and degree ofprematurity pose additional risks. IUGR fetuses areat higher risk for neonatal complications than their



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appropriately grown counterparts6365. This risk iseven higher for the preterm IUGR fetus and appearsindependent of Doppler status38,66,67. The summation ofthese factors is responsible for high morbidity, mortalityand adverse neurodevelopmental outcome of the pretermIUGRfetus, particularly if deliveredbefore 28 weeks6669.

These associations determine the relative balance ofmanagement decisions. Near-term delivery outweighs therisks of temporizing intervention and delivery is generallyindicated. The risk for adverse neonatal outcomes islow and benefits of modified perinatal interventions aremore likely to be reflected in long-term outcomes. In thepreterm IUGR fetus intervention is triggered by balancingfetal and neonatal risks and its success is measuredby impacts on short-term variables such as perinatalmortality and morbidity.

W H Y C O M B I N E A N T E N A T A L T E S T I N G

M O D A L I T I E S ?The clinical spectrum of IUGR is wide, both inpresentation and progression. Gestational age, differentialfetal maturation, maternal condition, and therapeuticinterventions (possibly) modulate the presentation andmanifestation of fetal disease in various testing modalities.There is normal variation in biological parameters andtheir relationship with fetal acidbase status. As a resultthe prevalence of abnormal test results in a single testingmodality and their relationship between acidbase statusare inconsistent. Therefore, no single test provides well-validatedcut-offs to accurately depict fetal status in IUGR.

Two principal approaches may be taken to solve theproblem of accurate fetal assessment.

One approach to the diversity of the clinical spec-trum is to increase the level of sophistication for testingmodalities. Measurement of venous volume flow, incor-poration of multiple oxygen-sensitive vascular beds andvalidation of venous flow abnormalities through mea-surements of the vessel diameter may be incorporatedto enhance the sensitivity of Doppler surveillance23,7072.Similarly, computerized analysis of percentage of fetalactivity, fractal fetal behavior, percentage of rapid eyemovements and fetal movements during F2 activity statescan be incorporated into the biophysical assessment17,19.These techniques have yet to be validated and wouldsubstantially increase the technical complexity of routinefetal evaluation thus prohibiting large-scale application.An alternative approach is to combine antenatal testingmodalities currently in use to improve diagnostic andpredictive accuracy73.

The logic and potential value of combining antenataltesting modalities that are independent is illustrated wellby biophysical profile scoring. Each of the parameters ofthe BPS is independently altered by hypoxemia. Yet, thecombination of thefivecomponents into a compositescoreperforms better than each single parameter to predict fetal

well-being. The BPS has a reproducible relationship withthe fetal pH, perinatal morbidity and mortality from themid-trimester onwards in IUGR fetuses41,74,75.

As our understanding of fetal cardiovascularadaptationto IUGR has grown, Doppler surveillance has evolved toincorporate multiple vessels to enhance prediction of fetalacidbase status. A clinically validated risk stratificationand management protocol comparable to the BPS hasnot yet been presented using multivessel Doppler. Giventhe variable manifestations of IUGR it is intuitive toincorporatean even broader range of practicableantenataltesting variables into the development of a surveillanceprotocol that will accurately assess fetal status.

W H Y C O M B I N E D O P P L E R A N D B P S ?

Fetal deterioration may be manifested by through abnor-mal behavior, central deregulation of cardiorespiratoryfunction, alterations in vascular tone in oxygen-sensitivevessels and cardiovascular dysfunction. Each of the afore-mentioned fetal testing variables has an independentrelationship with metabolic status. But only their com-

bination evaluates the whole spectrum of cardiovascularand CNS manifestations found in IUGR fetuses.

Doppler ultrasound has been instrumental to ourunderstanding of the relationship between cardiovascularand metabolic deterioration. The initial alterations inDoppler velocities occur long before there are detectableabnormalities of growth and acidbase balance. As such,Doppler is a powerful diagnostic tool that allows theidentification of a pre-disease period during which anintervention could be applied. Neither the BPS nor theCTG alone provide this kind of information in theabsence of overt signs of compromise. Conceptually, the

application of Doppler and BPS information in tandemallows an assessment of the immediate fetal condition andthe institution of appropriate longitudinal management.The same cannot be said if one confines assessment to onemodality. For example, venous Doppler alone allows forthe detection of compromise in only 5060% of fetuseswith early onset IUGR, and an even lower proportionnear term10,27,33,34,38.

Fetaldeterioration of Doppler and biophysical variablesprogresses in different time frames. Arterial Dopplerchanges precede compromise by weeks, while changesin amniotic fluid volume, abnormal venous Doppler,and decline in fetal breathing, tone and movementoccur over progressively shorter periods. The integrationof multivessel Doppler and BPS allows for detectionof multiple patterns of placental insufficiency andfetal compromise76. Doppler and BPS will both detectdeterioration in severe early-onset IUGR27. In milder orlate-onset IUGR with equivocal Doppler findings the BPSwill detect fetal compromise. In addition, hypoxemiaor acidemia is also likely to be detected in apparentlynormally grown fetuses with mild placental dysfunction.If acute intervention is not mandated, the timeframe forongoing surveillance can be tailored based on the severityof the condition and the constellation of early vs. late

Doppler changes. This may include transfer to a referralcenter with highest level of perinatal care, admissionfor daily inpatient monitoring and administration of



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steroids in anticipation of preterm delivery3. The goal ofcomprehensive fetal assessment tailored to the conditioncan be achieved using widely available technology.

I S T H E R E E V I D E N C E T H A T S U P P O R T SI N T E G R A T I O N O F D O P P L E R A N D

B I O P H Y S I C A L P A R A M E T E R S?

