Integrated Testing and Management in Fetal Growth Restriction Sifa Turan, MD, RDMS, Jena Miller, MD, and Ahmet A

Integrated Testing and Management in Fetal Growth Restriction Sifa Turan, MD, RDMS, Jena Miller, MD, and Ahmet A. Baschat, MD

Growth-restricted fetuses are at higher risk for poor perinatal and long-term outcome than those who are appropriately grown. Multiple antenatal testing modalities can help document the sequence of fetal deterioration. The full extent of this compromise is best identified by a combination of fetal biometry, biophysical profile scoring, and arterial and venous Doppler. In the preterm growth-restricted fetus, timing of delivery is critically determined by the balance of fetal versus neonatal risks. In the near-term fetus, accurate diagnosis continues to be a challenge as unrecognized growth restriction contributes to a significant proportion of unexplained stillbirths. In this review, we present an integrated diagnostic and surveillance approach that accounts for these factors. Semin Perinatol 32:194-200 © 2008 Elsevier Inc. All rights reserved.

KEYWORDS fetal growth restriction, non stress testing, computerized cardiotocography, biophysical proﬁle scoring, Doppler ultrasound, integrated testing

valuation of fetal growth is common obstetric practice. havioral or cardiovascular responses to hypoxemia, but when EFetal growth restriction (FGR) affects 15% of pregnan- used in isolation may have limitations in the management of cies and is associated with significant morbidity and mortal- FGR. Integration of antenatal assessment modalities concur- ity in perinatal and adult life.1 Clinical suspicion of FGR rently evaluates physical, behavioral, and cardiovascular requires further investigation as growth delay may be the manifestations of FGR. This approach can bypass the limita- physical manifestation of many possible conditions. When tions of individual tests and therefore provide the most com- FGR is established early in pregnancy, the diagnosis is readily prehensive insight into the fetal condition to guide manage- made. In these patients, safe prolongation of pregnancy and ment. timing of delivery are critical issues. As gestational age at delivery has an independent effect on outcomes, early delivery can result in neonatal complications, whereas delayed Antenatal Surveillance Tests delivery can increase stillbirth risk.2 When FGR presents in Progression of fetal hypoxemia to acidemia is an important the third trimester, clinical manifestations and signs of dete- antecendent to adverse short- and long-term outcome. rioration may be more subtle. In these patients, accurate Therefore, antenatal surveillance aims to detect fetal re- identification of FGR provides a challenge. Failure to recog- sponses that accompany such deterioration. These responses nize clinically significant FGR may contribute to over 50% of include changes in fetal heart rate pattern, dynamic variables unexplained stillbirths near term.3 (tone, movement, breathing activity), amniotic fluid volume, Antenatal surveillance modalities can provide insight into placental Doppler studies, and fetal arterial and venous many aspects of fetal well-being. Available tests are the non- Doppler parameters. stress test (NST), computerized cardiotocography (cCTG), biophysical profile score (BPS), and multi-vessel arterial and venous Doppler. Each modality independently evaluates be- Fetal Heart Rate Analysis Fetal heart rate analysis in the form of the NST is one of the first surveillance tests introduced into obstetric practice. The Department of Obstetrics, Gynecology and Reproductive Sciences, Univer- NST can be used to assess central and autonomic control of sity of Maryland, Baltimore, MD. intrinsic cardiac activity by applying visual analysis accord- Address reprint requests to Ahmet A. Baschat, MD, Department of Obstet- rics, Gynecology & Reproductive Sciences, University of Maryland, Bal- ing to criteria that have recently been updated by the Amer- 4 timore, 405 Redwood Street, Baltimore, MD 21201. E-mail: aabaschat@ican College of Obstetricians and Gynecologists. However, hotmail.com heart rate variables such as the baseline, magnitude, and du-

