Absent End-Diastolic Velocity in the Umbilical Artery and Its Clinical Significance

Chapter 25 Absent End-Diastolic Velocity in the Umbilical Artery and Its Clinical Significance

Dev Maulik, Reinaldo Figueroa

Among the characteristics of the umbilical arterial prognosis. With the further increase of impedance, Doppler waveform, the end-diastolic velocity is of the end-diastolic velocity eventually becomes absent. primary hemodynamic and clinical significance. As Such a development, though rare, is ominous and re- discussed in Chap. 10, the end-diastolic velocity dem- sults in a profoundly adverse perinatal outcome. An onstrates an impressive continuous increase through- example of absent end-diastolic velocity (AEDV) is out the gestation which is attributable to an ever-in- shown in Fig. 25.1. Occasionally, further hemody- creasing decline of the fetoplacental flow impedance. namic deterioration occurs, resulting in reversal of It results in a concomitant decrease in the pulsatility the end-diastolic velocity (Fig. 25.2). The impressive of the waveform and is reflected in the Doppler in- amount of information [1±26] now available on the dices such as the systolic/diastolic (S/D) ratio and the clinical significance of the absent and reversed end- resistance index (RI), both of which progressively de- diastolic velocity in the umbilical artery is appraised cline with the advancing gestation. These changes are in this chapter. prognostically reassuring. In contrast, any decline in the end-diastolic velocity with the consequently rising Doppler indices indicates rising impedance in the fetoplacental vascular bed and signifies a worsening

Fig. 25.2. Progressive disappearance of the end-diastolic frequency shift in the umbilical arterial Doppler waveforms from a pregnancy complicated with severe fetal growth restriction at 33 weeks' gestation. Top left: Presence of the end-diastolic frequency shift, although the Doppler indices Fig. 25.1. Example of absent end-diastolic velocity in the were high for the gestational age (systolic/diastolic ratio 5; umbilical artery. Top: Color Doppler-directed pulsed Dop- resistance index 0.8). Top right: Absence of the end-diastol- pler interrogation of the umbilical vessels. Bottom: umbili- ic frequency shift. Bottom left: Spontaneous deceleration cal arterial Doppler waveforms. Note that there is no no- with prolongation of the diastolic phase and the appear- ticeable loss of low frequency shift information, as the ance of umbilical venous pulsation. Bottom right: Progres- high-pass filter was set at 50 Hz sion to the reversal of the end-diastolic frequency shift 376 D. Maulik, R. Figueroa

Table 25.1. Incidence of absent and reversed end-diastolic velocity in high- and low-risk populations

Study, No. of Risk category Doppler type High-pass filter AEDV first author patients (Hz) No. % Johnstone [7] 380 High PW, CW 150 24 6.30 Beattie [27] 2,097 Low CW 200 6 0.29 Huneke [14] 226 High CW 200 18 8.00 Malcolm [15] 1,000 High PW 100 25 2.50 Wenstrom [17] 450 High PW 100 22 4.90 Weiss [19] 2,400 Unselected PW 50 51 2.10 Battaglia [23] a 46 Very high PW 100 26 56.20 Pattinson [22] 342 Very high PW, CW 150 120 34.50 200 Rizzo [25] 6,134 High PW 100 192 3.10 Karsdorp [24] a 459 Very high ?PW Lowest 245 53.40 CW, continuous wave; PW, pulsed wave; AEDV, absent end-diastolic velocity. a Fetuses with congenital anomalies and dyskaryosis were clearly excluded. The other studies either included these fetuses or are unclear about it.

