intrauterine growth restriction

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OBSTETRICS

Intrauterine growth restriction: new concepts in antenatalsurveillance, diagnosis, and management
Francesc Figueras, MD, PhD; Jason Gardosi, MD, FRCOG
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Intrauterine growth restriction (IUGR)is associated with stillbirth, neonatal

death, and perinatal morbidity as well asdelayed effects including cerebral palsy(CP) and adult diseases.1-3 In most cases,IUGR is due to placental insufficiency butmay also be due to a number of other con-ditions such as congenital anomalies, in-fections, or drug and substance misuse.

However, the study of the natural his-tory of IUGR or fetal growth restriction(FGR) has particular challenges. First,growth failure is often not detected ante-natally, and in routine clinical practice,as many as three-quarters of babies atrisk of IUGR are not recognized as suchbefore delivery.4 In low-risk pregnancy,with a lower threshold of suspicion, thedetection rate is even lower, about 15%.5

From the Department of Maternal-FetalMedicine, University of Barcelona, HospitalClinic, Barcelona, Spain (Dr Figueras); andWest Midlands Perinatal Institute,Birmingham, UK (Dr Gardosi).

Received June 2, 2010; revised Aug. 10, 2010;accepted Aug. 27, 2010.

Reprints: Jason Gardosi, MD, FRCOG,Director, West Midlands Perinatal Institute,Birmingham B6 5RQ, [email protected].

0002-9378/$36.00© 2011 Mosby, Inc. All rights reserved.

Intrauterine growth restriction (IUGR) remainImprovements have to start from a better dfetal growth potential. Customized standarddetection of IUGR by better distinction betwand have led to internationally applicable noinsights in the assessment of risk and survemeasurement plotted on customized charbiometry and Doppler flow are the mainsAppropriate protocols based on available esessment are essential to ensure good ma

Key words: birthweight, customized charts

doi: 10.1016/j.ajog.2010.08.055

288 American Journal of Obstetrics & Gynecology

Second, when IUGR is recognized, theregnancy is likely to be interrupted if therowth failure is considered severe and ifhe babies are mature enough to have aetter chance ex utero. Therefore, mostualitative and quantitative evidence forhe significance of IUGR comes from theetrospective assessment of the birth-eight of live or stillborn babies.Studies have been hampered by theidespread practice of using the terms

mall for gestational age (SGA) andUGR synonymously. SGA simply referso a weight for gestation below a givenhreshold, but a significant proportion ofmallness is due to constitutional orhysiological causes, which means thathe association between pathologicalmallness and adverse outcome islurred. However, such factors can nowe adjusted for by the use of the custom-

zed growth potential, which improveshe association between low birthweightnd pathology, as explained in the nextection.

Association betweenIUGR and outcomeNew tools and new insightsIn modern epidemiological research, thestandard for birthweight for gestationhas been refined to be able to assessbirthweight not against the average of

e of the main challenges in maternity care.ition of IUGR, applying the concept of ther fetal growth and birthweight improve thephysiological and pathological smallness

. Such developments have resulted in newnce during pregnancy. Serial fundal heightis a useful screening tool, whereas fetalfor investigation and diagnosis of IUGR.

ence as well as individualized clinical as-ement and timely delivery.

tal growth, growth potential

the population but against an individual w

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growth potential calculated for eachbaby in each pregnancy.

This is based on 3 principles.6,7 First,the standard is adjusted or customizedfor sex as well as maternal characteristicssuch as height, weight, parity, and ethnicorigin on the principle that one size doesnot fit all.8 The stepwise improvement ofprediction through this method is illus-trated in Figure 1.

Second, pathological factors such assmoking, hypertension, diabetes, andpreterm delivery are excluded to predictthe optimum weight that a baby canreach at the end of a normal pregnancy.