194 0146-0005/08/$-see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.semperi.2008.02.008 Integrated testing and management in FGR 195 ration of accelerations as well as decelerations are influenced of progressive hypoxemia and acidemia produce a predict- by many factors, including the maturational state of the fetal able effect on fetal behaviors.8 Fetal breathing movement central nervous system, gestational age, behavioral state, am- ceases first, but this may be observed over a wide pH range. niotic fluid volume, maternal status, and medications. In ad- Gross body movements and tone decrease further until they dition, there is significant intraobserver and interobserver are no longer observed over extended periods of time. Loss of variability in the interpretation of key heart rate variables, fetal tone and movement are typically observed at a median 5 even when strict interpretative guidelines are applied. Ac- pH of 7.10, and therefore provide the most consistent pre- cordingly, a “normal” reactive NST provides strong evidence diction of prelabor acidemia.11 However, when dynamic fetal of fetal well-being and absence of hypoxemia. However, a variables are considered in isolation, their predictive accu- “nonreactive” NST is a nonspecific finding, particularly in the racy for acidemia is limited by the physiologic variation that setting of FGR where delayed maturation of central fetal heart is observed in normal pregnancies.9 rate control contributes to a higher incidence of nonreactive NSTs.1 The cCTG was developed to compensate for the limita- Placental Doppler tions of visual fetal heart rate analysis. It is not widely used in the United States, but decreases inconsistencies of visual NST Doppler ultrasound of the uterine and umbilical arteries as- analysis by providing an objective interpretation of the fetal sesses the integrity of the maternal and fetal vascular com- heart rate. In addition, computer-generated variables, such as partments of the placenta. In the uterine arteries, increased the short-term variation (SVT), are derived.6 The STV ex- blood flow resistance and/or prolonged gestational persis- presses the variance in beat-to-beat intervals during a fixed tence of a diastolic notch indicates abnormal trophoblast in- time period in milliseconds. A decrease in the short-term vasion. Such suboptimal maternal placental vascularization variation below 3.5 milliseconds has been suggested as an predisposes to maternal hypertensive disorders, FGR, and optimal cutoff to identify prelabor acidemia in FGR, provid- fetal demise. In the umbilical arteries, a decline in end-dia- 7 ing superior prediction compared with the traditional NST. stolic blood flow velocities correlates with the degree of ab- An additional advantage of the cCTG is the ability to evaluate normalities in the villous vascular tree and the risk for fetal longitudinal trends of multiple fetal heart rate variables that hypoxemia, acidemia, and stillbirth.1 However, as placental cannot be assessed with the traditional NST.8 Doppler studies do not directly reflect the degree of fetal compromise, they have a limited predictive accuracy for aci- Amniotic Fluid demia and stillbirth in FGR.12 Volume Assessment Ultrasound assessment of amniotic fluid volume was added Fetal Doppler to antenatal testing to improve the prediction of poor perina- Fetal cardiovascular responses to abnormal placentation can tal outcome.9 Regulation of amniotic fluid volume is com- be observed in multiple vascular beds. From a practical plex, but by the second trimester primarily reflects fetal urine standpoint, the cerebral and precordial venous circulations production. Placental dysfunction and fetal hypoxemia may have been most widely studied in the human fetus. Increases both cause redistribution of renal blood flow leading to fetal in placental blood flow resistance and perceived fetal hypox- oliguria and consequently oligohydramnios. However, the correlation between both the four-quadrant amniotic fluid emia are associated with a decrease in the cerebroplacental index (Ͻ5 cm) or a single vertical pocket (Ͻ2 cm) with the Doppler ratio and/or increased end-diastolic velocity in the 1 actual decline in amniotic fluid volume is limited. Although cerebral circulation. These responses contribute to the pref- multiple studies have related oligohydramnios with in- erential distribution of well-oxygenated blood from the duc- creased risk for FGR, congenital abnormalities, postdates tus venosus to the brain, upper body, and the heart. With pregnancy, meconium passage, abnormal FHR patterns, and progressive placental dysfunction, abnormalities may be ob- lower Apgar scores, a reliable concordance with more objec- served in the venous flow velocity waveforms. An associated tive outcome measures such as fetal acidosis has not been decline in forward velocities during atrial systole indicates demonstrated.10 abnormalities in forward cardiac function that may be related to worsening placental disease and/or cardiac impacts of metabolic compromise. The most severe venous Doppler abnor- Dynamic Fetal Variables malities include absence/reversal of the ductus venosus atrial Dynamic fetal variables including tone, movement, and systolic forward velocity and bi-triphasic pulsations in the breathing activity are centrally regulated components of fetal umbilical venous flow velocity profile. However, as vascu- behavior. Although these individual variables can be ob- lar parameters are influenced by several variables, includ- served as early as the first trimester, their frequency and ing gestational age, blood viscosity, and blood pressure, persistence is determined by central nervous system devel- there is a wide range in the distribution of blood gas values opment, maternal factors, and oxygenation of the regulatory associated with abnormal arterial and venous Doppler centers. When these factors are accounted for, central effects findings (Fig. 1). 196 S. Turan, J. Miller, and A.A. Baschat

tal acidemia with 70% to 90% sensitivity and speciﬁ- city.16,17 Similarly, absence or reversal of the ductus venosus a wave and multiphasic umbilical venous pulsation predict subsequent stillbirth with 65% sensitivity and 95% speciﬁcity.18,19