Incidence in this manner, 245 developed AREDV, for an incidence of 53.4%. In comparison, Beattie and Dornan [27] found that only 6 of 2,097 singleton pregnancies The frequency with which absent or reversed end- developed AREDV for an incidence of 0.29%. The ac- diastolic velocity (AREDV) is encountered in the um- tual rate might even be lower if we consider that the bilical artery varies according to the risk category of high-pass filter setting was 200 Hz, which is relatively the obstetric population, the time of gestation at high for umbilical arterial Doppler insonation. which the observation is made, and the Doppler examination technique. For high-risk pregnancies the incidence varies from 2.1% to 56.0% (Table 25.1). Technical Considerations Such a wide range may be explained by the differing definitions of high-risk pregnancy used by the inves- As alluded to above and discussed elsewhere in this tigators and by the level of the high-pass filter used. book, the procedure used for Doppler measurement For example, the basis for high-risk categorization of may affect the measured magnitude of the end-dia- a pregnancy may range from clearly defined clinical stolic frequency shift. It is apparent from the basic criteria, such as hypertension, to ill-defined group- principles of the Doppler shift that shifted frequen- ings of various clinical conditions. In contrast to that cies can only be underestimated, not overestimated. in the high-risk population, the incidence of AREDV There are two technical sources of this problem: (1) may be as low as 0.29% in an obstetric population the threshold setting of the high-pass filter; and (2) with a low prevalence of pregnancy complications. the angle of insonation between the Doppler beam The following two examples illustrate this point. In and the flow axis. The high-pass filter (see Chap. 3) probably the largest reported series on AREDV, Kars- eliminates from the Doppler signal the low-fre- dorp et al. [24] used well-defined criteria for select- quency/high-amplitude frequency component and is ing the population for a multicenter study. Only pa- used to remove signals generated by movement of the tients with hypertension or fetal growth restriction vascular wall or other adjacent tissues. This filter, (or both) were included. Hypertension was defined as however, also removes low-frequency components a diastolic pressure of 110 mmHg by a single mea- generated from the slow-moving blood flow as en- surement or 90 mmHg by two or more measure- countered during the end-diastolic phase of the cardi- ments. Also included were patients with hypertension ac cycle. Thus end-diastolic frequencies are removed plus proteinuria; the latter was defined as urinary from the umbilical Doppler waveform. A relatively protein loss of more than 300 mg in 24 h. Intrauterine high setting of the filter therefore leads to a false di- growth restriction (IUGR) was defined as the abdom- agnosis of AEDV. It is strongly recommended that inal circumference measuring less than the 5th per- the high-pass filter should be at the lowest possible centile for gestational age based on local population- setting, which may not exceed 100 Hz. The second specific nomograms. The lowest possible high-pass consideration is related to the angle of insonation, filter threshold was used. Of the 459 patients selected which is inversely related to the magnitude of the es- a Chapter 25 Absent End-Diastolic Velocity in the Umbilical Artery and Its Clinical Significance 377 timated Doppler shift because of the cosine function Table 25.2. Absent and reverse end-diastolic velocity in of the angle in the Doppler equation (see Chap. 2). A the umbilical artery and adverse perinatal outcome larger angle therefore leads to a lower frequency mea- Perinatal outcome Mean Range surement, which leads to disappearance of the end- diastolic frequency even in the presence of end-dia- Death (%) 45 17±100 stolic flow. Gestational age (weeks) 31.6 29±33 Birth weight (g) 1,056 910±1,481 Absent End-Diastolic Velocity Small-for-gestational age (%) 68 53±100 Cesarean section for fetal 73 24±100 and Adverse Perinatal Outcome distress (%) Apgar score <7 at 5 min (%) 26 7±69 There is an ominous association between the AREDV Admission to neonatal 84 77±97 in the umbilical artery and adverse perinatal outcome intensive care unit (%) (Table 25.2). The latter includes not only morbid Congenital anomalies (%) 10 0±24 states, such as fetal growth restriction, developmental anomalies, and abnormal chromosomes, but also a Aneuploidy (%) 6.4 0±18 substantial increase in perinatal deaths. In addition, there is a significant association with pregnancy complications, such as hypertensive disease of pregnancy and oligohydramnios.

Perinatal Mortality One of the most remarkable features of umbilical arterial absent and reverse flow is the catastrophic increase of deaths of fetuses in utero and of neonates. From a total of 1,126 cases of AREDV reviewed in this chapter, 193 were stillborn and 312 died during the neonatal period. These data translate into a 170/ 1,000 stillbirth rate and 280/1,000 neonatal mortality rate, respectively ± hence a 450/1,000 perinatal mortality rate. Most deaths are attributable to obstetric complications, such as growth restriction and hypertension with the underlying pathology of chronic in utero respiratory and nutritional deprivation, but they Fig. 25.3. Umbilical arterial Doppler velocimetry showing an agonal pattern. Note that reverse end-diastolic velocity also may be attributed to the higher frequency of was present for most of the cardiac cycle (60%±70%). This anomalies and aneuploidy encountered in these in- pattern signifies that fetoplacental