Early Human Development (2005) 81, 877 887

www.elsevier.com/locate/earlhumdev

REVIEW

Arterial and venous Doppler in the diagnosis and management of early onset fetal growth restriction
Ahmet Alexander Baschat *
Department of Obstetrics and Prenatal Medicine, University Hospital Hamburg Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany

KEYWORDS
Growth restriction; Doppler ultrasound; Venous Doppler; Randomized trials

Abstract Key issues in the management of early onset fetal growth restriction (IUGR b 34 weeks) are accurate diagnosis and assessment of fetal well-being to optimize timing of delivery by weighing fetal vs. neonatal risks. Cardiovascular, behavioral and fetal heart rate patterns in IUGR follow a predictable progression that corresponds with the severity of compromise. Umbilical artery (UA) Doppler primarily serves as a placental function test providing insufficient information to solely direct perinatal management. Venosus Doppler is an independent predictor of stillbirth and acidemia and needs to be examined when the UA index is elevated, especially if end-diastolic velocities are absent. Neonatal outcomes are primarily determined by gestational age and their antenatal prediction is too ineffective to guide management. Abnormal venous Doppler, biophysical profile score and mean minute variation of the fetal heart rate are strong predictors of fetal compromise therefore favoring delivery. Randomized trials indicate that delayed delivery has little effects on short-term outcome while producing a trend towards improved early childhood neurodevelopment. This stresses the need for excellent fetal surveillance techniques and their ongoing investigation through randomized management trials. D 2005 Published by Elsevier Ireland Ltd.

Contents 1. 2. 3. 4. 5. 6. Key issues in preterm fetal growth restriction . . . . . . . . . Fetal assessment tools . . . . . . . . . . . . . . . . . . . . . . Doppler evidence of placental dysfunction . . . . . . . . . . . Fetal responses to placental dysfunction . . . . . . . . . . . . Progression to fetal compromise. . . . . . . . . . . . . . . . . Relationship between fetal testing parameters and outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 878 878 879 880 880 882

* Tel.: +49 40 42803 9408; fax: +49 40 42803. E-mail address: aabaschat@hotmail.com. 0378-3782/$ - see front matter D 2005 Published by Elsevier Ireland Ltd. doi:10.1016/j.earlhumdev.2005.09.008

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6.1. Prediction of acidemia . . . . . . . . . 6.2. Prediction of stillbirth . . . . . . . . . 6.3. Prediction of neonatal complications . 6.4. Prediction of neonatal mortality . . . 7. Clinical management. . . . . . . . . . . . . . 7.1. Diagnosis of fetal growth restriction . 7.2. Choice of monitoring intervals. . . . . 7.3. Timing of intervention . . . . . . . . . 8. Key guidelines . . . . . . . . . . . . . . . . . 9. Research directions . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

A.A. Baschat
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1. Key issues in preterm fetal growth restriction

Every fetus has his genetically predetermined growth potential that can be predicted from parental characteristics [1]. Abnormalities in fetal genetic makeup, external factors (e.g. viral infections and toxins), deficient placental development and maternal disease can interfere sufficiently with placental and fetal development to cause intrauterine growth restriction (IUGR). In aneuploidy, non-aneuploid syndromes and viral infections outcomes are largely determined by the underlying etiology. In placental insufficiency, however, outcome is determined by the interactions of fetal condition, maternal status, gestational age and intervention. IUGR fetuses carry the risk of increased perinatal mortality, morbidity as well as developmental delay and health problems all the way into adult life calling for continuous efforts to optimize prenatal identification and management [1]. Although 10% of fetuses have a weight estimate below the 10th percentile the majority of these are normally grown and their classification as bIUGRQ purely increases the risk for iatrogenic prematurity [2]. Identification of IUGR due to placental insufficiency requires exclusion of fetuses with appropriate growth, aneuploidy, syndromes and viral infections. In placental-based IUGR fetal vascular responses are a prominent feature and knowledge of Doppler status improves outcome [3]. While management recommendations have traditionally been based on placental Doppler studies considerable new information on fetal cardiovascular responses has emerged requiring reappraisal and revision of this approach [4]. Most importantly, however, results of both randomized trials and observational studies agree that gestational age remains the major contributor to adverse perinatal outcome with the greatest risk in patients delivered prior to 3234 weeks

gestation [57]. Therefore the key issues in IUGR management today remain: (1) the accurate diagnosis of IUGR; (2) exclusion of fetuses unlikely to benefit from intervention; (3) selection of appropriate fetal surveillance; (4) optimizing timing of intervention, particularly in the subset of IUGR fetuses presenting before 34 weeks gestation. The aim of this article is to address how these issues may be tackled by evaluation of fetal responses to placental dysfunction in recognition of their relationships with fetal status and impacts on perinatal outcome.