Third, the term optimal weight andassociated normal range is projectedbackward for all gestational age points,using an ultrasound growth based pro-portionality curve; this avoids basing thestandard on preterm neonatal weights,which by definition are derived frompregnancies with a pathological (pre-term) outcome and hence do not repre-sent the growth potential.6,7

Recent studies have shown that thisprinciple is also internationally applica-ble, with striking similarities of the pre-dicted birthweight of a baby born to astandard European mother in the UnitedKingdom, Australasia, and the UnitedStates.9,10 In practice, the fetal growth

otential, and the individually adjustedr customized normal limits (eg, the0th and 90th centile), are calculated byomputer software11 because of the infi-ite number of possible variations.

alidationhe new standard has been applied to the

esearch of birthweight as well as fetaleight and has helped to improve ournderstanding of the association be-

ween smallness and outcome.In studies of birthweight databases,

GA based on the customized growthotential is more strongly associated

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ings, fetal distress, cesarean section,admission, and prolonged stay in neo-natal intensive care as well as stillbirthsand neonatal deaths than centilesbased on population standards.12-16 Inact, SGA by population centiles butormal size by customized growth po-

ential can be termed physiologicalmallness because it is not associatedith adverse outcome. Importantly,

he customized standard also detects aubstantial number of additional, sig-ificantly at-risk cases that were notagged up as SGA by the populationorm.12,13,16 This dual effect of identi-

ying normal-small cases not at risk,nd pathologically small cases that aret risk, is illustrated in Figure 2. Suchndings lead to the useful conclusion

hat “SGA by customized growth po-ential” represents pathological small-ess and can be used interchangeablyith “IUGR” for retrospective researchn pregnancy outcome.Estimated fetal weight also varies with

ndividual characteristics in low- as wells high-risk pregnancies.17,18 An adjust-ble standard improves the associationith pathology, while reducing false-ositive assessments by adjusting foronstitutional smallness.19 This can havelinical relevance when seeking to reducealse-positive diagnoses of IUGR and un-ecessary intervention.20

Recent work has shown that the lengthof growth deficit is linked with perinatalmorbidity,21 in that morbidity is worsethe longer the slow growth has occurredin utero. A similar principle could be in-ferred from the findings of a case controlstudy of birthweight and CP,2 in whichIUGR at term was highly associated withan increased risk of CP, whereas it didnot increase the risk in early and late pre-term gestations.

Stillbirth and IUGRSuch validation of the principles of thegrowth potential have allowed IUGR orFGR to be introduced as an additionalcategory when classifying stillbirth andfound that after excluding congenitalanomalies, more than 50% of stillbirthshad preceding IUGR (�10th customizedcentile). As a result, the proportion of
unexplained stillbirths drops from 65-
70% using the Wigglesworth classifica-tion to 15%.22 This has since been con-firmed in an independent comparativestudy.23 While IUGR is usually the result

f underlying placental pathology andot in itself the cause of the demise,24 it is

a clinically relevant condition. Aware-ness of this strong link allows a renewedfocus of attention on the antenatal iden-tification of IUGR as a first step towardprevention. Antenatal awareness that thefetus is not growing well is an essential

FIGURE 1Accuracy of birthweight predictioncharacteristics (n � 313,285)

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sex only, to 0.73 with all variables included. UppReproduced, with permission, from Francis and Gardosi.152

Figueras and Gardosi. Intrauterine growth restriction. Am J O

quality indicator of maternity care.

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Purpose of detectionFirst, detection informs the clinician andthence the mother that the pregnancy isat increased risk, allowing consider-ations on the optimal timing for delivery.Depending on severity, babies that arenot fulfilling their growth potential havea 5- to 10-fold risk of dying in utero.12

Second, the information is importantto prompt further investigation such asumbilical artery Doppler, which hasbeen shown to reduce stillbirth and in-

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Reviews Obstetrics www.AJOG.org

ing neonatal mortality.25 In a large sin-le-center retrospective study, Lindqvistnd Molin26 found that antenatal detec-ion of SGA led to significantly improvedutcome.

Screening for the at-risk fetusHistoryPrevious history of growth restriction orstillbirth. Women with a previousgrowth-restricted baby have a 50% in-creased risk of severe growth restrictionin the current pregnancy,27 and serialhird-trimester assessment for this indi-ation is common practice. A history oftillbirth is also an accepted indicationor intensive antepartum surveillanceecause more than half of normallyormed stillbirths are associated withUGR.22 Stillbirths before 32 weeks’ ges-ation have a particularly strong associa-ion with IUGR.28 Previous stillbirthould appear to be a significant risk fac-

or, especially when associated with a di-gnosis of hypertension or clinical

FIGURE 2Stillbirth and SGA status by custom

Small for gestational age was defined accordingSGA by customized centiles (all SGA by Cust) (blue(Pop and Cust SGA), by the population method on(Cust only SGA) (red markers) are shown. OddsSGA, small for gestational age.Reproduced, with permission, from Gardosi and Francis.15