perfusion, which is nor- fants, as well as prematurity. It is difficult to correct mally present for the duration of the cardiac cycle, was the mortality figures for congenital malformations seen in this case for only a fraction of that time and chromosomal abnormalities, as most studies do not explicitly report this information. However, it appears that the corrected perinatal mortality is ap- Perinatal Morbidity proximately 340/1,000 births. When the end-diastolic Not only is there a high rate of perinatal loss, the sur- flow in the umbilical artery is reversed, the outcome viving fetuses and infants demonstrate signs of pro- is abysmal. The European Multicenter Study observed found compromise, with a marked increase in the that 98% of such infants required NICU admission, incidence of various measures of morbidity (Table and the odds ratio for perinatal mortality was 10.6 25.2). One of the main complications of AREDV is a when compared to those with positive end-diastolic high frequency of fetal anatomic malformations and velocity. The reverse flow therefore indicates severe aneuploidy. In addition, there is a great preponder- fetal decompensation and, if unattended, eventually ance of preterm births and low birth weight infants, leads to an agonal pattern and fetal death. An exam- which are mostly attributable to fetal or maternal ple is presented in Fig. 25.3. complications mandating early intervention. Thus there is a three- to fourfold increase in the number of cesarean deliveries because of fetal distress. These infants are of low birth weight because they are not only preterm but also suffer from growth deficit. 378 D. Maulik, R. Figueroa

There is a much higher frequency of fetal acidosis, countered with equal frequency, and most cases of ominous cardiotocographic findings, low Apgar score, multiple anomalies are seen with aneuploidy. Hence and the need for NICU admission. Furthermore, the most cases with normal chromosomes have isolated combination of fetal asphyxia and prematurity ex- malformations, whereas most cases of aneuploidy are poses the fetus to the additional danger of end-organ associated with multiple malformations. damage, such as necrotizing enterocolitis and cerebral The frequency of chromosomal abnormalities is 1 hemorrhage. in 16. Autosomal trisomy dominates, with trisomy 18 being the most frequently encountered aneuploidy. Congenital Malformation The relative distribution of various chromosomal and Chromosomal Abnormalities anomalies in AREDV fetuses is shown in Fig. 25.4. The risk factors for chromosomal aberrations include There is a preponderance of congenital malformations (1) an absence of obstetric complications, such as and abnormal chromosomes in fetuses afflicted with gestational hypertension or preeclampsia; (2) the umbilical arterial AREDV. Cumulative data, as summa- presence of fetal malformations; and (3) the appear- rized in Table 25.2, demonstrate that one in ten fetuses ance of absent end-diastolic velocity (AEDV) at an with AREDV have anatomic maldevelopment. There is early gestational age. Although these fetuses are se- heterogeneity, however, in the reported incidence. In verely growth-restricted, there is no difference in the studies with small populations the frequency may be pattern of growth compromise between those with in excess of one in five. On the other hand, not all abnormal chromosomes and those without. Snijders studies encountered fetal anomalies associated with and associates [28] studied a population of 458 AREDV that frequently. Pattinson and associates [22], growth-restricted fetuses and observed that the fe- in a reported series of 120 AREDV infants, observed tuses with chromosomal abnormalities had a higher no anomalies independent of aneuploidy. The largest mean head-circumference/abdominal circumference series of malformations in relation to umbilical arterial ratio than fetuses with a normal karyotype. More spe- AREDV was reported by Rizzo and colleagues [25], cifically, Rizzo and associates [25], in their investiga- who found 25 fetuses with anomalies among 192 with tion of fetuses with AEDV, found no signifcant differ- AREDV; of these anomalies, 14 were associated with ence in head/abdomen circumference between those aneuploidy. with abnormal karyotype and those with a normal The AREDV-associated anomalies involve most or- karyotype. This finding is contrary to the conven- gan systems (Table 25.3), although anomalies of the tional wisdom, which holds that fetuses with chromo- cardiovascular system are encountered most fre- somal aberrations suffer from symmetric growth quently. Isolated and multiple malformations are en- compromise. Many of these infants also tend to develop abnormal fetal heart rate patterns during labor, which may Table 25.3. Absent end-diastolic velocity and congenital lead to cesarean delivery unless the fetal karyotype is malformations known. The mechanism of increased fetoplacental impedance is not fully understood. The work of Rochel- Cardiovascular system son and colleagues [29], however, shed considerable Ventricular septal defect light on this phenomenon. A quantitative morpho- Hypoplastic left heart syndrome metric analysis of placentas revealed a significant re- Double-outlet right ventricle Ebstein anomaly duction in the small muscular artery count and the Arrhythmia: congenital heart block small muscular artery/villus ratio. Abnormal Doppler Central nervous system Hydrocephaly Holoprosencephaly Agenesis of corpus callosum Urogenital system Renal agenesis Hydronephrosis Gastrointestinal system/abdominal wall Esophageal atresia Omphalocele Gastroschisis Skeletal system Polydactyly Fig. 25.4. Relative frequency of the