Fetal growth restriction due to placental disease

Fetal Growth Restriction due to Placental Disease Ahmet A. Baschat* and Kurt Hecher†

Normal fetal growth depends on the genetically predetermined growth potential and its modulation by the health of the fetus, placenta and the mother. Fetuses that are small because of intrauterine growth restriction (IUGR) are at higher risk for poor perinatal and long-term outcome than those who are appropriately grown. Of the many potential underlying processes that may result in IUGR, placental disease is clinically the most relevant. Fetal cardiovascular and behavioral responses to placental insufficiency and the metabolic status are interrelated. The concurrent evaluation of fetal biometry, amniotic fluid volume, heart rate patterns, arterial and venous Doppler, and biophysical variables therefore allow the most comprehensive fetal evaluation in IUGR. In the absence of successful intrauterine therapy, the timing of delivery is perhaps the most critical aspect of the antenatal management. A discussion of the fetal responses to placental insufficiency and a management protocol that accounts for multiple Doppler and biophysical parameters as well as gestational age is provided in this review. © 2004 Elsevier Inc. All rights reserved. ince the landmark observations of Lubchenco et al in 1963, it is becoming increasingly apparent that neonates who fail to fulfill their growth potential in fetal life are at increased risk for adverse health events throughout life.1-5 It is the aim of modern perinatology to identify fetuses with intrauterine growth restriction (IUGR) early enough to institute appropriate intervention and hopefully prevent further damage. This process requires knowledge about the etiology, pathophysiology, natural history, prognostic factors, and effects of intervention. Because our knowledge is expanding in all aspects of this disease, ongoing reappraisal is necessary to incorporate new information into the clinical management. Neonatal weight, size and condition at birth are dependent on 4 principle variables. The genetically predetermined growth potential modulated by the health of the fetus, placenta, and the mother. Successful implantation of a genetically normal fetus and placenta in a healthy mother is most likely to produce a healthy baby. On the other hand, if any of these factors is deficient, adverse pregnancy outcome and/or fetal growth restriction may be the consequence. Therefore, IUGR is a not a specific disease per se, because it may be the manifestation of a variety of conditions. Because outcome is often dependent on the etiology an attempt at identification of the underlying disease is an essential

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first step to direct appropriate management in a patient in whom fetal growth failure is suspected. The many causes of IUGR have traditionally been subdivided into fetal, placental and maternal. From a clinicians standpoint fetal abnormalities (both chromosomal and/or anatomic) and abnormal placental vascular development in the fetal and/or maternal compartments are responsible for the vast majority of IUGR in singleton pregnancies.6-10 Maternal causes such as chronic renal disease, hypertension, collagen vascular disease, thrombophilia, and aggravating circumstances such as smoking, malnutrition, and drug use are either readily apparent through the maternal history or can be determined with relatively minor effort. Prenatal ultrasound evaluation and invasive fetal testing offer the opportunity to investigate fetal causes. This review focuses on the pathophysiology, diFrom the *Department of Obstetrics, Gynecology & Reproductive Sciences, Center for Advanced Fetal Care, University of Maryland, Baltimore, MD; and †Department of Fetal Diagnosis and Therapy, Allgemeines Krankenhaus Barmbek, Hamburg, Germany. Address reprint requests to Ahmet A. Baschat, MD, Department of Obstetrics, Gynecology & Reproductive Sciences, Center for Advanced Fetal Care, 405 W. Redwood St, 4th Floor, University of Maryland, Baltimore, MD 21201. © 2004 Elsevier Inc. All rights reserved. 0146-0005/04/2801-0008$30.00/0 doi:10.1053/j.semperi.2003.10.014

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agnosis, and management of IUGR caused by placental vascular disturbance.

Fetal Consequences of Placental Vascular Insufficiency Adequate fetal growth depends on the efficient delivery of nutrients from the mother to the fetus and therefore requires normal uterine perfusion, normal transplacental exchange of nutrients and waste and normal umbilical perfusion. Glucose and essential aminoacids are actively transported across the placenta and metabolized aerobically by the fetus.11,12 The glucose/insulin/insulin-like growth factor (ILF) axis plays a central role in tissue-specific growth regulation during critical periods of development and overall regulation of fetal growth.13 Because approximately 70% of glucose and 45% of oxygen are used by the placenta itself, adequate fetal delivery of nutrients and oxygen is dependent on uterine perfusion, fetoplacental exchange area and high oxygen affinity of fetal hemoglobin.14,15 Drastic changes in maternal and fetal placental blood flow dynamics are necessary to accommodate accelerating fetal growth with advancing gestation. With successful trophoblast invasion and increased compliance of the spiral arteries a low impedance high capacitance placental vascular bed is established. As a result, an increasing proportion of maternal cardiac output is distributed to placental cotyledons as gestation advances and blood flow volumes reach 500 to 600 mL/minute at term.16-18 In the fetal vascular compartment of the placenta, this process is paralleled by increases in villous and capillary surface areas resulting in marked decrease in umbilical vascular resistance and an increase in the exchange area.19 Concurrently fetal cardiac function increases exponentially permitting an almost 5- to 10-fold rise in umbilical artery and venous volume flow with advancing gestation.20-23 This increase is necessary to maintain a relatively constant blood flow volume/Kg fetal body weight throughout gestation.21,22 Once nutrients have entered the fetal circulation through the umbilical vein their distribution to vital organs such as the liver, heart, brain, and kidney is insured by the unique dynamics of the fetal circulation. Venous shunting at the level of the ductus venosus modifies the proportion of nutrient rich blood that is distributed to

the liver and heart.24 At the level of the right atrium differential directionality of the incoming bloodstreams ensures that nutrient rich blood is distributed to the heart and brain while venous return is distributed to the placenta for re-oxygenation and nutrient and waste exchange.25,26 In addition to this overall distribution of left- and right-sided cardiac output, several organs are able to modify local blood flow to meet oxygen and nutrient demands by the process of autoregulation.23 The consequences of uteroplacental insufficiency are complex since fetoplacental respiratory function is affected at multiple levels. Nutrient delivery, placental uptake, and distribution within the fetus as well as delivery of waste to the placenta are deficient. The combination of these factors is responsible for the multisystem disorder that constitutes IUGR. In IUGR fetuses, transplacental transfer of oxygen, glucose, and aminoacids is impaired and pancreatic insulin responses to glucose are blunted.28-31 The relative hypoinsulinemia may decrease placental glucose transfer even further.32,33 This places the fetus into a situation where supply of oxygen and substrate and therefore the ability for aerobic metabolism and tissue growth become limited. Enhanced erythropoiesis may improve oxygen carrying and buffering capacity through increases in red cell mass and hemoglobin concentration.34 Other nutrient demands are harder to accommodate. Hepatic glycogen stores may initially provide a limited supply of glucose. Eventually gluconeogenic aminoacids from endogenous tissue catabolism may serve as an alternative nutrient sources.35-39 With these limitations, lactate production through anaerobic metabolism increases. Although glucose is the primary fuel for the brain and heart, lactate and ketones become substitutes during prolonged hypoglycemia.40 Under such circumstances cardiac metabolism may remove up to 80% of the circulating lactate.41,42 Concurrently increases in vessel caliber in various oxygen sensitive vascular beds optimize perfusion in vital organs while perfusion to less vital parts of the body may be compromised. Sequential decline in fetal dynamic variables such as heart rate variation, movement, and tone help to conserve energy.43 Fetal adaptations are therefore made at many levels and if compensatory mechanisms are suc-

