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CHIEF EDITORS NOTE: This article is part of a series of continuing education activities in this Journal through which a totalof 36 AMA/PRA category 1 credit hours can be earned in 2004. Instructions for how CME credits can be earned appear onthe last page of the Table of Contents.

Pathophysiology of Fetal GrowthRestriction: Implications for Diagnosis

and SurveillanceAhmet Alexander Baschat, MD

Clinical Instructor, Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland,Baltimore, Maryland

Normal fetal growth depends on the genetically predetermined growth potential and is modu-lated by fetal, placental, maternal, and external factors. Fetuses with intrauterine growth restriction(IUGR) are at high risk for poor short- and long-term outcome. Although there are many underlyingetiologies, IUGR resulting from placental insufficiency is most relevant clinically because outcomecould be altered by appropriate diagnosis and timely delivery. A diagnostic approach that aims toseparate IUGR resulting from placental disease from constitutionally small fetuses and those withother underlying etiologies (e.g., aneuploidy, viral infection, nonaneuploid syndromes) needs tointegrate multiple imaging modalities. In placental-based IUGR, cardiovascular and behavioralresponses are interrelated with the disease severity. Ultrasound assessment of fetal anatomy,amniotic fluid volume, and growth is complementary to the Doppler investigation of fetoplacentalblood flow dynamics. A diagnostic approach to IUGR combining these modalities is presented inthis review.Target Audience: Obstetricians & Gynecologists, Family PhysiciansLearning Objectives: After completion of this article, the reader should be able to describe the

development of the placental interface, to outline the mechanisms of placental insufficiency, and to listthe manifestations of placental insufficiency and the tests that can be used to diagnose fetal growthrestriction.

Appropriate fetal growth depends on 4 principalvariables. Every fetus has a genetically predeter-mined growth potential that can be predicted fromparental characteristics (1). This growth potential isfurther modulated by fetal health, maternal health,and placental function. If all of these 3 additionalvariables are normal, the fetus will fulfill his growthpotential. Poor fetal and/or maternal health and ab-normal placental function could provide a challengeto the growing fetus. If these challenges are of suf-

ficient magnitude, fetal growth restriction develops.Growth-restricted fetuses are at increased risk foradverse health events all the way into adult life andtherefore constitute a high-risk group of patients thatrequire our full attention (26). Effective diagnosis,prognostic assessment, and management requireknowledge of the interactions between etiology, clin-ical presentation, prognostic factors, and the effectsof intervention. This review focuses on the relation-ships between pathophysiology and clinical presen-tation in pregnancies complicated by placental insuf-ficiency highlighting implications for the diagnosticapproach to such pregnancies.The placenta forms the interface between the fetal

and maternal circulations. For this reason, fetal disease,

Reprint requests to: Ahmet Alexander Baschat, MD, Depart-ment of Obstetrics, Gynecology & Reproductive Sciences, Univer-sity of Maryland, Baltimore, 405 West Redwood Street, 4th Floor,Baltimore, MD 21201. E-mail: [email protected] author has disclosed no significant financial or other rela-

tionship with any commercial entity.

CME REVIEWARTICLEVolume 59, Number 8OBSTETRICAL AND GYNECOLOGICAL SURVEYCopyright 2004by Lippincott Williams & Wilkins 23

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Margarita Ceccopieri Rojano




maternal disease, primary placental disease, and extrin-sic factors could all interfere with the efficiency ofnutrient and waste exchange and result in growth re-striction. Fetal growth restriction is a physical signrather than a single disease. There are a wide range ofprincipal conditions that are associated with restrictedgrowth (Fig. 1). In some fetal disorders, intrauterinegrowth restricton (IUGR) could be the only sign of theunderlying disorder, whereas in other cases, growthrestriction could accompany abnormalities in severalorgan systems. Maternal diseases such as chronic renaldisease, hypertension, collagen vascular disease, throm-bophilia, and socioeconomic factors such as smoking,malnutrition, and drug use are also associated withIUGR. Many of these are readily apparent through thematernal history or can be determined with relativelyminor effort, and exert their effects by impacting onplacental function and development. Overall, fetal ab-normalities (both chromosomal and/or anatomic) andabnormal placental vascular development in the fetaland/or maternal compartments are responsible for thevast majority of IUGR in singleton pregnancies (711).Because outcome in the latter forms can be influencedby management, detection of this subset of patients isdesirable. To formulate a uniform diagnostic approach,an understanding of the critical milestones in placentaldevelopment is helpful.