various chromosomal Dysplasia abnormalities associated with umbilical arterial absent end- diastolic velocity a Chapter 25 Absent End-Diastolic Velocity in the Umbilical Artery and Its Clinical Significance 379 waveforms correlated closely with reduced small mus- arterial AREDV. It is noteworthy that pregnancies cular artery counts. It is apparent that aneuploidy ad- complicated by both growth restriction and hyperten- versely affects fetoplacental vascularization, which re- sion demonstrate a greater propensity for developing sults in increased fetoplacental circulatory impedance AREDV than those with either growth restriction or and may contribute to fetal growth restriction. hypertension [24]. Recently, Doppler flow studies in the umbilical artery were performed in first trimester fetuses. Borrell Fetal Asphyxia and Hypoxia and colleagues [30] screened 2,970 pregnancies at 10± 14 weeks' gestation and observed 11 cases of reversed Fetal asphyxia and hypoxia can largely be attributed end-diastolic flow for an incidence of 0.4%. Seven of to fetal exposure to chronic hypoxic and asphyxial in- the 11 fetuses had an autosomal trisomy and two sult. The significant association between abnormal other fetuses had a congenital heart defect. umbilical arterial Doppler indices and fetal hypoxia Earlier, Martinez and associates [31] had prospec- and acidosis is discussed in Chap. 24. It is apparent tively recorded the umbilical artery pulsatility index that the umbilical hemodynamics are affected more (PI) in 1,785 pregnancies before undergoing chorio- by asphyxia or acidosis and less by hypoxia. One of nic villus sampling or genetic amniocentesis. They the most impressive pieces of evidence has been pro- had shown that fetuses with trisomy 18 had an ele- vided by Nicolaides and associates [32], who mea- vated PI. The PI was measured transvaginally for sured umbilical venous blood gases by cordocentesis pregnancies from 10 to 13 weeks and transabdomin- in 59 fetuses suspected of growth restriction (abdom- ally for pregnancies from 14 to 18 weeks. Seven of inal circumference below the 5th percentile for gesta- the ten fetuses with trisomy 18 had an elevated PI tional age). These fetuses also demonstrated absent above the 95th percentile; nine fetuses had an ele- umbilical arterial end-diastolic flow. In 88% of the vated PI above the 90th percentile. PI as a marker for cases the blood gases were abnormal; 42% of the fe- trisomy 18 had good sensitivity (70%±90%), specifici- tuses were hypoxic, 37% asphyxiated, and 9% acido- ty (>90%), and negative predictive value (99%) but a tic. Futhermore, there was a poor correlation between poor positive predictive value (5%±7%). Reversed the degree of fetal smallness and acidosis or severity end-diastolic flow was detected in two cases, both of of hypoxia. Other investigators [33] have also ob- which had trisomy 18. served this efficacy of absent end-diastolic flow and fetal acidosis. The AEDV identified acidosis with a sensi- Intrauterine Growth Restriction tivity of 90%, specificity 92%, positive predictive value (PPV) 53%, and negative predictive value (NPV) 100%. The strength of the relation between AREDV and fetal It is important to note that not all fetuses with growth compromise depends on the stringency of the AREDV are hypoxic or acidotic. Normal fetal blood definition of growth restriction. A small-for-gesta- gas values, however, do not ensure fetal well-being. tional-age (SGA) fetus is not necessarily growth-re- Several investigators have noted progressive fetal de- stricted, as fetal ªsmallnessº may also be constitu- terioration and adverse perinatal outcome in fetuses tional in nature. It is also probable that a fetus who with AREDV despite normal fetal acid-base status as fails to realize its full growth potential may not neces- determined by cordocentesis [34, 35]. It appears that sarily be SGA. Indeed, the terms IUGR and SGA progressive fetal hemodynamic decline, as manifested demonstrate diagnostic uncertainty and lack prog- by umbilical arterial AREDV, is not necessarily re- nostic reliability. Being SGA does not necessarily in- lated to fetal asphyxia and presents a serious threat to dicate a compromised outcome. Despite these ambig- the fetus independent of fetal hypoxia or acidosis. uities, fetuses experiencing a substantial defined growth failure often suffer from in utero asphyxia Cerebral Hemorrhage and its adverse consequences. These fetuses also have Doppler evidence of increasing fetoplacental arterial One of the major concerns regarding chronic intraut- impedance. Thus 50% or more of the fetuses with erine asphyxia is its effect on the fetal brain. AREDV demonstrate a growth disturbance (Table Although the risk of fetal brain damage due to pre- 25.2). A similar proportion of fetuses with sono- maturity and birth asphyxia has been well investi- graphic evidence of growth restriction develop gated, the role of antepartum asphyxia in fetal neuro- AREDV. Thus Battaglia and associates [23] noted that logic damage due to hypoxemic ischemic injury re- 57% of the fetuses identified as being growth re- quires elucidation. One of the gross lesions from such stricted by serial ultrasound measurements developed injury is cerebral hemorrhage, which has been re- AEDV. Similarly, Pattinson and colleagues [22] ob- ported in association with AREDV. The main ques- served that 48% of the fetuses suspected of severe tion is whether this association is independent of the growth restriction in their series developed umbilical preterm birth of these infants. 380 D. Maulik, R. Figueroa