2. Fetal assessment tools

Placental vascular dysfunction results in decreased placental nutrient and gas exchange and affects almost every fetal organ system correlating with disease severity [8]. Although fetal manifestations are many, non-invasive assessment today focuses on the cardiovascular and central nervous system effects of placental insufficiency. Doppler assessment, biophysical profile scoring (BPS) and fetal heart rate (FHR) analysis are the primary fetal surveillance modalities. Arterial Doppler waveforms reflect vascular resistance therefore providing information on downstream distribution of cardiac output. Since changes in blood flow resistance relate to vascular structure (e.g. placental histology) and as well as vascular tone (e.g. oxygen-related autoregulation) the primary determinant of the Doppler waveform dependent on the vascular bed was examined. The most widely used arterial indices are the systolic/ diastolic ratio, the resistance index and the pulsatility index (PI). The PI has a smaller measurement error, narrower reference limits and the theoretical advantage of ongoing numerical analysis even when end-diastolic velocity is lost [1]. However, examination of fetal cardiovascular status remains incomplete without knowledge cardiac forward

Arterial and venous Doppler in early onset fetal growth restriction function as assessed by venous Doppler. Forward blood flow in the venous system is determined by cardiac compliance, contractility and afterload and characterized by a triphasic flow pattern (Fig. 1). The magnitude of forward flow during the atrial systole (a-wave) varies considerably in individual veins and reversal may be physiologic in the inferior vena cava and hepatic veins but is always abnormal in the ductus venosus. Abnormal venous flow is characterized by decreasing forward velocities during the a-wave and to a lesser extent during the D-wave [1] (Fig. 1). Multiple venous Doppler indices have been described to characterize this complex waveform without any clear advantages of individual indices [9]. Fetal behavioral responses are related to neurodevelopmental status and the impact of ambient oxygen tension on central regulation of fetal behaviors. Characteristics of the fetal heart rate are determined by autonomic control mechanisms superimposed on intrinsic cardiac activity and the effects of oxygen on their central regulatory centers. With the maturation of the vasomotor center, reticular activating system and central

879

connections increasing central processing of information affects heart rate characteristics throughout gestation. Under normal circumstances successive fulfillment of behavioral milestones progresses from the initiation of gross body movements and fetal breathing, to coupling of fetal behavior (e.g. heart rate reactivity) and integration of restactivity cycles into stable behavioral states (14 F). These developments are accompanied by a steady decrease in heart rate baseline (reflecting increasing vagal tone) and increasing short and long-term variability and variation (reflecting increased central processing). These milestones are generally completed by 32 weeks and heart rate reactivity by traditional criteria is present in 80% of fetuses by this time. The 5 component BPS provides a means to quantify fetal behavior by assessing tone, movement, breathing activity and fetal heart rate reactivity. Amniotic fluid volume (AFV) assessment has traditionally been a part of the BPS. In the second trimester amniotic fluid production is primarily related to fetal urine production and therefore renal perfusion. Through its relationship with vascular status AFV assessment provides the main longitudinal monitoring component of the BPS and accordingly carries a higher weight in the overall grading of the score. Visual FHR analysis has traditionally been the method of choice posing the problems of inter- and intraobserver variability. These are circumvented by computerized analysis of the fetal heart rate (cCTG). The cCTG assesses short-term, long-term and mean minute variation in addition to traditional FHR parameters that also allow longitudinal observations [1].

3. Doppler evidence of placental dysfunction

Figure 1 Top panel: In the venous Doppler waveform systolic and diastolic peaks (the S- and D-wave) are generated by the descent of the AV-ring during ventricular systole and passive diastolic ventricular filling, respectively. A second late diastolic trough after the Dwave is the consequence of sharply increasing right atrial pressures during atrial systole (the a-wave). Middle panel: With declining forward cardiac function forward velocity during atrial systole (*) and to a lesser degree during diastole decreased. This is associated with an increase in venous Doppler indices. Bottom panel: When ductus venosus Doppler indices escalate absence or reversal of forward flow during atrial systole (**) may be observed as the most marked Doppler abnormality.

Placental dysfunction in IUGR pregnancies can affect the maternal-, fetal-, or both placental vascular compartments. Defective trophoblast invasion and failure of physiologic transformation of uterine vessels result in persistent uterine artery bnotchingQ and/or elevation of the uterine artery Doppler index [1]. Abnormal vascular tone as well as obliterative loss of fetal villous vessels raises umbilical artery Doppler resistance. A decrease in end-diastolic velocity becomes apparent when some 30% of placenta is affected and progresses to absent- or reversed end-diastolic velocity (UA A/REDV) when the damage extends to 6070% [1].