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cessful fetal survival and even growth are possible. Fetal decompensation sets in when adaptation cannot maintain organ function and is characterized by concurrent failure of forward cardiac function, metabolic acidemia and loss of normal fetal behavior and finally stillbirth.44-46 Impairment of placental transport mechanism cannot be directly measured but may be inferred by the degree of vascular insufficiency. A number of cardiovascular and central nervous system (CNS) responses in IUGR fetuses have been described.

Circulatory Findings in Uteroplacental Insufficiency Elevation of the uterine artery Doppler index and/or persistence of an early diastolic notch beyond the mid-trimester is evidence of abnormal trophoblast invasion, placental bed infarcts and enhanced apoptosis47,48 (Fig 1). Decrease, absence, or reversal of umbilical artery end-diastolic velocity indicate progressive increases in blood flow resistance due to loss of tertiary villous vessels49 (Fig 2). Disturbed feto-placental perfusion also effects venous return and a decrease in umbilical venous volume flow is observed and precedes the onset of overt growth delay.50 Abnormal flow patterns in the uterine arteries identify patients at risk for pre eclampsia, placental abruption, and IUGR,51 while abnormal umbilical flow patterns indicate increased risk for hypoxemia and acidemia proportional to the severity of Doppler abnormality.49 Several fetal arterial blood flow characteristics may accompany elevated placental blood flow resistance. There may be elevation of thoracic and descending aortic blood flow impedance,52-54 reflecting the elevated blood flow resistance in the placenta and/or the lower limb (“hind limb reflex”).55 Through the parallel arrangement of the fetal circulation elevated fetoplacental blood flow resistance favors redistribution of cardiac output towards the left ventricle and therefore cardiac and cerebral circulations. This redistribution can be verified by direct measurement of cardiac output or by demonstrating end-diastolic flow reversal in the aortic isthmus.56-58 Enhanced cerebral perfusion can be documented in two principal ways. Doppler examination of the middle cerebral artery wave-

Figure 1. Flow velocity waveforms obtained from the uterine artery beyond 24 weeks gestation. In the first patient (A) high volume diastolic flow is established indicating successful trophoblast invasion. (B) Elevated placental vascular resistance is associated with a decline in diastolic velocities and a subsequent rise in the Doppler index. Persistence of an early diastolic notch in the uterine artery flow velocity waveform is evidence of increased spiral artery blood flow resistance. (C) Frequently “notching” is more subtle beyond 32 weeks (C) than in the (D) late second or early third trimesters.

form may indicate decreased blood flow impedance (“brain sparing”)59 (Fig 3). Alternatively, the ratio between cerebral and descending thoracic aorta or placental Doppler indices (cerebroplacental ratio) enhances the detection of centralization of cardiac output toward the cerebral circulation particularly in fetuses with more subtle Doppler findings.60-64 Enhanced perfusion of the myocardium on the other hand is evident through examination of the coronary circulation.65 Examination of multiple arterial beds suggests that blood flow in the adrenal glands,66 spleen,67 and liver68 is enhanced while perfusion of the lungs,69 bowel,70 and kidneys71 is decreased with further compromise. Although arterial Doppler can provide information on downstream distribution of cardiac output this information is incomplete without the evalua-

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Figure 2. (A) The normal umbilical artery flow velocity waveform has marked positive end-diastolic velocity that increases in proportion to systole toward term. (B) Moderate abnormalities in the villous vascular structure raise the blood flow resistance and are associated with a decline in end-diastolic velocities. When a significant proportion of the villous vascular tree is abnormal (50%-70%), end-diastolic velocities may be (C) absent or even (D) reversed. Depending on the magnitude of placental blood flow resistance and the fetal cardiac function reversal of end-diastolic velocities may be (D) minimal, (E) moderate, or (F) severe. In the latter case, precordial venous flows were universally abnormal.

tion of cardiac function. Failure of forward cardiac function is the hallmark of cardiovascular deterioration in IUGR72 and can be associated with deregulation of cardiovascular homeostasis (normalization of cerebral Doppler indices,73,74 which in turn could affect reliability of arterial Doppler analysis. Under such circumstances examination of the venous system provides documentation of cardiac status and therefore improves detection of further compromise. Forward blood flow in the venous system is determined by cardiac compliance, contractility and afterload. A decline in forward velocities during atrial systole (a-wave) results in increased venous Doppler indices and suggests impaired preload handling75-77 (Fig 4 and 5). Evidence of impaired cardiac forward function has been documented in the precordial veins (ductus venosus,77 inferior vena cava,78 superior vena cava79), the hepatic veins (right, middle and left hepatic80,81) and head and neck veins (jugular veins82 and cerebral transverse sinus83). If failure to accommodate preload is progressive umbilical venous pulsations may be observed as the ultimate reflection of increased central venous pressure84 (Fig 6). In the final stages of compromise cardiac dilatation with holosystolic tricus-

pid insufficiency may be observed preceding intrauterine demise.85

Fetal Biophysical Responses in Uteroplacental Insufficiency Normal development of fetal behavior involves incorporation of isolated movements into patterns and finally behavioral states. Once organized behavioral states are established diurnal and responsive cyclicity (eg, fetal movement coupling with heart rate variables) are generally achieved by 28 weeks of gestation.86 In IUGR fetuses with chronic hypoxemia all aspects of this process may be delayed. This includes the establishment of organized behavior and transition between behavioral states as well as decreases in overall unstimulated and stimulated (ie, vibroacoustic stimulation) behavior. These behavioral alterations are particularly evident between 28 to 32 week’s gestation.87-91 The decrease in all behavioral variables and probably also delayed maturation in the central integration of fetal heart rate control results in higher basal heart rates and lower short- and long-term variation on computerized analysis.92,93 Progressive hypoxemia is associated with gradual de-