Table 25.4. Umbilical arterial absence of end-diastolic (Table 25.2) and are therefore more apt to develop velocity and cerebral hemorrhage these complications independent of the existence of AREDV. Study, Cerebral hemorrhage p first author The issue is again whether AREDV contributes to Control group AREDV group this complication independent of prematurity. Hackett Weiss [19] a 3/47 (6%) 7/47 (15%) >0.05 and colleagues [4] investigated 82 consecutive cases of Pattinson [21] a 3/16 (19%) 4/16 (25%) >0.05 fetal growth restriction and identified 29 fetuses with Karsdorp [24] b 1/124 (1%) 27/168 (16%) <0.02 an absence of end-diastolic frequencies in the fetal aorta. These fetuses were significantly more growth-re- a Case-control study, matched for gestational age. b Corrected for gestational age by multiple logistic regres- stricted (p<0.001), delivered earlier (p<0.001), and sion. were more apt to suffer perinatal death (p<0.05), necrotizing enterocolitis (p<0.01), or hemorrhage (p<0.05). Malcolm and coinvestigators [15] studied Weiss and associates [19] conducted a case-control 25 high-risk pregnancies with AREDV in the umbilical study, comparing 47 fetuses with AREDV of the um- artery and observed a highly significant increased risk bilical artery to 47 control fetuses matched for gesta- of necrotizing enterocolitis in the morphologically nor- tional age and with normal umbilical artery flow mal fetuses (53%) compared with the controls (6%), velocity waveforms. Fetuses with AREDV showed an who demonstrated umbilical artery end-diastolic flow increased incidence of cerebral hemorrhage (Table in utero. This increased risk appeared to be indepen- 25.4), but it was not statistically significant. Pattinson dent of the degree of growth restriction, prematurity, and associates [21] also performed a case-control or perinatal asphyxia. These findings were supported study that showed no difference in cerebral hemor- by those of McDonnell and colleagues [36], who noted rhage between the 16 matched pairs of fetuses with that the infants who had AREDV were started on en- the presence or absence of umbilical artery end-dia- teral feeds later, were more likely ro receive parenteral stolic velocity. Both of the above findings were re- nutrition, and developed necrotizing enterocolitis futed by the much larger European Community Mul- more frequently than a gestationally matched control ticenter Study [24], which found a significantly in- group. creased incidence of severe cerebral hemorrhage in The conclusion that AREDV may increase the risk the fetuses with AREDV (Table 25.4). Although it was of developing necrotizing enterocolitis independent of not a case-control study, the contribution of premat- prematurity, however, was not supported by Karsdorp urity was corrected by multiple logistic regression. and associates [24] in their European multicenter re- The odds for cerebral hemorrhage increased by 2.6 search project. Although proportionately more infants when the end-diastolic velocity was absent and by 4.8 with AREDV developed necrotizing enterocolitis, the when the velocity was reversed. It appears that in a difference was not statistically significant (p=0.20). pregnancy complicated with fetal growth restriction Moreover, when corrected for gestational age, the ab- or hypotension (or both) AREDV may be associated sence or reversal of umbilical arterial end-diastolic with an increased risk of fetal cerebral hemorrhage. flow did not influence the risk of respiratory distress Such hemorrhagic complication may be related to syndrome or necrotizing enterocolitis of the neonate. hypoxemic ischemic injury induced by antepartum Other investigators have not confirmed the find- asphyxial insult and may be causally related to reper- ings of Hackett [4] and Malcolm [15]. Kirsten and fusion. This consideration is important when criti- colleagues [37] evaluated 242 infants born to women cally examining the role of Doppler velocimetry of with severe early preeclampsia (before 34 weeks' ges- the fetal circulation as an indicator for antepartum tation). Sixty-eight (28%) of these infants had AEDV asphyxia-related gross brain injury. Obviously, more while 131 (54%) had normal umbilical artery Doppler work is needed in this area to clarify these issues. flow velocities. Twenty infants developed definite (grade 2) and advanced (grade 3) necrotizing entero- Necrotizing Enterocolitis colitis and 21 infants had suspected (grade 1) necrotizing enterocolitis. None of the infants with definite Several investigators have reported on the increased necrotizing enterocolitis had AEDV. In addition, the risk of necrotizing enterocolitis in neonates who had prevalence of suspected necrotizing enterocolitis be- suffered in utero from AREDV of the umbilical artery tween the infants with AEDV and the infants with or the aorta. This serious complication is typically normal umbilical artery Doppler flow studies was seen in premature neonates who experienced perina- similar (48% versus 43%). Kirsten and associates pos- tal asphyxia, often secondary to the respiratory dis- tulated that the suspected necrotizing enterocolitis tress syndrome caused by pulmonic immaturity. Most could have been a disturbance of the motility of the infants with AREDV are delivered before 32 weeks gastrointestinal tract as a result of the preeclampsia a Chapter 25 Absent End-Diastolic Velocity in the Umbilical Artery and Its Clinical Significance 381 or the administration of magnesium sulfate to the Hypoglycemia mother and not necessarily necrotizing enterocolitis. Suspected necrotizing enterocolitis is a clinical diag- Infants with AREDV become hypoglycemic more fre- nosis and, in the majority of cases, the condition im- quently, and it cannot be fully attributable to preterm proves with conservative