880

A.A. Baschat typically observed at a mean pH between 7.10 and 7.20. Abolition of tone and movement is characteristic as the pH drops further [1]. Fetal heart rate variability and variation decline under these circumstances and overt decelerations of the fetal heart rate may occur. If reduction of amniotic fluid volume leads to oligo- or even anhydramnios variable decelerations are likely. Late decelerations of the fetal heart rate are due to a relative drop in oxygen tension that exceeds 8 Torr (classical late decelerations), or due to depressed cardiac contractility (cardiac late decelerations).

4. Fetal responses to placental dysfunction

Once placental vascular dysfunction compromises nutrient delivery sufficiently to trigger fetal mobilization of hepatic glycogen stores physical manifestation of growth delay becomes apparent. In addition to the physical manifestation of growth delay characteristic cardiovascular and behavioral responses may be observed. In the fetal circulation the combination of elevated placental blood flow resistance and impaired transplacental gas transfer has several effects. Venous shunting across the ductus venosus increases the proportion of umbilical venous blood that bypasses the liver and reaches the left side of the heart through the foramen ovale [1,8]. Elevation of right ventricular afterload (placental resistance) forces redistribution of cardiac output towards the left ventricle and the relative proportion of left ventricular output rises. Through these two mechanisms the supply of nutrient and oxygen-rich blood to the heart and brain increases [1,8]. Several vascular beds show individual changes in blood flow dynamics (Table 1). The overall effect of these vascular responses appears to be increased perfusion of organs that are vital in fetal life by compromising blood flow to less critical organs. Decompensation of cardiovascular function is due to a decline in forward cardiac function and manifested by abnormal venous Doppler indices [1,8,10]. This impaired preload handling can be documented in the precordial veins (ductus venosus, inferior vena cava, superior vena cava), the hepatic veins as well as head and neck veins (jugular vein and cerebral transverse sinus) [1,8]. If this failure to accommodate preload is progressive, umbilical venous pulsations may be observed as the ultimate reflection of increased central venous pressure. Organ autoregulation may become dysfunctional (normalization of cerebral Doppler indices), or exaggerated (coronary vasodilatation, liver sparing) [1,8]. Persistent excessive shunting across the ductus venosus compromises hepatic perfusion triggering hepatic artery vasodilatation as an alternative source of hepatic blood supply. Liver damage with elevated transaminases is an important contributor to metabolic deterioration under these circumstances [8] (Table 1). Effects of placental insufficiency on biophysical parameters are related to deterioration of fetal acid-base status. Reduction of global fetal activity and loss of fetal coupling (abolition of heart rate reactivity and fetal breathing movements) are

5. Progression to fetal compromise

Longitudinal observation of fetal cardiovascular and biophysical parameters offers insight into disease severity and acceleration and therefore is critical for the planning of longitudinal surveillance. With advancing fetal metabolic compromise progression of early to late cardiovascular and behavioral responses follows a reasonably predictable pattern in preterm IUGR [7,1113]. Early cardiovascular responses are readily apparent when detection of abnormalities in biophysical parameters requires sophisticated examination techniques. In contrast, late cardiovascular abnormalities require a more advanced Doppler examination technique while biophysical abnormalities become readily recognizable (Fig. 2). With mild placental vascular abnormality umbilical and middle cerebral artery Doppler index deviations may be subtle. In such circumstances a decrease in the cerebroplacental Doppler ratio provides an early and sensitive marker of redistribution of cardiac output often preceding overt growth delay by up to 2 weeks [14]. With more marked placental disease the reduction of fetal growth velocity generally mirrors the elevation in umbilical artery blood flow resistance and is followed by decreasing middle cerebral artery impedance and a decline in amniotic fluid index [4,13,14]. At this time traditional heart rate reactivity may also be lost. Once the nadir of cerebral blood flow resistance is reached aortic blood flow impedance increases [15,16]. These bearlyQ responses are typically accompanied by impedance changes in several peripheral arterial vascular beds that are mediated through intact autoregulation and contribute to preferential perfusion of vital organs and the placenta. At this stage behavioral and FHR responses primarily reflect delayed maturation of central control mechanisms [1,8].