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The biophysical profile score is a composite score that applies categorical cut-offs for dynamic variables such as fetal tone, breathing movement, gross body movement, and the amniotic fluid volume as well as traditional fetal heart rate analysis. Although a gradual decline in all of these parameters precedes an overtly abnormal BPS analysis of percentage changes in these variables offers no advantage in the prediction of acidemia.95 The BPS shows a reliable and reproducible relationship with the fetal pH irrespective of the underlying pathology and gestational age.105,106

Identification of the Small Fetus at Risk for Adverse Outcome The first step in the management of IUGR fetuses is to identify those fetuses that are truly at risk for adverse outcome. This requires exclusion of small fetuses that are normally grown and

Figure 3. (A) The normal middle cerebral artery flow pattern has relatively little diastolic flow. With elevation of placental blood flow resistance the changes in the middle cerebral artery waveform may be subtle, although the cerebroplacental ratio may become abnormal as in fetus B. With progressive placental dysfunction there may be increase in the diastolic velocity resulting in a decrease in the Doppler index (Brain sparing, C). With marked brain sparing the systolic down slope of the waveform becomes smoother so that the waveform almost resembles that of the umbilical artery (D). The associated rise in the mean velocity results in a marked decline in the Doppler index.

cline in amniotic fluid volume, fetal breathing, gross body movements, tone and computerized heart rate variables.94-96 While this development may be associated with abnormal Doppler findings in the placental, arterial, and venous circulations, the decline of biophysical variables is determined by effects of hypoxemia/acidemia on the central regulation of fetal behavior rather than vascular status.43,46,97,98-100 With the development of acidemia fetal movement and tone are lost and overtly abnormal heart rate patterns may be observed.97,101 These may include overt late decelerations and/or a decrease of the short term variation on computerized analysis.46,74,83,102,103,104 (Fig 7).

Figure 4. The venous flow velocity waveform reflects atrial pressure changes during the cardiac cycle and therefore has a triphasic flow pattern. In the inferior vena cava blood flow may be antegrade toward the heart throughout the whole cardiac cycle (A) or brief reversal of blood flow during atrial systole (B) is normal. However a relative decrease of diastolic forward velocity (*) and marked reversal of the a-wave (⫹) is abnormal and in this fetus (C) was associated with cardiac dilatation, tricuspid insufficiency and subsequent stillbirth.

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Figure 5. In the ductus venosus, blood flow is always antegrade throughout the cardiac cycle under normal circumstances. Pulsatility is less pronounced in waveform patterns obtained at the inlet (A) versus the outlet (B). With impaired cardiac forward function there is a decline in forward flow during atrial systole (C). If progressive atrial forward flow may be lost (D) or reversed (E). In the last fetus with this severely abnormal waveform pattern at 28 weeks (F), the neonatal course was complicated by circulatory insufficiency, necrotising enterocolitis, grade IV intraventricular hemorrhage and finally neonatal death.

Figure 6. In the umbilical vein the normally constant waveform pattern may show subtle pulsations with elevated placental blood flow resistance (A). With progressive increase in precordial venous indices monophasic, biphasic and even triphasic pulsations may be observed (B,C,D).

those in whom IUGR is due to an underlying condition where management will not alter outcome (eg, aneuploidy, nonaneuploid syndromes, viral infection). The initial focus therefore lies on a complete maternal history and physical examination and a thorough ultrasound evaluation of fetal anatomy, size, symmetry, and amniotic fluid volume. Identification of small fetal size is initially based on combined measurements of head size [biparietal diameter and head circumference (HC)], abdominal circumference (AC) and bone length [femur (FL) and humerus length]. IUGR may be defined as an estimated fetal weight (calculated through algorisms using the HC, AC and FL) below the 10th percentile or an AC below the 5th, 3rd, or 2nd percentiles. The AC offers superior sensitivity that may be further enhanced by serial measurements at least 14 days apart.107,108 Fetal asymmetry of the HC/AC ratio suggests altered growth dynamics, while symmetrically small growth may simply indicate reduced genetic potential.109-111 However, although biometry provides important clues to the presence of IUGR the liability of preterm delivery and iatrogenic complications is great if the diagnosis is based solely on biometry.112 The combination of biometry with umbilical and middle cerebral artery Doppler provides the best tool to identify small fetuses at risk for adverse outcome. This applies both to small fetuses with

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Figure 7. A progressive deterioration in fetal cardiovascular and behavioral variables that is observed with decline of metabolic status. In the majority of IUGR fetuses, Doppler abnormalities progress from the arterial to the venous side of the circulation. While cardiac adaptations and alterations in coronary blood flow dynamics may be operational for a variable period, overt abnormalities of cardiac function and evidence of markedly enhanced coronary blood flow is generally not observed until the late stages of disease. The decline in biophysical variables shows a reproducible relationship with acid base status. If adaptation mechanisms fail, stillbirth ensues. UA, umbilical artery; EDV, end-diastolic velocity; UV, umbilical vein; AV, atrioventricular valves; FH, fetal heart rate; BPS, biophysical profile score.

elevated umbilical artery, and those with evidence of brain sparing and normal umbilical artery Doppler.63,107,111,113,114 Randomized trials and meta-analyses confirm that the use of umbilical artery Doppler in this setting results in a significant reduction in perinatal mortality.114-116 Once the suspicion of IUGR is confirmed fetal karyotyping should be offered and further specialized tests such as maternal serology (TORCH), thrombophilia studies, or amniotic fluid viral DNA testing, may be indicated. Once nontreatable underlying fetal conditions and chromosome abnormalities have been ruled out further antenatal surveillance should be instituted based on the severity of the maternal and/or fetal condition.

Antenatal Surveillance of the High-risk Fetus Antenatal surveillance should provide longitudinal assessment that is tailored to the severity of the fetal condition and directs appropriate in-

tervention to improve outcomes of critical importance. Although assessment should be detailed, antenatal tests also need be practicable to facilitate application on a large scale as is necessary for a global problem such as IUGR. Fetal heart rate analysis (both traditional and computerized), Doppler ultrasound, measurement of amniotic fluid volume, assessment of fetal breathing, movement, and tone are primary fetal assessment tools. Traditional heart rate analysis has the advantage of widespread familiarity but carries the disadvantage of poor inter- and intraobserver agreement even in the interpretation of key factors such as accelerations, reactivity and decelerations.117 While a reactive CTG even by criteria graded for gestational age virtually excludes hypoxemia, a nonreactive CTG has a poor correlation with fetal status unless overtly abnormal patterns are observed.46,74,118 The computerized analysis circumvents some of these problems as it provides an objective and reproducible means of longitudinal analysis of fetal heart rate characteristics.