management. gestational age or IUGR. The odds for developing hypoglycemia is 5.0 compared to growth-compromised fetuses without AREDV [24]. The reason for this me- Hematologic Changes tabolic problem remains unclear. Neonates with AREDV during fetal life are apt to develop thrombocytopenia and anemia. They may have Neurodevelopmental Sequelae a low platelet count at birth and are more likely to become significantly thrombocytopenic during the Any examination of the efficacy of umbilical arterial first week of life [36]. They are also at increased risk AREDV for fetal prognostication must go beyond look- of being anemic. It has also been reported [24] that ing for gross cerebral lesions (e.g., hemorrhage) and the infants with absent or reversed end-diastolic encompass immediate and long-term neurologic per- velocity had odds ratios of 3.0 and 6.1, respectively, formance. Furthermore, its imperative that neurologic for developing anemia compared to a control group outcome measures should be extended to include not of infants. The latter were growth-restricted and their only moderate to severe neurologic deficits but also mothers had hypertension, but they had umbilical ar- more subtle compromises in cognitive and motor per- terial end-diastolic forward flow. The reason for de- formance. Although there it is a paucity of information veloping anemia independent of prematurity and in this area, a few preliminary reports are available other known complications remains to be determined concerning the neurodevelopmental significance of [24]. AREDV. Weiss and associates [19] observed in their Baschat and colleagues [38] have also shown that case-control study (see above) an increase in abnormal AREDV in growth-restricted fetuses is associated with neurologic signs in the AREDV group. The pediatric an increased risk of neonatal thrombocytopenia. In a neurologic assessment was blinded to the fetal Doppler study comparing 67 fetuses with elevated PI (more results. The adverse signs included persistent hyperre- than two standard deviations above the mean) to 48 flexia, hypo- or hypertonia, seizures, and cerebral fetuses with AREDV, 22 of the 48 fetuses with AREDV palsy. Fourteen fetuses in the index group (30%) and had thrombocytopenia (<100,000 mm3) compared to three fetuses in the control group (6%) demonstrated 3 of the 67 fetuses in the control group. Neonates abnormal neurologic signs at the time of discharge. with AREDV had a relative risk of 10.3 or a tenfold The results were statistically significant (p<0.006). increase in the incidence of thrombocytopenia when In a more comprehensive and long-term investiga- compared to the control group. In addition, neonates tion, Valcamonico and associates [40] conducted a with AREDV had a higher nucleated red blood cell cohort study in a group of 31 fetuses with IUGR and count than the control group. High numbers of nu- AREDV in the umbilical artery and 40 growth-re- cleated red blood cells in the umbilical cord have stricted fetuses with detectable diastolic flow in the been associated with hypoxemia during intrauterine umbilical artery divided into two control groups. The life and subsequent neurologic impairment. survivors of the perinatal period were followed for a Similarly, Axt-Fliedner and coinvestigators [39] re- mean of 18 months (range 12±24 months). Twenty ported an increased number of nucleated red blood surviving neonates with AREDV demonstrated a cells in the umbilical artery at birth in growth±re- greater risk of permanent neurologic sequelae (35% stricted neonates with AREDV during fetal life when versus 0% and 12%) than the two control groups. compared to neonates with elevated Doppler studies. Although the results suggest that growth-compro- Moreover, the nucleated red blood cells persisted in mised fetuses with AREDV are at a significant risk of the neonatal circulation for a longer period of time sustaining long-term permanent neurologic damage, in the neonates with AREDV. Nucleated red blood it may be premature to draw a definitive conclusion cells are immature erythrocytes. They are seen in on the neurodevelopmental significance of AREDV. variable numbers in the newborn circulation. This hesitation is based on such observations as those Although an increased number of nucleated red blood of Pillai and James [41], who performed serial behav- cells has been attributed to increased erythropoiesis ioral observations in four severely growth-restricted in the fetal liver as a result of chronic hypoxemia, singleton fetuses who had persistent AREDV for 2±9 these studies [38, 39] have shown that the neonates weeks. Comparison with 45 low-risk singleton fetuses with a higher number of nucleated red blood cells at comparable gestations revealed no significant dif- have lower hematocrits, hemoglobin levels, and plate- ferences in the development of behavioral cycles, the let counts that the other neonates studied. proportion of time spent in quiet cycles, or the 382 D. Maulik, R. Figueroa amount of fetal breathing. The heart rate pattern re- Other maternal disorders associated with the de- mained normal in all the fetuses. Kirsten and asso- velopment of AREDV in the umbilical artery include ciates [42a] evaluated the neurodevelopmental out- systemic lupus erythematosus and diabetes mellitus come of a group of infants of 242 women with severe of long duration with vasculopathy. Most such cases early preeclampsia (<34 weeks). Sixty-eight of these are also complicated by fetal growth restriction or hy- women had neonates with AEDV in fetal life. In total, pertension. 