Arterial and venous Doppler in early onset fetal growth restriction

Table 1 Summary of arterial and venous Doppler findings in placental insufficiency
Physiologic significance

881

Doppler finding Uterine artery notching

Decreased, absent, or reversed umbilical artery end-diastolic velocity

Elevation of blood flow resistance in the thoracic aorta and iliac artery

1.) Decrease in the cerebroplacental Doppler ratio 2.) Direct measurement of cardiac output 3.) Reversal of end-diastolic velocity in the aortic isthmus 4.) Absence or reversal of umbilical artery end-diastolic velocity Decrease in the carotid-, or middle cerebral artery Doppler index Increased superior mesenteric artery Doppler resistance

Decrease in the splenic artery Doppler index

Decreased Doppler resistance in the celiac axis

Increased Doppler resistance in peripheral pulmonary arteries

Increased Doppler resistance in the renal arteries

Measured dilation of the ductus venosus with elevated Doppler index accompanied by a decreased hepatic artery Doppler index Decreased Doppler index in the adrenal artery flow velocity waveforms Umbilical venous pulsations in association with elevated venous Doppler indices Normalization of cerebral Doppler indices after a period of bbrain sparingQ

Sudden ability to visualize and measure coronary. Blood flow in a setting of deteriorating venous Doppler indices in a premature IUGR fetus

Trophoblast invasion remains limited to the myometrial portion of the spiral arteries. Subsequent failure to fully transform into a low resistance, high capacitance vascular bed increases risk for subsequent IUGR and/or preeclampsia. Abnormal terminal villi and stem arteries result in increased placental vascular resistance and a proportional decrease in the umbilical artery end-diastolic velocity. Associated placental perfusion defects are responsible for impaired feto-maternal gas and nutrient exchange. Hind limb reflex: Diversion of blood flow away from the carcass at the expense of the lower body. Achieved through increase in right ventricular afterload proximal to the umbilical arteries as well as increased blood flow resistance distally. In addition to centralization (see below) descending aortic blood flow is also preferentially distributed to the placenta. Centralization: A measurable shift in the relationship between right and left ventricular afterload, that results in redistribution of cardiac output in favor of the left ventricle (i.e. the heart and brain). This can be passively mediated purely by an increase in placental blood flow resistance and therefore right ventricular afterload. Brain sparing: Cerebral vasodilatation in response to perceived hypoxemia. During perceived hypoxemia and/or redistribution of cardiac output blood flow to the gut as a nonessential organ in utero is compromised. Splenic artery vasodilatation enhances perfusion of this important hematopoietic organ possibly facilitating an increase in red cell mass. The may be a reflection of blood flow augmentation in the hepatic and splenic arteries which are the main branches of this axis. As non-essential organs in fetal life lung perfusion may be further compromised by increased vascular resistance in the pulmonary circulation ensuring that a greater proportion of right ventricular output bypasses the lungs to reach the placenta. Redistribution and increased renal vascular tome may be the mediators of oliguria and oligohydramnios observed with chronic and/or progressive hypoxemia. Liver sparing: Preferential arterial blood supply to the fetal liver invoked when increased diversion of umbilical venous blood through the ductus venosus jeopardizes hepatic perfusion. Adrenal sparing: Enhanced adrenal perfusion is triggered as part of the fetal stress response to chronic or acute-on-chronic malnutrition. Evidence of inefficient forward delivery of cardiac output with subsequent elevation of central venous pressure that is transmitted all the way back into the umbilical vein With advanced cardiovascular deterioration brain autoregulation may become abnormal. Probably in association with a decrease in cardiac function the interval between systolic and diastolic velocities widens resulting in an increase (thus normalization) of the Doppler index. Heart sparing: Marked augmentation of coronary blood flow in situations of acute on chronic hypoxemia that is achieved through up-regulation of coronary vascular reserve and vasodilatation.

882
Early
abnormal UA (EDV decreased) redistribution of cardiac output (decreased CPR)

A.A. Baschat
Late
absent / reversed UA EDV Normalization abnormal precordial veins UV-pulsation DV-RAV declining amniotic fluid volume

Doppler

brain sparing

BPS

Fetal Death

Delayed maturation of fetal behavioral states

Delayed maturation of FHR control

FHR

declining global activity Loss of breathing Loss of movement Increased baseline Loss of tone Absent reactivity Decreasing variation variation loss late decelerations

Acid base

pO2

pH

Figure 2 Early and late fetal cardiovascular and behavioral responses to placental insufficiency follow a relatively predictable progression as displayed in this diagram. Elevation of the umbilical artery (UA) Doppler index, redistribution of blood flow and/or brain sparing are early Doppler signs evident before biophysical (BPS) and fetal heart rate (FHR) abnormalities are clinically manifested. With progressive cardiovascular deterioration absent, or reversed umbilical artery end-diastolic velocity (EDV) and venous Doppler abnormality is characteristic. These changes often precede the sequential loss of fetal dynamic variables frequently accompanied by a decline in amniotic fluid volume. Absence, or reversal of atrial forward velocities in the ductus venosus (DV RAV) and cessation of movement and tone are associated with metabolic acidemia and a high risk for stillbirth. If adaptation mechanisms fail and the fetus remains undelivered stillbirth ensues.