Clinical Features of FGR There are several clinical features that are unique to placenta- based fetal growth restriction that require consideration in the diagnosis and management. As one of the earliest manifestations of placental dysfunction, a reduction in umbilical venous volume flow leads to decreased nutrient delivery to the fetal liver.20 Accordingly, a decrease in liver size and Figure 1 This figure displays a diagramatic representation of pH abdominal circumference is the first fetal physical manifesta- deviation from the gestational age mean (⌬pH) with abnormal test tion of placental dysfunction. More widespread placental dis- results in various antenatal tests. These include fetal heart rate ease leads to either a decrease in umbilical artery end-dia- (FHR) analysis using traditional nonstress testing (NST; –react, non- stolic velocity when the villous vascular tree is abnormal or reactive) and the computerized cardiotocogram (cCTG; ϩacc, ac- isolated brain-sparing if placental gas exchange is affected. celerations present; ϩdec, obvious decelerations present; STV, short-term variation). Biophysical variables (AFV, amniotic fluid Chronic nutrient deprivation has multiple organ effects that volume; FBM, fetal body movement; FGM, fetal gross movement). are proportional to the degree of placental dysfunction. Of The same relationships are expressed for umbilical artery absent particular relevance to fetal surveillance are central nervous end-diastolic velocity (AEDV) and deviation of the arterial or venous system and cardiovascular effects. Growth-restricted fetuses Doppler index Ͼ2 SD from the gestational age mean for the thoracic exhibit delayed maturation of behavioral milestones, includ- aorta (TAO), descending aorta (DAO), the middle cerebral artery ing a delay in the development of fetal heart rate reactivity. (MCA), cerebroplacental ratio (CPR), and the ductus venosus (DV). Despite this delay in behavioral development, the responses The median pH values for abnormal BPS and Doppler findings are to deteriorating acid-base status are preserved.1 In the cardio- indicated by bars. vascular system, development of brain sparing typically fol- lows blood flow abnormalities in the placental vascular bed. When placental blood flow resistance is significantly in- Integrated Approaches creased, umbilical artery end-diastolic velocity ceases, or may to Fetal Surveillance reverse (UA-REDV). In this setting, a progressive rise in venous Doppler indices may be observed which will eventually The rationale to combine surveillance modalities is based on escalate over a wide range.12,18,19 the recognition that, in the absence of overt abnormalities, The behavioral and cardiovascular responses to placental individual tests have a limited ability to distinguish between dysfunction can be subdivided into early and late. Early re- physiologic and pathologic variation in fetal status. The five- sponses include delayed behavioral maturation (including a component BPS demonstrates best how integration of short- nonreactive NST), elevated umbilical artery Doppler index, term parameters of fetal well-being (tone, movement, breath- and brain sparing. These findings may be observed early in ing, fetal heart rate reactivity) and amniotic fluid volume the clinical course in preterm FGR, or as isolated findings in status as a marker of chronic changes in fetal status results in late onset disease beyond 34 weeks, where behavioral and the most reliable and reproducible relationship with the fetal vascular manifestations are typically more subtle.1 Their pH irrespective of the underlying pathology and gestational value is therefore primarily to aid in the diagnosis of placental age.13 The modified biophysical profile score introduced by dysfunction. In contrast, late responses include UA-REDV Nageotte and coworkers14 combines the NST and the amni- and progressive venous Doppler abnormalities. These typi- otic fluid index and provides an economical first-line triage in cally accompany the sequential loss of biophysical variables low-risk populations. but precede the rapid deterioration of the five-component Analogous to the development of biophysical testing, BPS (Fig. 2). When these late responses are observed, FGR is Doppler surveillance has evolved, integrating several vascu- typically clinically apparent. In this setting, late Doppler find- lar beds. Specific to FGR, assessment of the placental and fetal ings and declining amniotic fluid volume indicate acceler- circulations is necessary to accurately stratify the risk for ating disease and, therefore, are useful to modify monitor- adverse outcome. Elevated umbilical artery Doppler index ing intervals. Given the differential diagnosis of FGR, the and brain sparing in the presence of normal venous Doppler range of manifestations, and time courses of clinical pro- parameters is typically associated with a normal pH.15 How- gression, integration of antenatal testing modalities offers ever, elevation of venous Doppler indices, either alone or in the most comprehensive approach to diagnosis and man- combination with umbilical artery pulsations, predicts fe- agement. Integrated testing and management in FGR 197