193 infants, 51 with AEDV, survived to hospital discharge and were evaluated every 6 months until 48 months of age. In all, 126 infants were assessed at 24 Reappearance months of age. The infants with AEDV scored signifi- of End-Diastolic Velocity cantly lower in the performance subscale compared to the infants who had normal or elevated umbilical Once AREDV develops in the umbilical artery, it is artery flow studies. In total, 157 infants were assessed usually regarded as a nonreversible phenomenon dur- at 48 months of age. No differences were noted in de- ing the course of progressive fetal decompensation. velopmental quotients, verbal and nonverbal quoti- Several investigators, however, have reported apparent ents, or in any of the nonverbal intelligence subscales improvement of the hemodynamic situation, as indi- based on umbilical artery flow velocities. Multiple re- cated by reappearance of forward flow during the gression analysis showed that socioeconomic status umbilical artery end-diastolic phase. Hanretty and was significantly associated with lower developmental colleagues [42b] were among the first to report the quotients. Cerebral palsy was identified in four of the reappearance in a case report where the mother was infants evaluated; AEDV was not associated with cere- treated for hypertension. Subsequently, Brar and Platt bral palsy. The mean developmental quotient at 24 [10] reported improvement of the end-diastolic velo- and at 48 months of age was not associated with AEDV. city in 5 of 31 cases of AREDV followed closely dur- It appears that prenatal neurobehavioral development ing hospitalization. The improved fetuses had better is not necessarily compromised even by long-term perinatal outcome than those with continuing AREDV. Although the above investigations did not uti- AREDV. This observation received support from lize similar or even comparable methods of neurologic others. Sengupta and associates [16] used prospective assessment, it is obvious that additional in-depth and conservative management (bed rest and fetal surveil- long-term investigations are necessary to reconcile lance) in pregnancies complicated by AREDV and these apparently contradictory findings and to eluci- found those who improved had a better outcome. Bell date their implications for clinical management. and associates [20] used retrospective data analysis See Chap. 12 for further discussions on Doppler and also found improved outcome. The above three ultrasound and neurological outcomes. studies noted the reappearance of end-diastolic velocity in 19.0%±51.5% cases of AREDV and a conse- quent increase in the diagnosis-delivery interval by Maternal Hypertension 11±37 days, gestational age by 2±4 weeks, and birth and Absent End-Diastolic Velocity weight by 400±1,400 g. These results, particularly the frequency of reappearance and the impressive im- The most frequent maternal complications seen in provements in the perinatal outcome noted in one of conjunction with AREDV are the various types of hy- the studies [20], are remarkable, are not encountered pertensive disorders encountered during pregnancy, in common experience, and require corroboration. with a preponderance of primary preeclampsia and The study design of Karsdorp and associates [43] preeclampsia superimposed on chronic hypertensive differed from those described above. Theirs was a disease. The frequency with which hypertension is as- controlled intervention study with seven patients in sociated with AREDV varies from 40% to 70%. On each arm. The study group received daily volume ex- the other hand, the proportion of hypertensive pansion in addition to management by bed rest and mothers who develop umbilical artery AREDV may antihypertensive medications, which were also used be as high as 36% [22]. It is noteworthy that when in the control group. The Doppler waveform im- pregnancy is complicated with hypertension alone proved in the volume-expansion group, which dem- the risk of developing AREDV is significantly lower onstrated statistically significant improved survival than when fetal growth restriction complicates hyper- (five of seven in the study and one of seven in the tension. This risk was quantified by Karsdorp and his control group, p<0.05). There were no significant dif- colleagues [24], who noted that in comparison with ferences between the groups with regard to birth hypertension the odds ratio for developing AREDV weight or gestational age. Although the results are en- was 3.1 with growth restriction alone and 7.4 when couraging, this investigation should be regarded as hypertension was complicated by growth restriction. preliminary because of the lack of randomization and a Chapter 25 Absent End-Diastolic Velocity in the Umbilical Artery and Its Clinical Significance 383 AREDV and Other Emergent Signs of Fetal Compromise The homeostatic significance of absent end-diastolic velocity in relation to alterations in other components of the fetal circulation and other parameters of fetal well-being needs clarification. Some of these issues, particularly those related to the diagnostic efficacy of fetal Doppler indices, are discussed in Chap. 24. Although some degree of overlap is inevitable, the fo- cus of this chapter is specifically on the umbilical arterial AREDV. Reports provide considerable insight in this area. Teyssier et al. [45] observed in an animal model a hierarchic sequence in the decline of the Fig. 25.5. Doppler sonogram of the umbilical artery show- end-diastolic flow when fetoplacental vascular resis- ing transient absence and reversal of end-diastolic velocity tance increased; flow in the aortic isthmus was af- followed by prompt recovery of a discordant twin fected first, followed by flow in the descending aorta and the umbilical artery. Preliminary clinical