Accelerating disease and the onset of decompensation are evident through parallel elevations in placental blood flow resistance and precordial venous Doppler indices (inferior vena cava and ductus venosus) that are inversely correlated with fetal heart rate variation and variability [7,12,13]. Absence of umbilical artery end-diastolic velocity is characteristic in this setting. With chronic fetal hypoxemia global fetal activity declines and breathing movements are lost [8,13]. When fetal compromise accelerates there is a further steady rise in umbilical blood flow resistance while venous Doppler indices escalate over a wide range [7,10,11]. Reversed umbilical artery end-diastolic velocity and overtly abnormal venous Doppler indices and the development of oligohydramnios are characteristic with ineffective downstream delivery of cardiac output, the short-term variation of the FHR becomes abnormal and tone and movement are lost [12,13,16]. Cardiac dilatation with holosystolic tricuspid insufficiency and spontaneous bcardiacQ late decelerations are preterminal events. If the fetus remains undelivered stillbirth is likely. The rate of this progression is variable and partly

determined by degree of placental vascular dysfunction, gestational age and the coexistence of maternal; disease [1,4,8] (Fig. 2).

6. Relationship between fetal testing parameters and outcome

The relationship between monitoring parameters and perinatal outcomes determines intervention thresholds. Prevention of long-term morbidity is an attractive goal but interactions between fetal status, gestational age at delivery, neonatal complications are still too incompletely understood to guide clinical management. Although a wide range of short-term outcome parameters has been investigated only few are presently of true clinical relevance. Fetal acidemia and major neonatal complications have a significant impact on subsequent neurodevelopment while the combination of fetal and neonatal deaths determines the overall perinatal mortality [1,4,17]. Antepartum prediction of fetal acidemia and stillbirth are therefore currently the strongest criteria

Arterial and venous Doppler in early onset fetal growth restriction driving intervention for fetal indications, while gestational age specific expectations for neonatal complications and survival force conservative management. Many arterial and venous Doppler parameters have been related to these critical perinatal outcomes, but to keep fetal surveillance practicable, representative and evidencebased, the examination needs to be limited to relevant vessels. Efficient and comprehensive assessment of placental vascular function and fetal cardiovascular status can be achieved by examination of the umbilical artery, middle cerebral artery, precordial veins (inferior vena cava, ductus venosus) and the umbilical vein. The umbilical artery flow velocity waveform primarily reflects villous vascular architecture and therefore serves as a placental function test. Although the risk for adverse outcome is proportional to the degree of UA Doppler abnormality their accurate prediction is not possible with the use of this vessel alone [4].

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6.2. Prediction of stillbirth

Abnormal venous Doppler parameters are the strongest peripheral Doppler predictors of stillbirth. Even among fetuses with severe arterial Doppler abnormalities (e.g. absent/reversed umbilical artery end-diastolic velocity) the risk of stillbirth is largely confined to those fetuses that have abnormal venous Dopplers [4]. The likelihood of stillbirth increases with the degree of venous Doppler abnormality. Venous Doppler findings that are particularly ominous are absence, or reversal of the ductus venous a-wave and biphasic/triphasic umbilical venous pulsations. In the setting of a 25% stillbirth rate in a preterm severe IUGR population these Doppler findings have a 65% predictive sensitivity and 95% specificity [4,20]. In IUGR fetuses the BPS deteriorates late and often rapidly making it unsuitable for the prediction of stillbirth unless daily testing is performed [13,21].