CRITICAL MILESTONES IN THE

DEVELOPMENT OF THE

PLACENTAL INTERFACE

Important developmental milestones at the placen-tal interface that enable coordinated maternalfetalexchange throughout pregnancy characterize the3 trimesters. Successful progression through thesemilestones permits the fetus to reach his growthand developmental potential in preparation for asuccessful transition to extrauterine life.In the first trimester, the cytotrophoblast migrates

to form anchoring sites and thus establishes placentaladherence. Subsequently, vascular connections be-tween the maternal circulation and the intervillousspace are established through angiogenesis. Fromthis time on, nutrient and oxygen delivery are suffi-cient to meet the demands of the growing trophoblastand the embryo (12,13). Elaboration of principalplacental functions now becomes possible. Increas-ing synthetic activity results in the appearance ofseveral secretory substances in the maternal circula-tion (e.g., human chorionic gonadotrophin and pla-cental lactogen). At a placental level, several para-crine-signaling substances appear (e.g., nitric oxide,endothelin). Active cellular transport systems for ma-jor nutrient classes (glucose, amino acids, and fatty

Fig. 1 The principal causes and most common conditions that are associated with fetal growth restriction.

618 Obstetrical and Gynecological Survey






acids) differentiate. Vascular function differentiatesby formation of the villous trophoblast that providesthe nutrient exchange interface and consists of amaternal microvillous and fetal basal layer (14). Ini-tiation of fetal cardiac activity allows the active dis-tribution of substances between fetus and placentaand therefore completes the functionality of the fe-toplacental unit. Achievement of these milestones isreflected in several characteristic ways. Maternal ad-aptations such as postprandial hyperglycemia, in-creased fasting levels of free fatty acids, triglyceridesand cholesterol, fat deposition, maternal intravascu-lar volume expansion, and relative refractoriness tovasoactive agents enhances substrate delivery to theplacenta (15). In the placenta, substrates are handledwith increasing efficiency to provide enough nutri-ents to the synthetically highly active trophoblast andtransporting the surplus for the fetus (1618). Pla-cental vascular autoregulation enhances the effi-ciency of maternalfetal nutrient exchange by match-ing perfusion between both compartments. Substrateis thus taken up by the functional villous circulationand distributed to the fetus through the umbilicalvein.Entering the second trimester, invasion of the tro-

phoblast into the maternal spiral arteries results inprogressive loss of musculoelastic media, first in thedecidual, then in the myometrial portion of thesevessels (19). Progressive thinning of the villous tro-phoblast down to 4 !m by the 16th week and a rapidincrease in villous surface area until 26 weeks isobserved (20). Concurrently, intermediary and termi-nal villi appear in the fetal compartment as the mainsites of exchange (21). An exponential rise in fetalcardiac output strikingly elevates the magnitude ofvillous blood flow and increases the capacity for fetalsubstrate uptake. As a result of these changes, high-capacitance low-resistance vascular compartmentsare established on both sides of the placenta (2225).In this gestational epoch, the placenta grows signif-icantly in size following a sigmoid growth curve. Theenlarging cell mass and rising DNA content is theresult of increased synthetic activity, transport activ-ity, and vascular mass (26). Consequently, nutrient-transporting capacity rises sufficiently to promote theexponential fetal growth spurt and differentiation oforgan systems.The third trimester is characterized by ongoing

organ differentiation. Increase in fetal size is typi-cally the result of longitudinal growth accompaniedby accumulation of essential body stores. These bodystores serve as a reservoir for nutrients during neo-natal life, when food intake could provide inconstant

amounts of essential substrate. For example, the rel-ative amount of body fat increases to almost 20% offetal body weight in the third trimester. This body fatserves as storage for essential fatty acids necessaryfor the maintenance of myelination and retinal function(27,28). The third trimester therefore is an importantperiod to prepare for the transition to extrauterine life.Realizing the importance of these gestational epochsallows a better understanding of how placental insuffi-ciency could manifest itself.