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Doppler analysis is an invaluable tool to grade the severity of the fetal disease. Although multiple vessels have been investigated in IUGR a combination of arterial and venous vessels is the most practicable to demonstrate 1) degree of placental disease, 2) level of redistribution, and 3) degree of cardiac compromise. The umbilical artery, middle cerebral artery, descending thoracic aorta, ductus venosus, inferior vena cava and free umbilical vein provide comprehensive evaluation of these aspects. Since the longitudinal progression of Doppler abnormalities advances from arterial to the venous side in the majority of cases46,73,74,102,104 multivessel Doppler is indispensable in planning the frequency of fetal testing.119 Although the combination of nonstress testing and amniotic fluid index (modified biophysical profile score)120 works well in a low-risk context assessment of many aspects of IUGR remains incomplete. The biophysical profile using the full five component score evaluates fetal responses to metabolic disturbance and provides accurate reflection of current metabolic status and can provide reasonable assurance of fetal well being.121 As a single assessment tool in IUGR, it has several disadvantages. Fetal heart rate scoring is based on visual assessment of reactivity and therefore has the same drawbacks as the traditional nonstress test. In the absence of oligohydramnios the biophysical profile score provides insufficient information on the severity of the fetal cardiovascular compromise to plan longitudinal assessment.46,118,119 Even more comprehensive fetal assessment can be provided through concurrent evaluation of arterial and venous Doppler waveforms and biophysical parameters (integrated fetal testing).118 In general, the most comprehensive prediction of critical perinatal variables is achieved when multiple testing modalities are combined.122 This can take the form of arterial and venous Doppler, the combination of Doppler and computerized CTG,104 5 component biophysical profile scoring or a combination of Doppler and biophysical profile scoring.123 The accurate guidance of intervention is of particular importance in the preterm IUGR fetus in whom risks of adverse outcome due to prematurity are disproportionally high.3,112

Timing of Intervention Intervention may be preventative or therapeutic. A recent Finnish prospective randomized study on first trimester low-dose aspirin administration in patients with abnormal uterine artery blood flow showed encouraging prevention of preeclampsia.124 Although the rate of IUGR was not significantly affected there are several arguments that support the use of low-dose Aspirin in high-risk pregnancies that are identified through abnormal uterine artery Doppler. The safety of Aspirin in pregnancy has been documented in a large number of patients.125,126 The severity of IUGR may be decreased127 and a decline of maternal delivery indications for preeclampsia is likely to decrease the preterm delivery rate. Placental disease with severe IUGR may be the first manifestation of previously undiagnosed underlying thrombophilia.128 Numerous studies have evaluated other therapeutic interventions such as maternal oxygen therapy,129 intravascular volume expansion,130 and administration of aminoacids131 to alleviate the fetal condition. The detailed appraisal of these approaches goes beyond the scope of this review. The universally available therapeutic options that currently show any promise in affecting outcome are the antenatal administration of steroids in preterm pregnancies and delivery at an institution with a neonatal care unit that is able to address the management complexities of the IUGR neonate. Antenatal steroids should be administered to any IUGR fetus in whom delivery is anticipated before 34 weeks’ gestation. The longheld belief that the “stress” of the intrauterine condition enhances maturation and is protective against the effects of prematurity is a myth that is not supported by large population studies of IUGR neonates.3,132 The timing of delivery is of greatest relevance to the managing physician. Unfortunately there are no randomized management trials that conclusively adress the issue of delivery timing across the whole clinical spectrum of IUGR. There are several difficulties in conducting such a trial. The background morbidity and mortality that is not affected through intervention is unknown. The critical perinatal variables that impact on short and in particular long-term quality of life are incompletely defined. Conclusive investigation of these issues requires large sample

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Figure 8. The management algorithm for pregnancies complicated by fetal growth restriction is based on the ability to perform arterial and venous Doppler as well as a full five component biophysical profile score. AC, abdominal circumference; AFV, amniotic fluid volume; A/REDV, absent/reversed end-diastolic velocity; BPS, biophysical profile score; CPR, cerebroplacental ratio; DV, ductus venosus; HC, head circumference; MCA, middle cerebral artery; NST, nonstress test; NICU, neonatal intensive care unit; tid, 3 times daily; UA, umbilical artery.

sizes that con only be accumulated through multi-center collaboration. The efficiency of these collaborations is hampered by regional differences in primary fetal assessment tools, criteria for definition of fetal status and standards of care that govern intervention. In principle delivery timing is straightforward in the term fetus, when fetal lung maturity has been documented, if there is fetal distress, or if the maternal condition dictates delivery. Management is more complicated for pregnancies between 25 to 32 weeks’ gestation, where each day gained in utero may improve survival by up to 1% to 2%.118 In recent years, several concepts have emerged that are likely to alter the standard of management in these pre-term IUGR pregnancies. Early delivery of IUGR fetuses with abnor-

mal umbilical artery waveform (after completion of antenatal steroid course) offers the benefit of a higher lifeborn rate and disadvantage of a high neonatal mortality. Delaying delivery until fetal distress evident may be associated with a higher stillbirth rate but a lower neonatal mortality. While overall mortality is not affected, significant intrauterine time and weight gain can be expected.133 Timing the delivery between these two points would be desirable. When a temporizing approach is elected assessment of fetal status needs to be accurate to avoid preventable adverse outcomes. The ultimate impact of antenatal management protocols on outcomes is likely to be greatest if critical outcomes are accurately predicted prenatally. Such outcomes include the risk for stillbirth and moderate to

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severe peripartum acidemia, which has been related to poor neuro-development.134 We use a monitoring approach that combines fetal heart rate analysis with Doppler and biophysical assessment of the fetus that is initiated at 24 weeks’ gestation. The management algorithm that is depicted in figure 8 requires the ability to perform arterial and venous Doppler studies and is aimed at defining three key aspects: 1) correct diagnosis of IUGR, 2) documentation of a fetal compensatory response 3) Evidence of fetal decompensation. The interventions are guided by severity of the fetal condition and gestational age at presentation. Our knowledge about the pathophysiology and clinical management impacts in IUGR are still evolving. The potential for improved clinical application of different fetal testing modalities is currently being investigated in 2 multicenter studies. An IUGR registry has been created to obtain observational data in order to define the combination of Doppler and biophysical variables that offer the most accurate prediction of adverse outcomes. The TRUFFLE study group is leading an interventional trial randomizing IUGR pregnancies before 32 weeks to delivery based on computer CTG versus ductus venosus Doppler.