UGR.29


Diabetes. Women with diabetes are atncreased risk of having a baby with mac-osomia as well as FGR, with increasedisk of perinatal morbidity and mortal-ty.30 Preeclampsia is observed in 15-

20% of pregnancies complicated by type1 diabetes mellitus without nephropathyand approximately 50% in the presenceof nephropathy.31 Preeclampsia is alsomore likely in women with hypertensionand poor glucose control.32 When as-sessed by customized standards, 15% ofwomen with type 2 diabetes are found tohave an SGA baby.33

Regular monitoring of fetal growthis recommended in diabetic pregnan-cies.34 Umbilical artery Doppler seemsto be more effective than biophysicalprofile or cardiotocography,35-37 butits use should be limited to womenwith additional risk factors for placen-tal insufficiency, such as SGA orpreeclampsia.

Obesity. Obesity has been considered a

ed and population-based centiles

population-based centiles (Popn only SGA) andrkers). Subgroups that are SGA by both methodsGA Pop only), or by the customized method onlys and 95% confidence intervals are shown.

t Gynecol 2011.

protective factor for growth restric-

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tion,38,39 but such findings are likely tobe artifactual because of the use of unad-justed population standards. When SGAis defined by customized centiles, obesityincreases the risk of SGA by 50%.15 Suchelative smallness is pathological: a largeopulation-based study40 reported that

in obese women, higher perinatal mor-tality is associated with higher rates ofSGA but only when SGA is defined bycustomized growth potential (Figure 3).Although obesity affects the accuracy ofultrasound biometry, it makes palpationand fundal height measurement evenmore difficult. A small series including42 obese women showed that ultrasoundestimation of fetal weight was more ac-curate than abdominal palpation in pre-dicting birthweight.41

Multiple pregnancy. Compared withsingletons, twin pregnancies have in-creased risk of mortality and morbid-ity.42 Because growth restriction and

eight discordance are responsible for aarge part of this higher risk of mortalitynd morbidity,43 optimal monitoring ofetal growth is essential. Clinical assess-

ent does not allow individual fetalvaluation, and therefore, serial fetaleight estimation by ultrasound from8 weeks is considered best practice.rowth standards for multiple pregnan-

ies have been published,44 but singletonnomograms are more commonly usedwith good accuracy.45

Customized charts for estimated fetalweight (EFW) can also be used for twinsbecause the growth potential up to 37weeks is similar to that in singleton preg-nancy.46 There is no consensus on the

est definition of weight discordancend its correlation to clinical events,43

but discordance greater than 20-25% iscertainly considered significant.

In addition, the clinical meaning ofgrowth discordance may differ greatlybetween monochorionic and dichori-onic pregnancies.42 Although it mayseem reasonable to incorporate umbili-cal artery Doppler for an earlier detec-tion of growth restriction, there is insuf-ficient evidence to support its use indichorionic multiple pregnancies not

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Screening in early pregnancyBiochemical markers. In the first trimes-ter, an unexplained low pregnancy-asso-ciated plasma protein A or human cho-rionic gonadotropin (hCG) is associatedwith an increased risk of placental-re-lated diseases such as IUGR or pre-eclampsia.49,50 In the second trimester,n unexplained elevation of serum al-ha-fetoprotein, hCG, or inhibin-A

s also associated with these adverseutcomes.51-54

In general, the association is moremarked for early-onset IUGR or pre-eclampsia.55 Despite these associations,the performance in terms of sensitivity/specificity and predictive values of thesemarkers individually or combined doesnot support their use. Moreover, no clearbenefit of intensive surveillance56 or pro-phylactic strategies57 in women with ab-

ormal biochemical markers has beenemonstrated.

arly growth restriction. Low first-tri-ester measurement of crown-rump

ength in pregnancies dated by the lastenstrual period is also linked with

GR.58,59 However, practical applicabil-ity is limited in spontaneously conceivedpregnancies because the exact date ofconception is usually not known, and acrown-rump length measurement can-not be used simultaneously for establish-ing gestational age and for assessing fetalsize for gestation.