Figure 2 This figure summarizes the early and late responses to placental insufficiency. Doppler variables in the placental circulation precede abnormalities in the cerebral circulation. Fetal heart rate (FHR), amniotic fluid volume (AFV), and biophysical parameters (BPS) are still normal at this time, and computerized analysis of fetal behavioral patterns is necessary to document a developmental delay. With progression to late responses, venous Doppler abnor- mality in the fetal circulation is characteristic, often preceding the sequential loss of fetal dynamic variables and frequently accompanying the decline in amniotic fluid volume. The * in the ductus venosus flow velocity waveform marks reversal of blood flow during atrial systole (a-wave). The decline in biophysical variables shows a reproducible relationship with acid base status. Because the BPS is a composite score of five variables, an abnormal BPS less than 6 often develops late and may be sudden. Absence or reversal of the ductus venous a-wave, decrease of the short-term variation (STV) of the computerized fetal heart rate analysis, spontaneous late decelerations, and an abnormal biophysical profile score are the most advanced testing abnormalities. If adaptation mechanisms fail and the fetus remains undelivered, stillbirth ensues. (Reproduced with permission: Baschat A: Intrauterine growth restriction, in Gabbe SG (ed): Obstetrics: Normal and Problem Pregnancies (ed 5). Philadelphia, PA, Churchill Livingstone, 2007, pp 771-814.)

An Integrated Approach value in clinical practice is as an additional diagnostic sign of placental dysfunction.9 In contrast, an increased amniotic to the Diagnosis of FGR fluid volume in the setting of small fetal size may suggest FGR may be a manifestation of placental insufficiency, aneu- aneuploidy or fetal infection.1 ploidy, genetic syndromes, or viral infection. With this dif- The diagnostic criteria that best identifies the growth-re- ferential diagnosis in mind, a detailed anatomic survey, fetal stricted fetus with placental disease at risk for adverse out- biometry, assessment of amniotic fluid volume, and placental come include a combination of biometry and Doppler pa- Doppler studies are necessary in any patient with suspected rameters. An AC below the 5th percentile predicts FGR with FGR. The formula for the sonographically estimated fetal a sensitivity of 98% but only has a positive predictive value of weight (SEFW) typically incorporates measurements of the 37%, whereas a SEFW below the 10th percentile has a sen- fetal head, abdomen, and femur length. As growth restriction sitivity of 86% but a positive predictive value of 51%. But affects the abdominal circumference (AC) first, this measure- when these biometric parameters are combined with an ab- ment is frequently abnormal, whereas the SEFW may still be normal umbilical artery Doppler index, sensitivity ranges in the normal range. The abdominal circumference, head to from 63% to 100%, and positive predictive values between abdomen symmetry, and long bone length should therefore 60% and 80% can be achieved.21 One notable exception is be reviewed individually as they may give additional pointers the near-term fetus, where umbilical artery Doppler studies toward aneuploidy or skeletal dysplasia. The finding of oli- may be normal but brain sparing is the only evidence of gohydramnios is another important marker of FGR and may placental dysfunction.22 An integrated diagnostic ap- be the first ultrasound sign. Although, oligohydramnios is a proach to FGR that incorporates these concepts is de- poor primary screening tool for FGR or fetal acidemia, its scribed in Figure 3. 198 S. Turan, J. Miller, and A.A. Baschat