References 1. Lubchenco LO, Hansman C, Boyd E: Intrauterine growth as estimated from live born birth-weight data at 24-42 weeks of gestation. Pediatrics 32:793, 1963 2. Battaglia FC, Lubchenco LO: A practical classification of newborn infants by weight and gestational age. J Pediatr 71:159-163, 1967 3. Bernstein IM, Horbar JD, Badger GJ, et al: Morbidity and mortality among very-low-birth-weight neonates with intrauterine growth restriction. The Vermont Oxford Network. Am J Obstet Gynecol 182:198-206, 2000 4. Schreuder AM, McDonnell M, Gaffney G, et al: Outcome at school age following antenatal detection of absent or reversed end diastolic flow velocity in the umbilical artery. Arch Dis Child Fetal Neonatal Ed 86:F108-14, 2002 5. Barker DJ: Fetal growth and adult disease. Br J Obstet Gynaecol 99:275-276, 1992 6. Snijders RJM, Sherrod C, Gosden CM, et al: Fetal growth retardation: Associated malformations and chromosome abnormalities. Am J Obstet Gynecol 168: 547-555, 1993 7. Khoury MJ, Erickson D, Cordero JE, et al: Congenital malformations and intrauterine growth retardation: A population study. Pediatrics 82:83-90, 1988

8. Sickler GK, Nyberg DA, Sohaey R, et al: Polyhydramnios and fetal intrauterine growth restriction: Ominous combination. J Ultrasound Med 16:609-614, 1997 9. Odegard RA, Vatten LJ, Nilsen ST, et al: Preeclampsia and fetal growth. Obstet Gynecol 96:950-955, 2000 10. Kupfermine MJ, Peri H, Zwang E, et al: High prevalence of the prothrombin gene mutation in women with intrauterine growth retardation, abruptio placentae and second trimester loss. Acta Obstet Gynecol Scand 79:963-967, 2000 11. Nicolini U, Hubinont C, Santolaya J, et al: Maternalfetal glucose gradient in normal pregnancies and in pregnancies complicated by alloimmunization and fetal growth retardation. Am J Obstet Gynecol 161:924927, 1989 12. Battaglia FC, Regnault TR: Placental transport and metabolism of amino acids. Placenta 22:145-161, 2001 13. Fant ME, Weisoly D: Insulin and insulin-like growth factors in human development: implications for the perinatal period. Semin Perinatol 25:426-435, 2001 14. Meschia G: Placenta respiratory gas exchange and fetal oxygenation, in Creasy RK, Resnik R (eds): Maternal Fetal medicine: Principles and Practice (ed 1). Philadelphia, PA, Saunders, 1987, pp 274 –285 15. Meschia G, Battaglia FC, Hay WW, et al: Utilization of substrates by the ovine placenta in vivo. Fed Proc 39: 245-249, 1980 16. Pijnenborg R, Bland JM, Robertson WB, et al: Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy. Placenta 4:397-413, 1983 17. Edman CD, Toofanian A, MacDonald PC, et al: Placental clearance rate of maternal plasma androstenedione through placental estradiol formation: An indirect method of assessing uteroplacental blood flow. Am J Obstet Gynecol 141:1029-1037, 1981 18. Maini CL, Rosati P, Galli G, et al: Non-invasive radioisotopic evaluation of placental blood flow. Gynecol Obstet Invest 19:196-206, 1985 19. Luckhardt M, Leiser R, Kingdom J, et al: Effect of physiologic perfusion-fixation on the morphometrically evaluated dimensions of the term placental cotyledon. J Soc Gynecol Investig 3:166-171, 1996 20. Sutton MG, Plappert T, Doubilet P: Relationship between placental blood flow and combined ventricular output with gestational age in normal human fetus. Cardiovasc Res 25:603-608, 1991 21. Boito S, Struijk PC, Ursem NT, et al: Umbilical venous volume flow in the normally developing and growthrestricted human fetus. Ultrasound Obstet Gynecol 19: 344-349, 2002 22. Sutton MS, Theard MA, Bhatia SJ, et al: Changes in placental blood flow in the normal human fetus with gestational age. Pediatr Res 28:383-387, 1990 23. Lees C, Albaiges G, Deane C, et al: Assessment of umbilical arterial and venous flow using color Doppler. Ultrasound Obstet Gynecol 14:250-255, 1999 24. Kiserud T: The ductus venosus. Semin Perinatol 25:1120, 2001 25. Rudolph AM: Distribution and regulation of blood flow in the fetal and neonatal lamb. Circ Res 57:811-821, 1985

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26. Pardi G, Marconi AM, Cetin I: Placental-fetal interrelationship in IUGR fetuses—A review. Placenta 23:S136141, 2002 (suppl A) 27. Guyton AC, Cowley AW Jr, Young DB, et al: Integration and control of circulatory function. Int Rev Physiol 9:341-385, 1996 28. Nicolini U, Hubinont C, Santolaya J, et al: Maternalfetal glucose gradient in normal pregnancies and in pregnancies complicated by alloimmunization and fetal growth retardation. Am J Obstet Gynecol 161:924927, 1989 29. Economides DL, Nicolaides KH: Blood glucose and oxygen tension levels in small-for-gestational-age fetuses. Am J Obstet Gynecol 160:385-389, 1989 30. Hubinont C, Nicolini U, Fisk NM, et al: Endocrine pancreatic function in growth-retarded fetuses. Obstet Gynecol 77:541-544, 1991 31. Van Assche FA, Aerts L, DePrins FA: The fetal endocrine pancreas. Eur J Obstet Gynecol Reprod Biol 18: 267-272, 1984 32. Jones CT, Ritchie JW, Walker D: The effects of hypoxia on glucose turnover in the fetal sheep. J Dev Physiol 5:223-235, 1983 33. Rebolledo OR, Hernandez RE, Zanetta AC, et al: Insulin secretion during acid-base alterations. Am J Physiol 234:E426-E439, 1978 34. Weiner CP, Williamson RA: Evaluation of severe growth retardation using cordocentesis—Hematologic and metabolic alterations by etiology. Obstet Gynecol 73: 225-9, 1989 35. Battaglia FC, Regnault TR: Placental transport and metabolism of amino acids. Placenta 22:145-161, 2001 36. Owens JA, Falconer J, Robinsin JS: Effect of restriction of placental growth on fetal uteroplacental metabolism. J Dev Physiol 9:225-238, 1987 37. Paolini CL, Marconi AM, Ronzoni S, et al: Placental transport of leucine, phenylalanine, glycine, and proline in intrauterine growth-restricted pregnancies. J Clin Endocrinol Metab 86:5427-5432, 2001 38. Economides DL, Nicolaides KH, Gahl WA, et al: Plasma amino acids in appropriate and small-forgestational-age fetuses. Am J Obstet Gynecol 161: 1219-1227, 1989 39. Bernstein IM, Silver R, Nair KS, et al: Amniotic fluid glycine-valine ratio and neonatal morbidity in fetal growth restriction. Obstet Gynecol 90:933-937, 1997 40. Vannucci RC, Vannucci SJ: Glucose metabolism in the developing brain. Semin Perinatol 24:107-115, 2000 41. Fisher DJ, Heymann MA, Rudolph AM: Fetal myocardial oxygen and carbohydrate consumption during acutely induced hypoxemia. Am J Physiol 242:H657H661, 1982 42. Spahr R, Probst I, Piper HM: Substrate utilization of adult cardiac myocytes. Basic Res Cardiol 80:53-56, 1985, (suppl 1) 43. Vintzileos AM, Fleming AD, Scorza WE, et al: Relationship between fetal biophysical activities and umbilical cord blood gas values. Am J Obstet Gynecol 165:707713, 1991 44. Hecher K, Campbell S, Doyle P, et al: Assessment of fetal compromise by Doppler ultrasound investigation

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59.