More recently, it has been demon-strated that slow growth between thefirst and second trimester is able toidentify a subgroup of slow-growingbabies that are at increased risk of peri-natal death before 34 weeks’ gestation,in most cases with growth restriction.60

An early indication of an increased riskwould allow more intensive fetal as-sessment and surveillance. Therefore,serial ultrasound evaluation of fetalgrowth in the third trimester seemsjustified in these cases.

Uterine artery. Uterine Doppler evalua-tion in the second or first trimester hasbeen proposed as a screening tool forearly-onset IUGR, with detection rates ofabout 75% and 25%, respectively, for a
false-positive rate of 5-10%.61,62 These e
ensitivities are higher for predictingarly IUGR associated with preeclampsiand lower for late IUGR. Different strat-gies combining maternal risk factors,lood pressure, and biochemical mark-rs have been published with detectionates greater than 90% for early-onsetreeclampsia,63,64 and associated IUGR.A metaanalysis65 of 5 randomized

tudies including 1052 women with ab-ormal uterine Doppler in the second

rimester treated with aspirin showed a0% reduction in the incidence of pre-clampsia, without reaching statisticalignificance (relative risk, 0.8; 95% con-dence interval, 0.61–1.06). Only 2 ran-omized studies (n � 225) have evalu-ted the efficacy of aspirin in womenith abnormal uterine Doppler in therst trimester,66,67 showing a pooled1% reduction in the incidence of pre-

FIGURE 3Perinatal mortality rate and SGA byand population-based centiles

Perinatal mortality rate (PMR) and SGA by cus(SGApop), according to maternal body mass indPMR vs SGAcust: P � .753; PMR vs SGApop: PSGA, small for gestational age.Reproduced, with permission, from Gardosi et al.40


clampsia. The limited number of cases

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ncluded a high incidence of preeclamp-ia in the control group, and there is un-ertainty whether the standard of careould be extrapolated between countrieso draw reliable conclusions.

Thus, so far, there is no evidence inavor of any prophylactic strategy inases of abnormal uterine artery Dopp-er. However, it could be useful in de-ning the standard of prenatal care byssessing the woman’s risk at the be-inning of the pregnancy. This is ingreement with the recommendationsade by the UK National Institute onlinical Excellence for risk-adjustedrenatal care.68

Screening in the third trimesterSerial fundal height measurement. Thefirst fundal height plot represents the ini-tial assessment as well as the baseline for

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ized (SGAcust) and population-based centiles(BMI). Comparison test for difference of slopes:.007.

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terpreted on the basis of the slope or ve-locity of growth. Indications for referralfor further investigations include cases inwhich the first fundal height measure-ment is below the 10th centile or consec-utive measurements suggest static orslow growth, meaning that the serialmeasurements do not follow the ex-pected slope of the growth curve. An au-dit on the population in the catchmentarea of a referral hospital in the WestMidlands (UK) showed that the detec-tion rates for SGA fetuses are improved ifreferral recommendations are fully ad-hered to, highlighting the need for a con-tinuous program of education andtraining.69

Not all pregnancies are suitable forprimary surveillance by fundal heightmeasurement and require ultrasound bi-ometry instead. In most instances, thesepregnancies fall into the following cate-gories: (1) fundal height measurementunsuitable (eg, due to fibroids, high ma-ternal body mass index) or (2) preg-nancy considered high risk (eg, due toprevious history of SGA).

Fundal height measurement is more ofa surveillance than a screening tool be-cause its strength lies in serial assess-ment. However, most clinicians are notformally taught how to measure fundalheight and use a variety of differentmethods. This reduces accuracy and in-creases interobserver variation. Not sur-prisingly, the evidence on fundal heightassessment is mixed, with some studiesreporting that it is a good predictor forIUGR,70-73 whereas others fail to find

uch benefit.74-78

A recent review has summarized theefforts being made to standardize thistool to improve its reliability and effec-tiveness.79 The name symphysis-fundus

eight is in fact misleading because the pre-erred direction of measurement is fromhe variable (the fundus) to the fixed pointthe top of the symphysis). The measure-ent should be along the fetal axis, with no

orrection of the fundus to the midline, us-ng a nonelastic tape.