brain sparing thereafter.26 There are important differences in the cardiovascular manifestations in FGR that are determined by the severity of placental disease and gestational age. In mild, nonprogressive placental dysfunction, the umbilical artery Doppler index does not increase above 3 standard devi- ations and vascular deterioration beyond brain sparing is not observed. In progressive placental dysfunction, disease onset is earlier in gestation and umbilical artery Doppler indices progressively rise. The most severe early-onset disease is associated with severe umbilical artery Doppler abnormalities. It is only in these two more severe patterns where progression to venous Doppler abnormalities is observed. Accordingly, once FGR has been diagnosed, weekly umbilical artery Doppler is suggested to determine the pattern of progression. After the initial 14 days, rapidly progressive severe disease Figure 3 This figure displays a decision tree following the evaluation will be revealed by definitive deterioration of umbilical artery of fetal anatomy, amniotic fluid volume, umbilical and middle ce- Doppler and emergence of additional vessel abnormalities. rebral artery Doppler. The most likely clinical diagnosis based on For the remainder, a less fulminant course is expected. If the test results is presented on the right hand side. A high index of there is still no change over the next 2 weeks, then venous suspicion for aneuploidy, viral, and nonaneuploid syndrome needs Doppler monitoring is unlikely to yield abnormal results.27 to be maintained at all times. (Reproduced with permission: Baschat A: Intrauterine growth restriction, in Gabbe SG (ed): Obstetrics: Normal and Problem Pregnancies (ed 5). Philadelphia, PA, Intervention Triggers Churchill Livingstone, 2007, pp 771-814.) There is only limited intrauterine therapy available once FGR is established, and delivery is frequently the only option. The decision on delivery timing is in principle determined by the Choosing Monitoring Intervals balance of fetal and postdelivery risks. These have mostly The choice of monitoring intervals depends on the antici- been studied for the preterm growth-restricted fetus as fetal 2,28 pated speed of clinical deterioration and risk for impending and neonatal risks are prominent in this subset of FGR. acidemia and/or stillbirth. With the exception of trend-anal- There are no randomized controlled studies that clarify when ysis of the cCTG short-term variation, amniotic fluid volume the preterm growth-restricted fetus should ideally be deliv- and short-term biophysical parameters provide limited infor- ered. Growth-restricted fetuses have a less than 50% chance mation on the rate of fetal deterioration since they are depen- of survival before 26 weeks and below a birth weight of 600 g. dent on the metabolic state at the time of testing. The need to Until 28 weeks gestation, a growth-restricted fetus may gain consider Doppler parameters was recognized almost two 2% increase in survival for each day he remains in utero.28 decades ago when Divon and coworkers published their out- The growth restriction intervention trial suggests that early come of FGR pregnancies with absent umbilical artery end- delivery carries the risk of higher neonatal mortality and ad- diastolic velocity that underwent daily biophysical profile verse neurodevelopment at age 2, which is predominantly scoring with strict criteria for delivery. Their management related to prematurity-related complications.2,29 Based on approach resulted in excellent outcome without any still- these observations, the prevailing opinion is that safe prolon- births or acidemia.23 gation of pregnancy in FGR presenting before 34 weeks is Today, with a better understanding of the sequence of desirable.28 However, delivery triggers have not been identi- deterioration in FGR, the value of integrating biophysical and fied and are based on expert opinion. Doppler parameters for FGR monitoring is even more appar- Several observations in preterm FGR strongly support the ent. For the fetus with mildly abnormal umbilical artery integration of biophysical and Doppler parameters. The se- Doppler studies, new onset of brain sparing or evidence of quence of arterial and venous Doppler abnormalities that decreasing amniotic fluid volume indicate accelerating dis- presage the deterioration of biophysical parameters has been ease.18,19,22 If absence/reversal of umbilical artery end-dia- reasonably well established.1,15,18,19,24,25,27,30 Biophysical vari- stolic velocity is observed, attention to venous Doppler stud- ables including the cCTG and arterial and venous Doppler ies is critical to assess the degree of disease acceleration. parameters appear to synergistically predict fetal risks.31-34 At When ductus venosus Doppler indices increase over the early gestational ages where safe prolongation of pregnancy is course of a week or absence or reversal of the ductus venosus important, close surveillance of biophysical and multivessel a-wave is observed, deterioration of the biophysical profile Doppler parameters may gain up to 1 week in utero.24,25,30 As score may be imminent.18,24,25 In a longitudinal monitoring gestational age remains the main determinant of neonatal study of growth-restricted fetuses, we observed a stillbirth outcomes, late Doppler findings such as an abnormal BPP rate of 11/1330 within 1 week of a normal BPS. These were and/or ductus venosus a-wave reversal may need to be predicted by an abnormal DV Doppler before 34 weeks or present before delivery is considered. The integrated man- Integrated testing and management in FGR 199