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of the fetal circulation. Arterial, intracardiac, and venous blood flow velocity studies. Circulation 91:129138, 1995 Severi FM, Rizzo G, Bocchi C, et al: Intrauterine growth retardation and fetal cardiac function. Fetal Diagn Ther 15:8-19, 2000 Baschat AA, Gembruch U, Harman CR: The sequence of changes in Doppler and biophysical parameters as severe fetal growth restriction worsens. Ultrasound Obstet Gynecol 18:571-577, 2001 Ferrazzi E, Bulfamante G, Mezzopane R, et al: Uterine Doppler velocimetry and placental hypoxic-ischaemic lesion in pregnancies with fetal intrauterine growth restriction. Placenta 20:389-394, 1999 Aardema MW, Oosterhof H, Timmer A, et al: Uterine artery Doppler flow and uteroplacental vascular pathology in normal pregnancies and pregnancies complicated by pre-eclampsia and small for gestational age fetuses. Placenta 22:405-411, 2001 Kingdom JC, Burrell SJ, Kaufmann P: Pathology and clinical implications of abnormal umbilical artery Doppler waveforms. Ultrasound Obstet Gynecol 9:271286, 1997 Rigano S, Bozzo M, Ferrazzi E, et al: Early and persistent reduction in umbilical vein blood flow in the growth-restricted fetus: A longitudinal study. Am J Obstet Gynecol 185:834-838, 2001 Papageorghiou AT, Yu CK, Cicero S, et al: Secondtrimester uterine artery Doppler screening in unselected populations: A review. J Matern Fetal Neonatal Med 12:78-88, 2002 Griffin D, Bilardo K, Masini L, et al: Doppler blood flow waveforms in the descending thoracic aorta of the human fetus. Br J Obstet Gynaecol 91:997-1006, 1984 Akalin-Sel T, Nicolaides KH, Peacock J, et al: Doppler dynamics and their complex interrelation with fetal oxygen pressure, carbon dioxide pressure, and pH in growth-retarded fetuses. Obstet Gynecol 84:439-444, 1994 Bilardo CM, Nicolaides KH, Campbell S: Doppler measurements of fetal and uteroplacental circulations: Relationship with umbilical venous blood gases measured at cordocentesis. Am J Obstet Gynecol 162:115-120, 1990 Mari G: Arterial blood flow velocity waveforms of the pelvis and lower extremities in normal and growthretarded fetuses. Am J Obstet Gynecol 165:143-151, 1991 Al Ghazali W, Chita SK, Chapman MG, et al: Evidence of redistribution of cardiac output in asymmetrical growth retardation. Br J Obstet Gynaecol 96:697-704, 1987 Fouron JC, Skoll A, Sonesson SE, et al: Relationship between flow through the fetal aortic isthmus and cerebral oxygenation during acute placental circulatory insufficiency in ovine fetuses. Am J Obstet Gynecol 181:1102-1107, 1999 Makikallio K, Jouppila P, Rasanen J: Retrograde net blood flow in the aortic isthmus in relation to human fetal arterial and venous circulations. Ultrasound Obstet Gynecol 19:147-152, 2002 Wladimiroff JW, Tonge HM, Stewart PA: Doppler ultra-

78

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

Baschat and Hecher

sound assessment of cerebral blood flow in the human fetus. Br J Obstet Gynaecol 93:471-475, 1986 Gramellini D, Folli MC, Raboni S, et al: Cerebral-umbilical Doppler ratio as a predictor of adverse perinatal outcome. Obstet Gynecol 79:416-420, 1992 Arbeille P, Maulik D, Fignon A, et al: Assessment of the fetal PO2 changes by cerebral and umbilical Doppler on lamb fetuses during acute hypoxia. Ultrasound Med Biol 21:861-870, 1995 Strigini FA, De Luca G, Lencioni G, et al: Middle cerebral artery velocimetry: Different clinical relevance depending on umbilical velocimetry. Obstet Gynecol 90:953-957, 1997 Hecher K, Spernol R, Stettner H, et al: Potential for diagnosing imminent risk for appropriate-and small for gestational fetuses by Doppler examination of umbilical and cerebral arterial blood flow. Ultrasound Obstet Gynecol 5:247-255, 1995 Severi FM, Bocchi C, Visentin A, et al: Uterine and fetal cerebral Doppler predict the outcome of third-trimester small-for-gestational age fetuses with normal umbilical artery Doppler. Ultrasound Obstet Gynecol 19:225228, 2002 Baschat AA, Gembruch U, Reiss I, et al: Demonstration of fetal coronary blood flow by Doppler ultrasound in relation to arterial and venous flow velocity waveforms and perinatal outcome—The “heart-sparing effect.” Ultrasound Obstet Gynecol 9:162-172, 1997 Tekay A, Jouppila P: Fetal adrenal artery velocimetry measurements in appropriate-for-gestational age and intrauterine growth-restricted fetuses. Ultrasound Obstet Gynecol 16:419-424, 2000 Abuhamad AZ, Mari G, Bogdan D, et al: Doppler flow velocimetry of the splenic artery in the human fetus: Is it a marker of chronic hypoxia? Am J Obstet Gynecol 172:820-825, 1993 Kilavuz O, Vetter K: Is the liver of the fetus the 4th preferential organ for arterial blood supply besides brain, heart, and adrenal glands? J Perinat Med 27:103106, 1999 Rizzo G, Capponi A, Chaoui R, et al: Blood flow velocity waveforms from peripheral pulmonary arteries in normally grown and growth-retarded fetuses. Ultrasound Obstet Gynecol 8:87-92, 1996 Mari G, Abuhamad AZ, Uerpairojkit B, et al: Blood flow velocity waveforms of the abdominal arteries in appropriate- and small-for-gestational-age fetuses. Ultrasound Obstet Gynecol 6:15-18, 1995 Arduini D, Rizzo G: Fetal renal artery velocity waveforms and amniotic fluid volume in growth-retarded and post-term fetuses. Obstet Gynecol 77:370-373, 1991 Rizzo G, Capponi A, Rinaldo D, et al: Ventricular ejection force in growth-retarded fetuses. Ultrasound Obstet Gynecol 5:247-255, 1995 Rowlands DJ, Vyas SK: Longitudinal study of fetal middle cerebral artery flow velocity waveforms preceding fetal death. Br J Obstet Gynaecol 102:888-890, 1995 Arduini D, Rizzo G, Romanini C: Changes of pulsatility index from fetal vessels preceding the onset of late decelerations in growth-retarded fetuses. Obstet Gynecol 79:605-610, 1992 Hecher K, Campbell S, Doyle P, et al: Assessment of

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

86. 87.