6.3. Prediction of neonatal complications 6.1. Prediction of acidemia

Since Doppler parameters are influenced by several variables their relationship with acid-base status is not only variable, but also dependent on the vascular system examined and prevalence of Doppler abnormality and acidemia in the tested population [1,9]. Brain sparing in the presence of normal venous Doppler parameters identifies IUGR fetuses at risk for hypoxemia. Elevation of venous Doppler indices, either alone, or in combination with umbilical venous pulsations increases the risk for fetal acidemia. This association is strengthened by serial elevations of the ductus venosus Doppler index [7]. Dependent on the cutoff (2 vs. 3SD) and the combinations of veins examined sensitivity for prediction of acidemia ranges from 7090% and specificity from 7080% [9,18]. Because IUGR fetuses preserve their central responses to acidbase status despite their maturational delay the close relationship between the BPS and arterial pH is maintained in the second half of pregnancy. An abnormal score of 4, or less is associated with a mean of pH b 7.20 and sensitivity in the prediction of acidemia is 100% for a score of 2, or less [13]. Combination of multi-vessel Doppler and BPS is therefore complementary in the prediction of acidbase status and critical perinatal outcomes [1]. When utilizing the cCTG analysis of the FHR a mean minute variation below 3.5 ms is most predictive of an umbilical artery cord pH b 7.20 at birth [19]. Gestational age is the primary determinant of neonatal complications such as respiratory distress syndrome, bronchopulmonary dysplasia and intraventricular hemorrhage followed by birth weight and the degree of growth restriction [1,47,23]. Therefore prediction of neonatal variables by fetal status is difficult. However, after gestational age is accounted for impacts of fetal Doppler status on neonatal outcomes become apparent. Arterial redistribution and brain sparing are not associated with a significant rise in perinatal morbidity. A 2 SD elevation of the DV Doppler index is associated with a 3-fold increase in major neonatal complications [4,5,7]. Further escalation of ductus venosus Doppler indices increases this relative risk to 11-fold [7]. The association between the BPS with neonatal morbidity is well documented in over 100,000 pregnancies. The neonatal complication rate of 35% in the presence of an equivocal score rises as high as 100% when the score deteriorates further [13].

6.4. Prediction of neonatal mortality

Neonatal mortality is determined by multiple factors including gestational age at delivery and the occurrence and severity of neonatal complications. The expected neonatal mortality rate of approximately in fetuses with UA A/REDV is variable ranging between 5 and 18% when the venous Doppler indices are normal. An increase in the DV Doppler index doubles this mortality rate although

884 predictive sensitivity is only 38% (specificity 98%) in this setting [4,20]. However although abnormal venous Doppler is associated with a higher rate of postpartum complications the ultimate impact on their occurrence and on overall mortality is due to gestational age at delivery [1,47,23].

A.A. Baschat BPS, cCTG or integrated fetal testing will improve short-term outcome in placental-based IUGR across the whole disease spectrum, or if benefits are confined to certain gestational ages. The following approach to the diagnosis, longitudinal monitoring and delivery timing based on the evaluation of fetal well-being has been put together with these caveats in mind.

7. Clinical management
Observational studies of IUGR pregnancies are essential to expand our knowledge on the pathophysiology and clinical features of this disease providing useful information on associations between fetal status and many outcome parameters. Because observational studies are often problem focused and biased they never truly reflect the complete picture and impacts of interventions needed to be investigated through prospective, randomized, management studies. There are only few randomized management studies of IUGR pregnancies that incorporate arterial Doppler findings and none that investigate management based on venous Doppler. Patient management that is directed towards fetuses with small size and abnormal placental Doppler studies reduces antenatal testing and induction rates in the low-risk population without jeopardizing outcome [3,23]. In IUGR pregnancies presenting in such a way before 34 weeks gestation obstetricians are sufficiently uncertain about delivery timing to accept random allocation. In these patients delivery timing had little effects on short-term outcome although earlier delivery produces a trend towards more disability in early childhood [22]. The lacking relationship between delivery timing and short-term outcomes suggests either that background morbidity predetermined by gestational age may not be altered by obstetric management and/or that physicians already deliver at an optimal time to minimize mortality. At the same time these data also suggest that monitoring and management protocols are insufficient to guide delivery prior to damage of brain development and/or fetal death. This stresses the need for excellent surveillance if conservative management is elected. Since prediction of fetal outcomes appears more accurate at the present time delivery indications presently need to be primarily based on fetal risks. It was previously shown that clinical management of IUGR fetuses with UA AEDV by daily BPS monitoring with strict delivery indications can prevent stillbirth and acidemia at birth [21]. It is presently unknown if management that is based on multi-vessel Doppler,

7.1. Diagnosis of fetal growth restriction

Identification of IUGR fetuses with placental insufficiency and exclusion of other etiologies not amenable to intervention can be achieved through a detailed anatomic survey, fetal biometry, assessment of amniotic fluid volume and placental Doppler studies. With normal fetal anatomy and normal or low amniotic fluid volume placental-based IUGR is likely when a small AC measurement is found in association with an elevated UA Doppler index, and/or a decreased cerebroplacental Doppler ratio [2325]. The smallest directly measured circumference obtained between fetal respirations should be used. A cutoff b 10th percentile is recommended if reference ranges are based on healthy women delivering appropriately nourished neonates at term, while the 2.5th percentile is more appropriate if cross-sectional population references include small, appropriately grown, preterm and term newborns. Sensitivity of this approach is enhanced by serial AC measurements at least 14 days apart. Fetal karyotyping should be considered in any fetus with suspected IUGR, although local practices may vary (Fig. 3).