One of the main problems has beenhe assumption that has crept into com-

on clinical practice, without any goodvidence, that 1 cm fundal height should
qual 1 week of gestation and the defini-

ion of normal as fundal height � 2 or �cm of gestational age. But as with birth-eight and ultrasound growth, one sizeoes not fit all, and different-sized moth-rs have different normal fundal heightrowth curves.80 As a serial assessment,he emphasis with fundal height mea-urement is on the slope of the curve. Re-erral guidelines for further investigationy ultrasound biometry and Doppler in-lude a single fundal height measurementhich plots below the 10th customized

entile, and serial measurements whichross centiles (ie, are slower than the pre-icted growth velocity).79

A controlled study of 1200 patientscompared measurement and plotting offundal height on customized growthcharts against routine clinical assessmentby palpation and found that it resulted ina significant increase in antenatal detec-tion of SGA babies from 29% to 54%.81

Furthermore, there was a significant re-duction of false-positive rates (ie, small-normal babies being referred unneces-sarily for investigation). The study wasnot powered to assess the effect on peri-natal mortality, and there is a paucity ofprospective trials large enough to be ableto assess the effect on hard outcomemeasures. However, the antenatal iden-tification of IUGR is already of provenbenefit in itself and allows further inves-tigations and interventions that areknown to improve outcome. Serial mea-surement of fundal height and plottingon customized growth charts are recom-mended by the Royal College of Obste-tricians and Gynaecologists guidelines.82

Routine/intermittent third-trimester ul-trasound biometry. The effectiveness ofthird-trimester ultrasound biometryfor the diagnosis of growth restrictionand its impact on perinatal outcome isuncertain. Sensitivity of abdominalcircumference for detecting a birth-weight less than the 10th centile rangesfrom 48% to 87%, with specificity from69% to 85%.83-88 For estimated fetalweight, sensitivities of 25-100% havebeen reported, with a specificity of69-97%.84,87-89

The high heterogeneity between stud-ies does not allow the calculation of
pooled values. The largest study,88 from i
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he United Kingdom, included 3616ow-risk women on whom a third-tri-

ester (28-36 weeks) ultrasound waserformed with abdominal circumfer-nce measurement. Sensitivity for birth-eight less than the 10th centile was8%, with a false-positive rate of 7%.indqvist and Molin26 introduced a pol-

cy of a routine scan at 32 weeks and ob-erved a detection rate of 54% for SGAdefined as birthweight deviation of ateast 22% from the mean, equivalent tohe third centile). Hedriana and Moore89

compared serial vs single scan in low-riskwomen between 28 and 42 weeks andfound that multiple ultrasonographicexaminations provided little improve-ment in the prediction of birthweightcompared with a single observation.McKenna et al90 tested randomly a pol-cy of 2 scans at 30 and 36 weeks andbserved that fewer babies were bornGA as a result of increased interventionn the study group, although no dataere given on actual detection rates.The impact of routine third-trimester

ltrasound on perinatal outcome is alsonclear. Seven trials83,85,86,91-94 haveeen included in a recently updatedetaanalysis95 that showed that routine

late pregnancy ultrasound in low-risk orunselected populations does not conferbenefit on mother or baby. Furthermore,it may be associated with a small increasein cesarean section rates.

However, it could be argued that theresults of this metaanalysis have limitedvalidity for contemporary practice be-cause it included studies that used out-dated surrogates of fetal growth suchas biparietal diameter measurement83

or protocols in which the diagnosis ofIUGR was not followed by a change inmanagement. A Swedish population-based study96 compared the perinatal

utcome of 56,371 unselected women inhom routine third-trimester ultra-

ound was performed with the outcomef 153,355 women with no such screen-

ng. No differences in perinatal mortalityr early neonatal morbidity were found.There is currently therefore insuffi-

ient evidence to support routine third-rimester ultrasound in all pregnancies.

management trial to investigate the
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would be feasible in terms of maternalwillingness to participate97 but will re-

uire a large sample size to test effect onard outcomes such as perinatal mortal-

ty. Further trials will also need to in-lude growth scans in the late third tri-ester because most cases of IUGR

eliver at term.98

Serial ultrasound biometry. For preg-nancies at risk, serial assessment of esti-mated fetal weight or abdominal cir-cumference is the best predictor of FGRas assessed by neonatal morphometry.99

Therefore, serial biometry is the recom-mended gold standard for assessingpregnancies that are high risk,82 either

n the basis of past history or because ofomplications that arose during the cur-ent pregnancy. In the absence of clearvidence and consensus about the fre-uency and timing of scans, protocolsnd individual management plans areften limited by the resources available.owever, more than fortnightly scans

re not indicated because the scan errors likely to exceed the increment in sizeecause of growth during the interval.82