88.

89.

90.

91.

fetal compromise by Doppler ultrasound investigation of the fetal circulation. Arterial, intracardiac, and venous blood flow velocity studies. Circulation 91:129138, 1995 Baschat AA, Gembruch U, Gortner L, et al: Coronary artery blood flow visualization signifies hemodynamic deterioration in growth-restricted fetuses. Ultrasound Obstet Gynecol 16:425-431, 2000 Kiserud T, Eik-Nes SH, Blaas HG, et al: Ductus venosus blood velocity and the umbilical circulation in the seriously growth retarded fetus. Ultrasound Obstet Gynecol 4:109-114, 1994 Rizzo G, Capponi A, Talone PE, et al: Doppler indices from inferior vena cava and ductus venosus in predicting pH and oxygen tension in umbilical blood at cordocentesis in growth-retarded fetuses. Ultrasound Obstet Gynecol 7:401-410, 1996 Fouron JC, Absi F, Skoll A, et al: Changes in flow velocity patterns of the superior and inferior venae cavae during placental circulatory insufficiency. Ultrasound Obstet Gynecol 21:53-56, 2003 Hecher K, Campbell S: Characteristics of fetal venous blood flow under normal circumstances and during fetal disease. Ultrasound Obstet Gynecol 7:68-83, 1996 Hofstaetter C, Gudmundsson S, Hansmann M: Venous Doppler velocimetry in the surveillance of severely compromised fetuses. Ultrasound Obstet Gynecol 20: 233-239, 2002 Weiner Z, Goldberg Y, Shalev E: Internal jugular vein blood flow in normal and growth-restricted fetuses. Obstet Gynecol 96:167-171, 2000 Senat MV, Schwarzler P, Alcais A, et al: Longitudinal changes in the ductus venosus, cerebral transverse sinus and cardiotocogram in fetal growth restriction. Ultrasound Obstet Gynecol 16:19-24, 2000 Gudmundsson S, Tulzer G, Huhta JC, et al: Venous Doppler in the fetus with absent end-diastolic flow in the umbilical artery. Ultrasound Obstet Gynecol 7:262267, 1996 Rizzo G, Capponi A, Pietropolli A, et al: Fetal cardiac and extracardiac flows preceding intrauterine death. Ultrasound Obstet Gynecol 4:139-142, 1994 Manning FA: Fetal biophysical profile. Obstet Gynecol Clin North Am 26:557-577, 1999 Arduini D, Rizzo G, Romanini C, et al: Computerized analysis of behavioural states in asymmetrical growth retarded fetuses. J Perinat Med 16:357-363, 1988 Arduini D, Rizzo G, Caforio L, et al: Behavioural state transitions in healthy and growth retarded fetuses. Early Hum Dev 19:155-165, 1989 Nijhuis IJ, ten Hof J, Nijhuis JG, et al: Temporal organisation of fetal behaviour from 24-weeks gestation onwards in normal and complicated pregnancies. Dev Psychobiol 34:257-268, 1999 Vindla S, James D, Sahota D: Computerised analysis of unstimulated and stimulated behaviour in fetuses with intrauterine growth restriction. Eur J Obstet Gynecol Reprod Biol 83:37-45, 1999 Yum MK, Park EY, Kim CR, et al: Alterations in irregular and fractal heart rate behavior in growth restricted fetuses. Eur J Obstet Gynecol Reprod Biol 94:51-58, 2001

Fetal Growth Restriction in Placental Disease

92. Nijhuis IJ, ten Hof J, Mulder EJ, et al: Fetal heart rate in relation to its variation in normal and growth retarded fetuses. Eur J Obstet Gynecol Reprod Biol 89:27-33, 2000 93. Henson G, Dawes GS, Redman CW: Characterization of the reduced heart rate variation in growth-retarded fetuses. Br J Obstet Gynaecol 91:751-755, 1984 94. Ribbert LS, Snijders RJ, Nicolaides KH, et al: Relation of fetal blood gases and data from computer-assisted analysis of fetal heart rate patterns in small for gestation fetuses. Br J Obstet Gynaecol 98:820-823, 1991 95. Ribbert LS, Nicolaides KH, Visser GH: Prediction of fetal acidaemia in intrauterine growth retardation: Comparison of quantified fetal activity with biophysical profile score. Br J Obstet Gynaecol 100:653-656, 1993 96. Smith JH, Anand KJ, Cotes PM, et al: Antenatal fetal heart rate variation in relation to the respiratory and metabolic status of the compromised human fetus. Br J Obstet Gynaecol 95:980-989, 1988 97. Ribbert LS, Visser GH, Mulder EJ, et al: Changes with time in fetal heart rate variation, movement incidences and haemodynamics in intrauterine growth retarded fetuses: A longitudinal approach to the assessment of fetal well being. Early Hum Dev 31:195-208, 1993 98. Pillai M, James D: Continuation of normal neurobehavioural development in fetuses with absent umbilical arterial end-diastolic velocities. Br J Obstet Gynaecol 98:277-281, 1991 99. Rizzo G, Arduini D, Pennestri F, et al: Fetal behaviour in growth retardation: Its relationship to fetal blood flow. Prenat Diagn 7:229-238, 1987 100. Arduini D, Rizzo G, Capponi A, et al: Fetal pH value determined by cordocentesis: An independent predictor of the development of antepartum fetal heart rate decelerations in growth retarded fetuses with absent end-diastolic velocity in umbilical artery. J Perinat Med 24:601-607, 1996 101. Ribbert LS, Snijders RJ, Nicolaides KH, et al: Relation of fetal blood gases and data from computer-assisted analysis of fetal heart rate patterns in small for gestation fetuses. Br J Obstet Gynaecol 98:820-823, 1991 102. Ferrazzi E, Bozzo M, Rigano S, et al: Temporal sequence of abnormal Doppler changes in the peripheral and central circulatory systems of the severely growthrestricted fetus. Ultrasound Obstet Gynecol 19:140-146, 2002 103. Guzman ER, Vintzileos AM, Martins M, et al: The efficacy of individual computer heart rate indices in detecting acidemia at birth in growth-restricted fetuses. Obstet Gynecol 87:969-974, 1986 104. Hecher K, Bilardo CM, Stigter RH, et al: Monitoring of fetuses with intrauterine growth restriction: A longitudinal study. Ultrasound Obstet Gynecol 18:564-570, 2001 105. Ribbert LS, Snijders RJ, Nicolaides KH, et al: Relationship of fetal biophysical profile and blood gas values at cordocentesis in severely growth-retarded fetuses. Am J Obstet Gynecol 163:569-571, 1990 106. Manning FA, Snijders R, Harman CR, et al: Fetal biophysical profile score. VI. Correlation with antepartum umbilical venous fetal pH. Am J Obstet Gynecol 169: 755-763, 1993