MECHANISMS OF PLACENTAL

INSUFFICIENCY

The precise mechanisms of how various diseasesaffect placental function are still under investigation. Inmaternal hypertensive disorders, increased syncytialknot formation indicates premature placental aging andapoptosis. Occlusive vasculopathy, which is most pro-nounced with antiphospholipid syndromes, affects thematernal and fetal circulations in the placenta. Placentalcauses could result in decreased placental blood flow oraltered transport mechanisms and abnormal cellular ho-meostasis at the placental level. Fetal causes could exerttheir effects of growth on multiple levels. Of the pos-sible etiologies, conditions that interfere with placentalvascular development account for the majority of preg-nancies complicated by fetal growth restriction (29). Inthese patients with underlying vascular disease, thegestational age and extent of interference with placentaldevelopment determine the various clinical scenarios.Early in the first trimester, interference with angio-

genesis is likely to prevent successful placental ad-herence and therefore lead to miscarriage. If suffi-cient supply to the placental mass can be established,further differentiation is possible. However, subopti-mal maternal adaptation to pregnancy and deficientnutrient delivery pose limitations at all levels ofplacental function. If the trophoblast invasion re-mains confined to the decidual portion of the myo-metrium, maternal spiral and radial arteries fail toundergo the physiological transformation into low-resistance vessels (30,31). Altered expression of va-soactive substances could increase vascular reactiv-ity, and if hypoxia-stimulated angiogenesis cannotovercome these challenges, placental autoregulationbecomes deficient. Maternal placental floor infarcts,fetal villous obliteration, and fibrosis each increaseplacental blood flow resistance, producing maternalfetal placental perfusion mismatch that decreases theeffective exchange area (3235). With progressivevascular occlusion, fetoplacental flow resistance isincreased throughout the vascular bed and eventually

Fetal Growth Restriction Y CME Review Article 619














































metabolically active placental mass is reduced. Ifadaptive mechanisms permit ongoing fetal survival,early-onset growth restriction with its many fetalmanifestations develops. This spectrum of fetal man-ifestations is determined by the balance of compen-satory and decompensatory responses in variousorgan systems. If compensatory mechanisms are un-successful, permanent fetal damage or stillbirth en-sues. With successful compensation, the conse-quences of nutrient shortage could remain largelysubclinical, only to be unmasked through its restric-tive effect on exponential fetal growth in the secondto third trimester. In these cases, vascular manifesta-tion could be less pronounced and physical charac-teristics more apparent. A decrease in adipose tissueor abnormal body proportions at birth could be theonly evidence. An appreciation of the multiple man-ifestations of placental insufficiency is key to formu-late a uniform diagnostic approach to fetuses withsuspected IUGR.

MANIFESTATIONS OF PLACENTAL

INSUFFICIENCY

A wide range of fetal manifestations of placentalinsufficiency has been documented in almost everyorgan system using invasive testing. With noninva-sive antenatal surveillance tools such as nonstresstesting, gray-scale and Doppler ultrasound fetal as-sessment becomes limited to cardiovascular and be-havioral responses. Nonetheless, a reasonable assess-ment of fetal status is made possible by extrapolationof study results that correlate noninvasive testingwith fetal outcomes.The severity of placental vascular dysfunction is

reflected in the uterine (maternal compartment) andumbilical arteries (fetal compartment). The presenceof an early diastolic notch in the uterine arteries at 12to 14 weeks is the earliest evidence of delayed tro-phoblast invasion, which is almost certain whennotching persists beyond 24 weeks (31,36,37). Re-duced umbilical venous blood flow volume (38) oran increase in multigate-measured placental bloodflow resistance (39) are the earliest Doppler sign ofdisturbed fetal villous perfusion. When some 30% ofthe fetal villous vessels are abnormal, umbilical ar-tery end-diastolic velocity apparently decreases andthe Doppler resistance indices become elevated (40).Absence (AEDV) or even reversal of umbilical arteryend-diastolic velocity (REDV) can occur when 60%to 70% of the villous vascular tree has been damaged(41). Increasing Doppler abnormality in the maternalvascular bed identifies patients at risk for preeclamp-

sia, abruption, and IUGR (42), whereas abnormalumbilical flows indicate increased risk for hypox-emia and acidemia proportional to the severity ofDoppler abnormality (43,44).Fetal circulatory responses to placental insuffi-