Diagnosis of IUGRCurrent thinking on the natural his-tory of growth restriction differentiatesbetween early-onset and late-onsetforms,100 which have different biochem-ical, histological, and clinical features.101

Whereas the former is usually diagnosedwith an abnormal umbilical arteryDoppler and is frequently associated with

reeclampsia, the latter is more prevalent,hows less change in umbilical flow pat-ern, and has a weaker association withreeclampsia.101

Umbilical artery DopplerMost instances of growth restriction cor-respond with cases of placental insuffi-ciency.102 Evaluation of placental func-tion by umbilical artery Doppler is aclinical standard to distinguish betweenSGA and IUGR.103-105 The pathophysio-logical progression of this parameter isillustrated in Figure 4. As suggested byanimal106 and mathematical107 modelsof chronic placental embolization, theobliteration of more than 50% of the pla-
cental vessels is required before absent or
FIGURE 4Insonation of the umbilical artery Doppler

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A, Site of insonation of the umbilical artery Doppler. Progressive waveform patterns with advancingseverity were: B, normal umbilical artery waveform, C, increased impedance to flow, D, absentnd-diastolic flow, and E, reversed end-diastolic flow.

Figueras and Gardosi. Intrauterine growth restriction. Am J Obstet Gynecol 2011.

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reversed end-diastolic velocities appear.There is good evidence that umbilicalDoppler ultrasound use in these preg-nancies improves a number of obstetriccare outcomes and reduces perinataldeaths.108

Whereas abnormal umbilical arteryDoppler is associated with adverse peri-natal and neurodevelopmental out-come,109-112 small fetuses with normal

mbilical artery Doppler are consideredo represent one end of the normal-sizepectrum, and the importance of manag-ng them as completely differently fromrue IUGR babies has been stressed.113,114

This may not be true for late-onset cases, inwhich a substantial proportion of caseswith a normal umbilical artery may havetrue growth restriction, and are at risk ofadverse perinatal outcome.109,110,115,116

Other Doppler parametersBecause the identification of late-onsetSGA fetuses with mild forms of growthrestriction cannot only be relied on byumbilical artery Doppler, other vascularterritories have been proposed. Abnor-mal uterine artery Doppler is compara-ble with umbilical artery Doppler as apredictor of adverse outcome in growth-restricted fetuses.116-118 Up to 20% of

GA fetuses have reduced resistance inhe middle cerebral artery (MCA), andhis sign is also associated with poorererinatal outcome116-119 and subopti-

mal neurodevelopmental developmentat 2 years of age.120 Umbilical and cere-

ral Doppler can be combined in theerebroplacental ratio. This ratio haseen demonstrated in animal121 and

clinical122 models to be more sensitive toypoxia than its individual componentsnd correlates better with adverseutcome.123

Assessment of the IUGR fetusBecause no treatment has been demon-strated to be of benefit for FGR,124-127

the assessment of fetal well-being andtimely delivery remains as the mainstrategy for management. Fetal well-be-ing tests could be classified as chronic oracute. Whereas, the former becomesprogressively abnormal because of in-creasing hypoxemia and/or hypoxia, the
latter correlates with acute changes oc- r

curring in advanced stages of fetal com-promise, characterized by severe hyp-oxia and metabolic acidosis, and usuallyprecedes fetal death by a few days. Be-cause a fixed sequence of fetal deteriora-tion does not exist, integration of severalwell-being tests into comprehensivemanagement protocols is required.

Chronic testsUmbilical artery. Absent or reversedend-diastolic velocities are mostly foundin early-onset IUGR, and these patternshave been reported to be present onaverage 1 week before the acute deterio-ration.128 Up to 40% of fetuses withcidosis show this umbilical flow pat-ern.128 Despite the fact that an associa-ion exists between the presence ofeversed end-diastolic flow in the umbil-cal artery and adverse perinatal out-ome (with a sensitivity and specificity ofbout 60%), it is not clear whether thisssociation is confounded by prematu-ity. More recent series129 of severelyompromised IUGR fetuses suggest thatuch a finding has value independentlyf gestational age in the prediction oferinatal morbidity and mortality.