79

107. Baschat AA, Weiner CP: Umbilical artery Doppler screening for detection of the small fetus in need of antepartum surveillance. Am J Obstet Gynecol 182:154158, 2000 108. Divon MY, Chamberlain PF, Sipos L, et al: Identification of the small for gestational age fetus with the use of gestational age-independent indices of fetal growth. Am J Obstet Gynecol 155:1197-1201, 1986 109. Dashe JS, McIntire DD, Lucas MJ, et al: Effects of symmetric and asymmetric fetal growth on pregnancy outcomes. Obstet Gynecol 96:321-327, 2000 110. Vinkesteijn AS, Mulder PG, Wladimiroff JW: Fetal transverse cerebellar diameter measurements in normal and reduced fetal growth. Ultrasound Obstet Gynecol 15: 47-51, 2000 111. Hershkovitz R, Kingdom JC, Geary M, et al: Fetal cerebral blood flow redistribution in late gestation: Identification of compromise in small fetuses with normal umbilical artery Doppler. Ultrasound Obstet Gynecol 15:209-212, 2000 112. Zeitlin J, Ancel PY, Saurel-Cubizolles MJ, et al: The relationship between intrauterine growth restriction and preterm delivery: An empirical approach using data from a European case-control study. Br J Obstet Gynecol 107:750-758, 2000 113. Ott WJ: Intrauterine growth restriction and Doppler ultrasonography. J Ultrasound Med 19:661-665, 2000 114. McGowan LME, Harding JE, Roberts AB, et al: A pilot randomized controlled trial of two regimens of fetal surveillance for small-for-gestational age fetuses with normal results of umbilical artery Doppler velocimetry. Am J Obstet Gynecol 182:81-86, 2000 115. Neilson JP, Alfirevic Z: Doppler ultrasound for fetal assessment in high risk pregnancies (Cochrane review), In: The Cochrane Library, Issue 1, 2002. Oxford: Update Software 116. Westergaard HB, Langhoff-Roos J, Lingman G, et al: A critical appraisal of the use of umbilical artery Doppler ultrasound in high-risk pregnancies: Use of meta-analyses in evidence-based obstetrics. Ultrasound Obstet Gynecol 17:466-476, 2001 117. Devoe L, Golde S, Kilman Y, et al: A comparison of visual analyses of intrapartum fetal heart rate tracings according to the new national institute of child health and human development guidelines with computer analyses by an automated fetal heart rate monitoring system. Am J Obstet Gynecol 183:361-366, 2000 118. Baschat AA: Integrated fetal testing in growth restriction: Combining multivessel Doppler and biophysical parameters. Ultrasound Obstet Gynecol 21:1-8, 2003 1119. Baschat AA, Harman CR: Antenatal assessment of the growth restricted fetus. Curr Opin Obstet Gynecol 13:161-168, 2001 120. Nageotte MP, Towers CV, Asrat T, et al: Perinatal outcome with the modified biophysical profile. Am J Obstet Gynecol 170:1672-1676, 1994 121. Dayal AK, Manning FA, Berck DJ, et al: Fetal death after normal biophysical profile score: An eighteen year experience. Am J Obstet Gynecol 181:1231, 1999 122. Morrison I, Menticoglou S, Manning FA, et al: Comparison of antepartum test results to perinatal outcome. J Matern Fet Medicine 3:75-83, 1994

80

Baschat and Hecher

123. Baschat AA, Gembruch U, Weiner CP, et al: Combining Doppler and biophysical assessment improves prediction of critical perinatal outcomes. Am J Obstet Gynecol 187:S147, 2002 124. Vainio M, Kujansuu E, Iso-Mustajarvi M, et al: Low dose acetylsalicylic acid in prevention of pregnancy-induced hypertension and intrauterine growth retardation in women with bilateral uterine artery notches. BJOG Br J Obstet Gynecol 109:161-167, 2002 125. CLASP: A randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. CLASP (Collaborative Lowdose Aspirin Study in Pregnancy) Collaborative Group. Lancet 343:619-629, 1994 126. Kozer E, Nikfar S, Costei A, et al: Aspirin consumption during the first trimester of pregnancy and congenital anomalies: a meta-analysis. Am J Obstet Gynecol 187: 1623-1630, 2002 127. Harrington K, Kurdi W, Aquilina J, et al: A prospective management study of slow-release aspirin in the palliation of uteroplacental insufficiency predicted by uterine artery Doppler at 20 weeks. Ultrasound Obstet Gynecol 15:13-18, 2000 128. Kupfermine MJ, Many A, Bar-Am A, et al: Mid-trimester severe intrauterine growth restriction is associated with

129.

130.

131.

132.

133.

134.

a high prevalence of thrombophilia. Br J Obstet Gynecol 109:1373-1376, 2002 Battaglia C, Artini PG, D’Ambrogio G, et al: Maternal hyperoxygenation in the treatment of intrauterine growth retardation. Am J Obstet Gynecol 167:430-435, 1992 Karsdorp VH, van Vugt JM, Dekker GA, et al: Reappearance of end-diastolic velocities in the umbilical artery following maternal volume expansion: a preliminary study. Obstet Gynecol 80:679-683, 1992 Ronzoni S, Marconi AM, Paolini CL, et al: The effect of a maternal infusion of amino acids on umbilical uptake in pregnancies complicated by intrauterine growth restriction. Am J Obstet Gynecol 187:741-746, 2002 Ley D, Wide-Swensson D, Lindroth M, et al: Respiratory distress syndrome in infants with impaired intrauterine growth. Acta Paediatr 86:1090-1096, 1997 The GRIT Study Group: A randomised trial of timed delivery for the compromised preterm fetus: Short term outcomes and Bayesian interpretation. Br J Obstet Gynecol 110:27-32, 2003 Soothill PW, Ajayi RA, Campbell S, et al: Fetal oxygenation at cordocentesis, maternal smoking and childhood neuro-development. Eur J Obstet Gynecol Reprod Biol 59:21-24, 1995