ciency can be subdivided into early and late corre-sponding to the degree of fetal compromise (45,46)(Fig. 2). These circulatory responses are in part pas-sive and result from the effects of placental afterloadon the distribution of cardiac output and in part as aresult of active organ autoregulation. Elevated pla-cental blood flow resistance increases right ventric-ular afterload. As a result of the parallel arrangementof the fetal circulation, this results in a shift ofcardiac output away from the right side of the heart.The result is a relative increase in left-sided cardiacoutput (47,48). Consequently, blood (and nutrient)supply to the upper part of the body by the leftventricle increases. This redistribution of cardiac out-put can be documented by a decrease in the ratio ofDoppler indices in cerebral and umbilical arteries(cerebroplacental Doppler ratio) (49). In addition,cerebral blood flow could be actively enhanced dur-ing periods of perceived hypoxemia by a decrease incerebral blood flow resistance. This results in a de-crease of the Doppler index in one of the cerebralvessels (brain-sparing) (50). Fetuses that showthese early Doppler changes are at increased risk forhypoxemia, whereas the pH is usually maintained inthe normal range (5153). Late Doppler changesappear with further metabolic deterioration. Underthese circumstances, declining forward cardiac func-tion and abnormal organ autoregulation supervene.Increasing venous Doppler indices are the hallmarkof advancing circulatory deterioration because theydocument the inability of the heart to accommodatevenous return (54). The venous flow velocity wave-form is triphasic and therefore more complex thanthe arterial waveform. It consists of systolic anddiastolic peaks (the S- and D-wave) that are gener-ated by the descent of the AV-ring during ventricularsystole and passive diastolic ventricular filling, re-spectively. The sudden increase in right atrial pres-sure with atrial contraction in late diastole causes avariable amount of reverse flow producing a secondtrough after the D-wave (the a-wave). In extremecases, atrial pressure waves are transmitted all theway back into the free umbilical vein resulting inpulsatile flow (Fig. 2). Further deterioration of car-diac function results in holosystolic tricuspid insuf-ficiency and spontaneous fetal heart rate decelera-tions, and finally leads to fetal demise (55,56).










Fetal behavioral responses to placental insufficiencycan also be subdivided into early and late. Earlychanges are predominantly the result of maturationaldelay in the central integration of fetal behaviors. Typ-ically, this delayed acquisition of behavioral milestonesis only apparent on computerized analysis of fetal be-havioral patterns (53). Fetal heart rate control is alsoaffected causing a delay in the gestational decrease inbaseline and delayed development of reactivity. Despitethe maturational delay of some aspects of central ner-vous system function, several centrally regulated re-sponses to acid base status are still preserved. Once fetalhypoxemia is perceived, a decline in global fetal activ-ity precedes the loss of individual biophysical variables

and is often also accompanied by a gradual decline inamniotic fluid volume (57,58). With increasing hypox-emia, fetal breathing movement ceases. Gross bodymovements and tone decrease further and are lost whenacidemia develops (59). Abnormal fetal heart rate pat-terns are generally also observed at this time (Fig. 2)(60,61). The biophysical profile score (BPS) as a com-posite score applies categorical cutoffs for fetal tone,breathing movement, gross body movement, amnioticfluid volume, as well as traditional fetal heart rateanalysis. Although a gradual decline in all of theseparameters precedes an overtly abnormal BPS, analysisof percentage changes in these variables offers no ad-vantage in the prediction of acidemia (57). The 5-com-

Fig. 2 Summary of the early and late responses to placental insufficiency. Doppler variables in the placental circulation precedeabnormality in the cerebral circulation. Biophysical parameters (BPS) are still normal at this time, and computerized analysis of fetalbehavioral patterns is necessary to document a developmental delay. With progression to late responses, venous Doppler abnormalityin the fetal circulation is characteristically often preceding the sequential loss of fetal dynamic variables and frequently accompanyingthe decline in amniotic fluid volume. The asterisk (*) in the ductus venosus flow velocity waveform marks reversal of blood flow duringatrial systole (a-wave). The decline in biophysical variables shows a reproducible relationship with acid base status. If adaptationmechanisms fail, stillbirth ensues.


ponent BPS shows a reliable and reproducible relation-ship with the fetal pH irrespective of the underlyingpathology and gestational age (60,62). Concurrent eval-uation of fetal cardiovascular and biophysical variablesindicates that Doppler deterioration precedes an abnor-mal BPS in the majority of IUGR fetuses (58). Whenthe relationship between the various testing modalitiesand fetal acid base status is compared, biophysical param-eters show a closer relationship with the pH, whereasDoppler parameters have a wider variance (Fig. 3).