iddle cerebral artery. Longitudinaltudies on deteriorating early-onsetUGR fetuses have reported that the pul-atility index in the MCA progressivelyecomes abnormal.130 Figure 5 shows

the progression of this parameter. Up to80% of fetuses have vasodilatation 2weeks before the acute deterioration,128

although other series have found this fig-ure to be less than 50%.129 Preliminary

ndings of an acute loss of the MCA va-odilatation in advanced stages of fetalompromise have not been confirmed inore recent series,128-131 and therefore

this sign does not seems to be clinicallyrelevant for management purposes inearly-onset cases. In late-onset IUGR,there is observational evidence116,119

that MCA vasodilatation is associatedwith adverse outcome independently ofthe umbilical artery. This suggests a roleof MCA Doppler for fetal monitoring inlate-onset IUGR cases, which needs fur-ther investigation in randomized trials.

Amniotic fluid. A metaanalysis132 of 18
andomized studies demonstrated that
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n amniotic fluid index of less than 5 isssociated with abnormal 5 minute Ap-ar score but failed to demonstrate anssociation with acidosis.

Longitudinal studies in early-onsetUGR fetuses have shown that the am-iotic fluid index progressively de-reases.129,130 Amniotic fluid volume is

believed to be a chronic parameter. Infact, among the components of biophys-ical profile, it is the only one that is notconsidered acute. One week before acutedeterioration, 20-30% of cases haveoligohydramnios.129,130

Acute markersDuctus venosus (DV). Early studies onIUGR fetuses demonstrated a good cor-relation of abnormal DV waveform withacidemia at cordocentesis,133 and thisDoppler sign is considered a surrogateparameter of the fetal base-acid status.The progression of this parameter isshown in Figure 6. Absent-reversed ve-locities during atrial contraction are asso-ciated with perinatal mortality indepen-dently of the gestational age at delivery,134

with a risk ranging from 60% to 100% infetuses with early-onset IUGR.135 How-ever, its sensitivity for perinatal death is still40-70%.134,136,137

Longitudinal studies have demon-strated that DV flow waveforms becomeabnormal only in advanced stages of fetalcompromise.128-131 Whereas in about

0% of cases abnormal DV precedes theoss of short-term variability in the fetaleart rate,130 in about 90% of cases it be-omes abnormal only 48-72 hours be-ore the biophysical profile.131 Debatexists regarding the advantages of DVoppler investigation over biophysicalrofile. However, observational stud-

es138 suggest the integration of both DVDoppler investigation and biophysicalprofile in the management of pretermIUGR because these strategies seem tostratify IUGR fetuses into risk categoriesmore effectively. An ongoing random-ized clinical trial (Trial of umbilical andfetal flow in Europe, TRUFFLE) is aimedat evaluating the role of DV assessmentover standard management based oncardiotocography for timely delivering
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Fetal heart rate (FHR) analysis. Earlystudies on high-risk pregnancies showedthat, although highly sensitive, cardioto-cography has a 50% rate of false positivesfor the prediction of adverse outcome.139

In addition, a metaanalysis140 of its ap-plication in high-risk pregnancies failedto demonstrate any beneficial effect inreducing perinatal mortality. Hence,there is no evidence to support the use oftraditional fetal heart rate monitoring ornonstress tests in IUGR fetuses. How-ever, these studies were conducted in theearly 1980s, and the control group hadno fetal well-being assessment or out-dated techniques such as biochemicaltests.

Computerized FHR has provided newinsight into the pathophysiology ofIUGR. Short-term variability closelycorrelates with acidosis and severe hyp-oxia as demonstrated by cord bloodsampling at the time of a cesarean sec-tion.141 Whereas Bracero et al142 demon-trated no significant differences in peri-atal outcome between visual andomputerized FHR, more recent longi-udinal series have pointed to a potentialole as an acute marker.130 Short-termariability becomes abnormal, coincid-ng with the DV: whereas in about half ofhe cases, abnormal DV precedes the lossf short-term FHR variability, the latter

s the first to become abnormal in thether cases.130 Both parameters are con-

sidered acute responses to fetal acidosis.