7.2. Choice of monitoring intervals

The choice of monitoring interval depends on the anticipated speed of clinical deterioration, risk for impending acidemia and/or stillbirth. In fetuses with elevated UA pulsatility and positive enddiastolic flow and absence of any additional abnormality fortnightly Doppler monitoring is sufficient. With the onset of brain sparing monitoring intervals should be shortened to weekly visits. In fetuses with oligohydramnios or UA AEDV surveillance every 34 days is suggested. Elevation of the ductus venosus Doppler index to N 2 SD should prompt 23 daily testing. With further increase of ductus venosus Doppler index daily testing becomes necessary and inpatient admission may be prudent based on local practice. Any change in maternal condition, especially the development of preeclampsia calls for reassess-

Arterial and venous Doppler in early onset fetal growth restriction

Abdominal circumference < 2.5 to 10th percentile

885
Likely diagnosis
Aneuploidy Syndromes Viral infection

Anatomy survey Amniotic fluid volume

If abnormal If increased

normal anatomy, normal or decreased amniotic fluid

Umbilical artery Middle cerebral artery Doppler

elevated index, A/REDV decreased index

Both normal

Cerebroplacental ratio

decreased ratio

Growth restriction secondary to placental insufficiency

Normal

repeat examination at 14 days

If normal

Constitutionally small fetus

Figure 3 The diagnostic approach to fetuses with a small abdominal circumference requires exclusion of nontreatable causes of IUGR and constitutionally small fetuses without growth restriction. This decision tree is based on evaluation of fetal anatomy, amniotic fluid volume, umbilical and middle cerebral artery Doppler and provides the most comprehensive approach. A high index of suspicion for aneuploidy, viral and non-aneuploid syndrome needs to be maintained. A/REDV = absent, or reversed end-diastolic velocity.

ment of fetal status irrespective of the last examination result.

7.3. Timing of intervention

The two principle therapeutic interventions in IUGR pregnancies are the administration of prenatal steroids and delivery. The administration of a completed course of steroids is recommended until 34 + 0 weeks gestation, as IUGR fetuses do not derive a maturation benefit from intrauterine stress that warrants the omission of this effective therapy [1,2,6,22]. Delivery is indicated when the risk for fetal acidemia and/or stillbirth is high. This is the case when the ductus venosus Doppler index elevation escalates beyond 3 standard deviations, DV-RAV is observed with accompanying umbilical venous pulsations. Other indicators are a BPS less than 6, anhydramnios, fetal heart rate variation below 3.5 ms or overt fetal distress. The interpretation if test results from the three modalities are in disagreement with each other has not been sufficiently studied. However, a vigorous fetus with normal amniotic fluid volume is unlikely to suffer relevant metabolic compromise even if the venous Doppler index is elevated. Conversely, isolated abnormality of the cCTG is unlikely to be of clinical relevance if all other testings are reassuring. Ultimately the decision for delivery is critically influenced by gestational

age. An ongoing study of prenatally identified IUGR fetuses with elevated placental blood flow resistance suggests that the effect of gestational age overshadows all other perinatal variables until approximately 27.0 weeks when survival and intact survival first exceed 50% (personal communication). The following approach is therefore suggested. Until 27.0 weeks gestation and/or an estimated fetal weight below 500 g delivery thresholds should be high. Indications for delivery should ideally be based on strong corroborating evidence for fetal compromise from several modalities. Abnormal venous Doppler abnormalities with an abnormal biophysical profile score provide the strongest evidence in this setting. Patients need to be counseled that chance for survival and intact survival is poor under these circumstances even with the highest level of neonatal intensive care. Once these gestational and weight thresholds are passed improved outcomes can be expected for similar delivery indications. It is currently unknown when this approach can be modified to deliver earlier in order to prevent ongoing fetal compromise. In over 300 IUGR fetuses delivered prior to 32 weeks of survival we observed survival and intact survival of 80% after 29 weeks of gestation (personal communication) suggesting that this may be a time to individualize intervention thresholds. However, in the absence of rando-

886 mized proof such practice needs to be included as part of multidisciplinary counseling.

A.A. Baschat ! Management thresholds with respect to gestational age and/or expected birth weight need to be established. ! Relationship between test results from different surveillance modalities and their relative accuracies in predicting critical outcomes still need to be determined. ! A randomized management study utilizing venous Doppler to direct delivery timing is necessary. ! Modification of neonatal management based on prenatally available information of fetal status is an almost unexplored avenue to improve outcome.