DIAGNOSTIC APPROACH IN SUSPECTED

FETAL GROWTH RESTRICTION

The many underlying etiologies and presentations offetal growth restriction require a diagnostic approachthat integrates information from several modalities.Only a complete evaluation of maternal history, fetal,placental, and amniotic fluid characteristics can directan appropriate diagnostic workup and perinatal man-agement. The accurate identification of those fetusesthat are truly at risk for adverse outcome requires ex-clusion of small fetuses that are normally grown and

those in whom IUGR is the result of an underlyingcondition not amenable to intervention. Among theseconditions, aneuploidy (especially trisomy 18, 13, and21), skeletal dysplasia, nonaneuploid syndromes, andviral infection should always remain high on the list ofdifferential diagnoses. Gray-scale ultrasound is the pri-mary diagnostic tool because it allows a detailed fetalanatomic survey, biometric assessment of fetal growth,assessment of amniotic fluid volume and placental ap-pearance. Although gray-scale ultrasound provides im-portant clues to the presence of IUGR, the liability ofpreterm delivery and iatrogenic complications is great ifthe diagnosis is based solely on biometry (63). It is thecombination of fetal biometry with Doppler that is thebest available tool for the identification of a small fetusat risk for adverse outcome from placental insufficiency(6467). The complementary use of these 2 ultrasoundimaging modalities is therefore necessary wheneverfetal growth restriction is suspected.A detailed anatomic survey is paramount in any

fetus with suspected IUGR. Critical evaluation foraneuploidy markers such as echogenic bowel, nuchalthickening, and abnormal hand positioning is neces-

Fig. 3 A diagrammatic representation of pH deviation from the gestational age mean (!pH) with abnormal test results in variousantenatal tests. These include fetal heart rate (FHR) analysis using traditional nonstress testing (NST; react " nonreactive) and thecomputerized cardiotocogram (cCTG; #acc " accelerations present; #dec " obvious decelerations present). Biophysical variables(AFV " amniotic fluid volume; FBM " fetal body movement; FGM " fetal gross movement). The same relationships are expressed forumbilical artery absent end-diastolic velocity (AEDV) and deviation of the arterial or venous Doppler index $2 standard deviations fromthe gestational age mean for the thoracic aorta (TAO), descending aorta (DAO), the middle cerebral artery (MCA), cerebroplacental ratio(CPR), and the ductus venosus (DV) (reproduced with permission from Baschat (53)).


sary. Important anomalies that are associated withIUGR include omphalocele, diaphragmatic hernia,and congenital heart defects. Assessment of the tho-racic shape can give clues to the presence of a skel-etal dysplasia. Markers for viral infection could benonspecific but include echogenicity and calcifica-tion in organs such as the brain and liver. Occasion-ally, hydrops may be present (68). The amniotic fluidvolume should be assessed together with the fetalanatomic survey. The regulation of amniotic fluidvolume is complex but by the third trimester primar-ily dependent on fetal urine production. Placentaldysfunction and fetal hypoxemia both could causefetal oliguria and consequently oligohydramnios.The accuracy of ultrasound in the assessment ofamniotic fluid volume is poor (69). Additionally,amniotic fluid measurement is a poor screening toolfor the prediction of IUGR and fetal acidosis (70,71).Nonetheless, assessment of amniotic fluid volume byany method (4-quadrant AFI and maximum verticalpocket), especially if performed serially, provides animportant diagnostic as well as prognostic tool. In thesetting of small fetal size, abundant amniotic fluidvolume is a pointer toward aneuploidy, or fetal in-fection (9), whereas normal or decreased amnioticfluid is compatible with placental insufficiency.The actual quantification of growth is based on the

fetal biometry. Because almost all fetal measure-ments change with gestation, an accurate assessmentof gestational age is a prerequisite for the calculationof percentile ranks of absolute measurements. Anestimated date of confinement (EDC) is based on thelast menstrual period when the sonographic estimate

of gestational age is within the predictive error (7days in the first, 14 days in the second, and 21 daysin the third trimester). Once the EDC is set by thismethod or a first-trimester ultrasound, it should notbe changed because such practice interferes with theability to diagnose fetal growth abnormalities. Oncethe EDC has been assigned, selection of appropriatereference ranges that are based on uncomplicatedpregnancies delivered at term is of importance. Indi-vidualized reference ranges of growth potential thataccount for maternal, ethnic, and fetal variables pro-vide the most accurate reference (1,72). Once gesta-tional age is assigned, the interpretation of the ultra-sound examination is based on the fetal anatomicsurvey, amniotic fluid volume, percentile rank offetal size measurements, the interval growth since thelast study, and a functional assessment of the feto-placental unit with Doppler ultrasound (Fig. 4).Of all fetal biometric measurements, the abdominal