Biophysical profile. Some observationalstudies show an association between ab-normal biophysical profile (BPP) andperinatal mortality and cerebral palsy,143

whereas others fail to demonstrate thisassociation.129 In IUGR infants, BBP was

ot predictive of cognitive function at 2ears.144 Similarly, whereas some studies

with cordocentesis demonstrated a cor-relation with acidosis,145 with fetal toneand gross motor movements the bestcorrelated components, others have notfound this correlation.146

As with FHR , a high false-positive rate(50%) limits the clinical usefulness of thebiophysical profile.147 A recent study148

has shown that BPP alone in fetusesweighting more than 1000 g is not a reli-
able test in the treatment of preterm
IUGR fetuses because of high false-posi-tive and -negative results. A metaanaly-sis149 showed no significant benefit of a

FIGURE 5Color Doppler assessment of the m

A

B

C

A, Color Doppler assessment of the MCA at the(high diastolic velocities and decreased pulsatilitACA, anterior cerebral artery; MCA, middle cerebral artery; PCA,

igueras and Gardosi. Intrauterine growth restriction. Am J O

biophysical profile in high-risk pregnan-

APRIL 2011 Am

cies, although more recent series150,151

on IUGR have suggested that bothDoppler and biophysical profile effec-

le cerebral artery

l of the circle of Willis. B, Normal and abnormaldex) C, waveforms are shown.rior cerebral artery.

t Gynecol 2011.

idd

levey inposte

bste

tively stratify IUGR fetuses into risk cat-


sucmbsafia

rlwHicwm

epmd


egories. Because fetal deterioration ap-pears to be independently reflected byboth tests, further studies are required toprove the usefulness of combining both

FIGURE 6Insonation of the ductusvenosus with color Doppler

A

B

C

D

E

A, Site of insonation of the DV with color Doppler.Progressive waveform patterns with advancingseverity are shown: B, normal DV waveform, C,increased impedance to flow, D, absent end-diastolic flow, and E, reversed end-diastolic flow.A, descendent aorta; DV, ductus venosus; H, heart; UV, umbilicalvein.

Figueras and Gardosi. Intrauterine growth restriction. Am JObstet Gynecol 2011.

testing modalities.


Longitudinal series131 have demon-trated that except for amniotic fluid vol-me and the fetal heart rate, the otheromponents (tone, breathing, and bodyovements) of the biophysical profile

ecome abnormal only in advancedtages of fetal compromise. In fact, inbout 90% of cases, the biophysical pro-le becomes abnormal only 48-72 hoursfter the ductus venosus.131

Timing of deliveryIUGR is one of the most common preg-nancy complications and substantiallyincreases the prospective risk of adverseoutcome. Yet according to pregnancyaudits, most instances of IUGR are notdetected as such antenatally. Modernobstetric care needs to raise the level ofawareness of the importance of this con-dition, and establish evidence-basedprotocols for improved surveillance.

Because the only current treatment forIUGR is delivery, the main considerationneeds to be appropriate timing, balanc-ing the risk of potential iatrogenic mor-bidity and continued exposure to anunfavorable intrauterine environment.Studies are now in progress with regardto late-onset IUGR to evaluate whetherelective induction beyond 36 weeks’ ges-tation is of benefit. To date, prospectivetrials have not been able to throw muchlight and are often underpowered orflawed.

Regarding early-onset IUGR, the mul-ticentre Growth Restriction Interven-tion Trial153 compared outcome afterandomization with early or delayed de-ivery and concluded that it was safe toait, especially at preterm gestations.owever, the study design has been crit-

cized because it did not account for theases that were not randomized andhich were estimated to represent theajority of all eligible cases:154 clinical

selection bias may have preferentially in-cluded the less severe cases, in which itwould be safe to wait anyway. Therefore,such results cannot be extrapolated to allcases with IUGR.

Improved definition of the intrauter-ine standard for IUGR by the use of thefetal growth potential allows a more dis-cerning assessment. A baby with an EFW
below the 10th customized centile has a
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significantly elevated risk of morbidity,even in the absence of an abnormal um-bilical artery Doppler.110 Added into thequation is the awareness that leavingregnancies with IUGR to deliver at termay also lead to perinatal morbidity and

elayed effects such as cerebral palsy.2

Therefore, current best practice wouldindicate that from the time fetal pulmo-nary maturity can be inferred, there islittle to be gained by allowing a preg-nancy to continue if good fetal growthcannot be demonstrated. However, eachcase needs to be carefully assessed andindividually considered, in consultationwith the parents. f

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