The concept of combining assessment of fetal growth withexamination of Doppler andbiophysical parameters in themanagement of high-risk patients is not new. Doppler andbiometry are essential to distinguish between the smallbut normally grown vs. the growth restricted fetus at riskfor adverse outcome36,77,78. Combining umbilical arteryDoppler with biometry preselects patients who will needantenatal surveillance. In low-risk patients, the frequencyof antenatal testing, labor induction and iatrogenicpreterm delivery can be reduced without jeopardizingoutcome79,80.

Perinatal morbidity and mortality are outcomes thatare currently used to measure impacts of perinatalinterventions. Since effective fetal therapy is currentlyunavailable and gestational age is a critical determinantof the therapeutic margin of interventions, timing ofdelivery is our current focus. A recent analysis by theGRIT study group suggests that delaying delivery byup to 2 weeks can achieve an average weight gain of200 g in the fetus without affecting overall perinatalmortality56. Therefore, temporizing intervention appearsjustified between 25 and 29 weeks, where each day inuteromay reduce neonatal mortality by 12%. However,

the increased stillbirth rate when delivery is triggeredby overt abnormalities of fetal testing such as recurrentspontaneous late decelerations stresses the importance ofdefining better tools to understand fetal compromise.

Several authors have prospectively documented thesuperiority of combined assessment. Arabin and cowork-ers used ROC analysis and showed that the combinationof umbilical/carotid artery Doppler and traditional CTGimproved prediction of fetal distress and low Apgar scoresand obviated the use of vibroacoustic stimulation orcontraction stress testing81. Ott and coworkers reportedimproved assessment of fetal well-being among small-for-gestational-age fetuses using the modified biophysicalscore in combination with umbilical and middle cerebralartery Doppler velocimetry. Doppler abnormalities wereused to determine the frequency of fetal testing and con-tributed to the earlier detection of fetal compromise82.It has been suggested that replacing standard CTG withcomputerized analysis further improves the prediction offetal distress and mortality in IUGR fetuses83. A decadeago, Arabin and coworkers constructed a fetal Apgar,substituting components traditionally used in the eval-uation of the neonate with a combination of Dopplerand biophysical parameters. Respiration and color wereexpressed through the uterine artery resistance index and

the carotid/umbilical artery Doppler ratio, respectively.Tone was assessed by BPS criteria, reflexes by vibroa-coustic stimulation and the heart rate was analyzed with

the Fisher score84. The fetal Apgar score was compa-rable to the BPS in the prediction of fetal distress andpoor transition to extrauterine life, but was superior inidentifying IUGR fetuses with acidemia at birth84. Mostrecently we were able to show that the combination ofthe BPS with multivessel arterial and venous Doppler is

better in the prediction of critical outcomes than eithermodality alone. In this study we evaluated prediction ofperinatal mortality, acidemia at birth and major neonatalmorbidity76.

While the study of associations provides insight intothe relationships between fetal status and outcome,the most compelling evidence is provided by clinicalmanagement studies. James and coworkers suggested thatonce placental-based IUGR is diagnosed by biometryand umbilical artery Doppler analysis, institution ofserial BPS can direct appropriate management byaccurately identifying the risk for acidemia and stillbirthirrespective of gestational age and Doppler pattern31.

Similarly, Divon and coworkers demonstrated that thecombination of umbilical artery Doppler and biophysicalprofile scoring produced excellent outcomes85. I n arandomized management protocol, fetuses with AEDVwere followed with daily BPS and delivered for worseningmaternal status, oligohydramnios, BPS < 6 or verifiedlung maturity. Compared to fetuses with positive end-diastolic velocities, there were no differences in pH andlow Apgar scores at birth. Moreover, there were noperinatal deaths in any of the treatment arms! Combinedlongitudinal fetal surveillance using combined multivesselDoppler and BPS is likely to enhance surveillance further

by early anticipation of deterioration and individualizedcare in the preterm IUGR fetus27.Prediction of long-termoutcomes is vastlyunderstudied

and associations are predominantly based on observa-tional data. Population-wide institution of BPS-directedmanagement has resulted in a 50% reduction of cerebralpalsy in the tested population86. In addition, relation-ships between the score and attention deficit disorder,mental retardation and emotional disorder have beendemonstrated8789. Doppler findings such brain sparing,absent aortic- and reversed umbilical artery end-diastolicvelocity have equally been associated with a variety ofneurodevelopmental impacts69,90,91. It stands to reason

that application of integrated fetal testing to a high-riskpopulation of IUGR fetuses is likely to clarify perinataldeterminants of long-term outcome.

W H A T T O C O N C L U D E ?

Doppler, CTG and BPS are widely available examinationtechniques that have evolved over the past 20 years. Itis clear that these monitoring systems combined providea wealth of information on fetal health, perinatal- andlong-term risks. It is also clear that their combinationenables a better understanding of fetal pathophysiology

in IUGR. Furthermore, impediments of the past such asequipment and personnel limitations and local standardsof care are less relevant. What is unclear is how they



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should be combined and whether an intervention willimprove long-term outcome. In addition we need moreinformation on what to do when test results are in conflictwith each other. The optimal combination requires arandomized comparison of management protocols. BothDoppler and biophysical information should be accuratelyrecorded in a standardized fashion in any randomizedtrial evaluating the impacts of interventions in IUGR.Irrespective of interventions and primary study endpointssuch an approach allows secondary analysis of multiplevariables for their predictive accuracy of short- and long-term outcomes. This will allow ongoing refinement offetal testing to direct the management in fetal growthrestriction under any condition.

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