circumference (AC) is related to the liver size as amajor indicator of fetal glycogen storage and there-fore the single best measurement with the highestsensitivity and negative predictive value for the de-tection of IUGR (7375). Its sensitivity is furtherenhanced by serial measurements at least 14 daysapart (76). The most accurate AC is the smallestdirectly measured circumference obtained at the levelof the hepatic vein between fetal respirations (77).Using a reference range based on healthy womendelivering appropriately nourished neonates at term,an AC %2.5 percentile for gestational age is consis-tent with IUGR. If cross-sectional population refer-ences, including small, appropriately grown, preterm

Fig. 4 A decision tree following the evaluation of fetal anatomy, amniotic fluid volume, umbilical and middle cerebral artery Doppler.The most likely clinical diagnosis is presented on the right-hand side. A high index of suspicion for aneuploidy, viral and nonaneuploidsyndrome needs to be maintained. IUGR " intrauterine growth restriction.


and term newborns are used, the 10th percentile ismore appropriate (78). Compared with the AC thebiparietal diameter, head circumference (HC) andtransverse cerebellar diameters are poor tools for thedetection of IUGR. This is in part the result of theinherent physiological variation in skull shape (79) orthe relative sparing of the head growth and thereforedelayed manifestation of placental insufficiency (80).Ratios of fetal measurements do not improve thedetection of growth delay but could be helpful point-ers toward underlying aneuploidy (8183). Concur-rent measurement of the HC, AC, and femur lengthallows calculation of the sonographically estimatedfetal weight (SEFW). An SEFW below the 10thpercentile for gestational age has a lower sensitivitythan the AC (85% vs. 98%) but a higher positivepredictive value (51% vs. 36%) (75).The next step in the diagnostic assessment is the

evaluation of fetoplacental vascular function. Ran-domized trials and metaanalyses confirm that the useof umbilical artery Doppler in suspected IUGR re-sults in a significant reduction in perinatal mortalityand iatrogenic intervention because documentationof placental vascular insufficiency effectively sepa-rates constitutionally small fetuses from those inneed for surveillance and possible intervention (8486). A more complete assessment of fetoplacentalvascular status can be achieved if the uterine andmiddle cerebral arteries are examined in addition tothe umbilical artery. For qualitative waveform anal-ysis, presence of uterine artery notching and umbil-ical artery end-diastolic velocity (positive, absent, orreversed) should be noted. For clinical Dopplerwaveform analysis, angle-independent indices areused. Of these, the pulsatility index offers the advan-tage of a smaller measurement error, narrower refer-ence limits, and the possibility for ongoing numericalanalysis even when end-diastolic velocity is absent(87,88). In fetuses presenting with IUGR as a resultof placental insufficiency before 34 weeks gestation,the umbilical artery Doppler waveform is frequentlyabnormal. Beyond this gestational age, the umbilicalartery Doppler waveform could be normal. At thesame time, cerebral artery Doppler responses to pla-cental insufficiency still occur (66,89). Therefore, themiddle cerebral-/umbilical-artery Doppler ratio (ce-rebroplacental ratio) could be abnormal in fetuseswith mild placental disease (64,90). Beyond 34weeks gestation, a decrease in the middle cerebralartery Doppler index or the cerebroplacental ratioshould therefore heighten suspicion for IUGR even ifthe umbilical artery blood flow is normal.

Once the suspicion of IUGR is confirmed, fetalkaryotyping should be offered and further specializedtests such as maternal serology (TORCH), thrombo-philia studies, or amniotic fluid viral DNA testingcould be indicated. Once non-treatable underlyingfetal conditions and chromosome abnormalities havebeen ruled out, further antenatal surveillance shouldbe instituted based on the severity of the maternaland/or fetal condition.