Figure 4 The management algorithm for pregnancies complicated by FGR is based on the ability to perform arterial and venous Doppler as well as a full five-component biophysical profile score. This is the typical management approach we practice at the University of Maryland, Baltimore for preterm growth restricted fetuses (unless otherwise indicated). Max, maximum; A/REDV, absent/reversed end-diastolic velocity; BPS, biophysical profile score; DV, ductus venosus; MCA, middle cerebral artery; NICU, neonatal intensive care unit; UA, umbilical artery. agement protocol that is practiced at our institution is dis- 4. American College of Obstetricians and Gynecologists: Intrapartum fetal played in Figure 4. heart rate monitoring. ACOG Practice Bulletin. Obstet Gynecol 106: In pregnancies presenting after 34 weeks gestation, the 1453-1460, 2005 5. Devoe L, Golde S, Kilman Y, et al: A comparison of visual analyses of neonatal risks are low. When these are related to the stillbirth intrapartum fetal heart rate tracings according to the new national risk for undelivered fetuses (prospective stillbirth risk), the institute of child health and human development guidelines with com- balance is in favor of delivery from 38 weeks onwards. Al- puter analyses by an automated fetal heart rate monitoring system. Am J though this has not been studied in a randomized fashion, Obstet Gynecol 183:361-366, 2000 these data support a low delivery threshold in growth-re- 6. Pardey J, Moulden M, Redman CW: A computer system for the numer- 3,35 ical analysis of nonstress tests. Am J Obstet Gynecol 186:1095-1103, stricted fetuses identified near term. 2002 7. Guzman ER, Vintzileos AM, Martins M, et al: The efficacy of individual computer heart rate indices in detecting acidemia at birth in growth Conclusion restricted fetuses. Obstet Gynecol 87:969-974, 1996 As our understanding of the multi-system impacts of placen- 8. Ribbert LS, Nicolaides KH, Visser GH: Prediction of fetal acidaemia in intrauterine growth retardation: comparison of quantified fetal tal dysfunction is evolving, there is little advance in the man- activity with biophysical profile score. Br J Obstet Gynaecol 100: agement approach to these pregnancies. Randomized evalu- 653, 1993 ation of preventive strategies, delivery triggers, and neonatal 9. Manning FA, Platt LD, Sipos L: Antepartum fetal evaluation: develop- management are of high priority. In this context, an inte- ment of a fetal biophysical profile. Am J Obstet Gynecol 136:787-795, grated approach to diagnosis and monitoring provides the 1980 most comprehensive framework to evaluate FGR. 10. Chauhan SP, Sanderson M, Hendrix NW, et al: Perinatal outcome and amniotic fluid index in the antepartum and intrapartum periods: a meta-analysis. Am J Obstet Gynecol 181:1473-1478, 1999 References 11. Vintzileos AM, Fleming AD, Scorza WE, et al: Relationship between 1. Baschat AA: Fetal responses to placental insufficiency: an update. Br J fetal biophysical activities and umbilical cord blood gas values. Am J Obstet Gynaecol 111:1031-1041, 2004 Obstet Gynecol 165:707-713, 1991 2. GRIT Study Group: A randomised trial of timed delivery for the com- 12. Baschat AA: Doppler application in the delivery timing of the preterm promised preterm fetus: short term outcomes and Bayesian interpreta- growth restricted fetus: another step in the right direction. Ultrasound tion. Br J Obstet Gynaecol 110:27-32, 2003 Obstet Gynecol 23:111-118, 2004 3. Froen JF, Gardosi JO, Thurmann A, et al: Restricted fetal growth in 13. Manning FA, Snijders R, Harman CR, et al: Fetal biophysical profile sudden intrauterine unexplained death. Acta Obstet Gynecol Scand score. VI. Correlation with antepartum umbilical venous fetal pH. Am J 83:801-807, 2004 Obstet Gynecol 169:755-763, 1993 200 S. Turan, J. Miller, and A.A. Baschat

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