8. Key guidelines
! An abdominal circumference below the b2.5 percentile (reference ranges based on a mixed group of high- and low-risk pregnancies) or below the 10th percentile (reference ranges based on normal pregnancies only) is the most sensitive biometric parameter to detect growth delay. ! Umbilical artery Doppler is the best method to evaluate the fetal compartment of the placental circulation. ! The combination of a small AC, normal anatomy, low or normal amniotic fluid volume and abnormal umbilical artery Doppler is strongly suggestive of IUGR due to placental insufficiency. ! The possibility of aneuploidy, syndromes and viral infection should always be considered and fetal karyotyping should be offered. ! Fetal cardiovascular and behavioral deterioration follows a relatively predictable pattern progressing from early to late changes. ! Direction of surveillance and intervention is inaccurate if based on umbilical artery Doppler alone. Examination of the cerebral and venous circulation is mandatory if Doppler surveillance is chosen as the primary management tool. ! For arterial vessels the Pulsatility index offers the narrowest reference limits and measurement error. Multiple venous Doppler indices have been described without any clear advantage of individual indices. ! The monitoring intervals are shortened with progressive cardiovascular compromise. ! Once delivery becomes imminent before 34 weeks steroids should be administered. ! Delivery should be performed when there is strong evidence for fetal acidemia and/or impending stillbirth. Ductus venosus index escalation beyond 3 SD deviation or absence or reversal of the a-wave, is strong evidence. Corroborating evidence from biophysical and computerized heart rate analysis should be sought whenever possible. ! Randomized management studies on venous Doppler for delivery timing of the preterm IUGR fetus are still lacking.

References
[1] Baschat AA, Hecher K. Fetal growth restriction due to placental disease. Semin Perinatol 2004;28:67 80. [2] Zeitlin J, Ancel PY, Saurel-Cubizolles MJ, Papiernik E. The relationship between intrauterine growth restriction and preterm delivery: an empirical approach using data from a European case-control study. BJOG 2000;107: 750 8. [3] Bakketeig LS, Jacobsen G, Brodtkorb CJ, Eriksen BC, EikNes S, Ulstein MK, et al. Randomized controlled trial of ultrasonographic screening in pregnancy. Lancet 1984;2: 207 11. [4] Baschat AA. Doppler application in the delivery timing of the preterm growth-restricted fetus: another step in the right direction. Ultrasound Obstet Gynecol 2004; 23:111 8. [5] Baschat AA, Gembruch U, Reiss I, Gortner L, Weiner CP, Harman CR. Relationship between arterial and venous Doppler and perinatal outcome in fetal growth restriction. Ultrasound Obstet Gynecol 2000;16:407 13. [6] The GRIT Study Group. A randomised trial of timed delivery for the compromised preterm fetus: short term outcomes and Bayesian interpretation. BJOG 2003;110:27 32. [7] Bilardo CM, Wolf H, Stigter RH, Ville Y, Baez E, Visser GHA, et al. Relationship between monitoring parameters and perinatal outcome in severe, early intrauterine growth restriction. Ultrasound Obstet Gynecol 2004;23:119 25. [8] Baschat AA. Fetal responses to placental insufficiency: an update. BJOG 2004;111:1031 41. [9] Baschat AA, Guclu S, Kush ML, Gembruch U, Weiner CP, Harman CR. Venous Doppler in the prediction of acid base status of growth-restricted fetuses with elevated placental blood flow resistance. Am J Obstet Gynecol 2004;191:277 84. [10] Hecher K, Campbell S, Doyle P, Harrington K, Nicolaides K. Assessment of fetal compromise by Doppler ultrasound investigation of the fetal circulation. Arterial, intracardiac, and venous blood flow velocity studies. Circulation 1995;91:129 38. [11] Ferrazzi E, Bozzo M, Rigano S, Bellotti M, Morabito A, Pardi G, et al. Temporal sequence of abnormal Doppler changes in the peripheral and central circulatory systems of the severely growth-restricted fetus. Ultrasound Obstet Gynecol 2002;19:140 6. [12] Hecher K, Bilardo CM, Stigter RH, Ville Y, Hackeloer BJ, Kok HJ, et al. Monitoring of fetuses with intrauterine growth restriction: a longitudinal study. Ultrasound Obstet Gynecol 2001;18:564 70.

9. Research directions
! Gestational age specific mortality and morbidity rates of placental-based IUGR fetuses still need to be established.

Arterial and venous Doppler in early onset fetal growth restriction

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