AN INTEGRATED APPROACH TO FETAL

SURVEILLANCE IN PLACENTAL

INSUFFICIENCY

Antenatal surveillance in IUGR pregnancies needsto provide longitudinal assessment that is tailored tothe severity of the fetal condition and predictive ofcritical outcomes. Because there are no effectivetherapies for in utero treatment of IUGR fetuses,management options usually include shortening ofmonitoring intervals and delivery when fetal testingsuggests that the intrauterine risks exceed neonatalrisks for adverse outcome. It is increasingly becom-ing apparent that IUGR fetuses are at particularlyhigh risk for prematurity-related complications andadverse outcomes, especially below 32 weeks gesta-tion (4,91). Therefore, the delivery threshold is high-est between viability and 32 weeks placing the great-est demands on the precision of fetal assessment.This requirement for detailed assessment is offset bythe need for practicability to facilitate generalizedapplication. Using our knowledge about the fetalresponses to placental insufficiency and the limita-tions of antenatal testing modalities helps us to for-mulate an appropriate monitoring approach to IUGRfetuses at highest risk. In this context, several prin-ciples are important.In pregnancies that present with fetal growth re-

striction before 34 weeks gestation, umbilical arteryblood flow changes usually precede other cardiovas-cular responses (90,92). Once the diagnosis of IUGRhas been made by biometry and Doppler (see previ-ously in this article), continuing evaluation for dete-rioration of fetal cardiovascular status requires ex-amination of the cerebral circulation and theprecordial veins. When brain-sparing develops, ve-nous Doppler indices are frequently still normal andbiophysical abnormalities are generally not clinicallydetectable. Development of abnormal venous Dopp-ler indices indicates accelerating deterioration(93,94). At this time, abnormalities in biophysicalparameters become clinically apparent. However, be-cause the biophysical profile score is a composite of






5 variables, the overall result may deteriorate rela-tively late (58). When Doppler and biophysical pa-rameters show abnormalities, the information gainedthrough their concurrent evaluation is complemen-tary and offers the best prediction of fetal status andoutcome (53).Accounting for these principles, we use a surveil-

lance approach to pregnancies with IUGR as a resultof placental disease that combines Doppler ultra-sound and biophysical profile scoring (integrated fe-tal testing). The testing is always supplemented withmaternal assessment of fetal movement (kickcounts). Doppler examination includes evaluationof the umbilical artery, middle cerebral artery, ductusvenosus, and free umbilical vein flow velocity wave-form. The traditional nonstress test component of thebiophysical profile score is supplemented by com-puterized fetal heart rate analysis. Monitoring fre-quencies are adjusted to the fetal condition. Before28 weeks, fetuses with isolated elevation of the um-bilical artery Doppler index are followed withweekly biophysical profile scoring and repeat Dopp-ler every other week. If umbilical artery end-diastolicvelocity disappears, MCA Doppler meet criteria forcentralization or amniotic fluid volume declines alltesting (Doppler and biophysical profile score) arerepeated every 3 to 4 days. In patients with elevatedductus venous Doppler index with umbilical venouspulsations, complete testing is repeated every 24hours.The issue of optimal delivery timing for IUGR

fetuses remains unresolved. In principle, the decisionfor delivery always weighs fetal versus neonatal in-tensive-care unit risks. Typically, decline in neonatalmortality is greatest between 24 and 28 weeks,whereas morbidity declines progressively thereaftertoward 32 weeks (91). Perinatal mortality and mor-bidity is greatest among IUGR fetuses with abnormalvenous Doppler indices irrespective of the umbilicalartery Doppler waveform (91,93). Therefore, basingdelivery decision on the umbilical artery waveformalone appears no longer appropriate (95). In pretermIUGR fetuses, we consider abnormal venous Dopplerindices and/or and abnormal BPS as indicators fordelivery. Beyond 34 weeks, in which the frequencyof dramatically abnormal Doppler is lower, we relyon BPS and obstetric factors.Because the outlined surveillance approach requires

multivessel Doppler as well as biophysical profile scor-ing, it can only be performed at centers that are familiarwith both techniques. Modifications of this surveillanceprotocol need to address the limitations of such anapproach. For example, the biophysical profile score

alone offers little in the prediction of longitudinal pro-gression. Thus, if biophysical profile scoring is the onlysurveillance tool, daily testing could be required toassure a good outcome (96). The conclusion of therandomized TRUFFLE study (Trial of umbilical andfetal flow in Europe) will hopefully clarify if deliverytrigger by Doppler versus computerized fetal heart rateanalysis has a measurable impact on outcome. Ongoingrandomized efforts are necessary to refine our under-standing on the relationship between fetal testing vari-ables, intervention, and outcomes.

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