observa- the small sample size. As the authors suggested, ran- tions tend to confirm this sequence [46]. domized trials should be conducted to confirm their Bekedam and associates [13] performed longitudi- observations. nal measurements of the umbilical arterial PI in 29 It should be recognized that the appearance of growth-restricted fetuses with antepartum late heart AREDV does not necessarily lead to immediate fetal rate decelerations. In 17 of these fetuses (59%), AEDV demise. Days to weeks may pass before the emer- preceded the occurrence of decelerations, with a med- gence of other ominous signs of fetal jeopardy neces- ian interval of 12 days. Arduini and colleagues [47] sitating delivery. In some cases the end-diastolic evaluated 37 fetuses without structural and chromo- velocity returns, and the fetal risk is diminished, somal abnormalities regarding the various maternal although it is highly unlikely that this occurrence is and fetal factors that affect the time interval between as frequent as some investigators have reported. On the occurrence of AEDV in the umbilical artery and rare occasions, apparently normal waveforms may either the development of abnormal fetal heart rate change to the ominous pattern of disappearance and patterns or delivery. The interval between the first reversal of the end-diastolic flow, returning quickly to occurrence of umbilical arterial AEDV and delivery the previous pattern; we observed this pattern in a ranged from 1 to 26 days. Multivariate analysis re- discordant twin (Fig. 25.5). Although the hemody- vealed that gestational age, the presence of hyperten- namic mechanism of this phenomenon remains to be sion, and the appearance of umbilical venous pulsa- elucidated, the fetus eventually developed persistent tion are the principal determinants of this time inter- AREDV. val. Finally, Weiner and associates [48] studied hemo- Variable end-diastolic velocity in the umbilical dynamic changes in the middle cerebral artery and artery of a donor fetus with twin-twin transfusion the aortic and pulmonic outflow tracts, correlating syndrome has been documented [44]. The umbilical these changes with the computerized fetal heart rate artery end-diastolic velocity in the donor fluctuated pattern in fetuses with AREDV in the umbilical ar- between positive, absent, and reversed. Eventually the tery. They observed that when the middle cerebral ar- fetus was delivered at 28 weeks because of fetal dis- tery began to lose its compensatory vasodilatation tress of the donor. A velamentous cord insertion, sus- other ominous fetal cardiovascular signs emerged, in- pected during the ultrasound evaluation, was con- cluding decreases in the left cardiac output (p<0.05) firmed. The significance of finding variable end-dia- and the fetal heart rate long-term variability stolic velocity is unknown at this time. (<30 ms) and the occurrence of repetitive fetal heart Finally, it should be emphasized that for reliable rate decelerations. These observations contribute to assessment of the end-diastolic velocity an appropri- elucidation of the evolving cardiovascular responses ate Doppler procedure must be used, ensuring a low to progressive fetal decompensation and should lead filter setting and a consistent sampling site in the to the development of more effective fetal surveillance cord if a pulsed-wave duplex system is used. The use and clinical intervention. of a high, inconsistent filter setting or different sam- Recently, Williams and associates [49] conducted a pling sites can lead to erroneous diagnosis of disap- prospective randomized study where women who had pearance and reappearance of the end-diastolic fre- been referred to their antepartum fetal testing unit quency. because of perceived increased fetal risk were ran- 384 D. Maulik, R. Figueroa domized to either umbilical artery Doppler studies or remarkably, these infants suffer from high perinatal nonstress testing as a screening test of fetal well- mortality and morbidity rates and demonstrate an in- being. In this investigation, normal studies were re- creased frequency of malformations and chromosom- peated with the same technique as initially assigned. al abnormalities, with a predominance of trisomies Women with umbilical artery S/D ratios over the 90th 13, 18, and 21. Most infants with AREDV require in- percentile or equivocal nonstress testing were sub- tensive care. Furthermore, the risk of cerebral hemor- jected to an additional test, the amniotic fluid index. rhage, anemia, and hypoglycemia is increased. It has When the amniotic fluid index was below the 5th been observed, however, that absent end-diastolic percentile, the S/D ratio had AREDV, or when the flow may improve, although often only transiently, nonstress test was abnormal, induction and delivery and that weeks or more may elapse before the fetus were recommended. More women in the Doppler shows additional evidence of compromise. Obviously, group than in the nonstress group underwent induc- the presence of absent end-diastolic flow should warn tion of labor (4.8% versus 1.9%, p<0.005). The main the physician of significantly increased fetal risk. Ap- outcome variable studied was the presence of peripar- propriate surveillance measures should be immedi- tum morbidity and was measured by the cesarean de- ately undertaken. If the pregnancy is significantly livery rate for fetal distress in labor. The incidence of preterm, consideration for delivery should include ad- cesarean delivery for fetal distress was lower in the ditional signs of fetal compromise. A more aggressive Doppler group compared with the nonstress group approach should be taken to ensure fetal maturity. If (4.6% versus 8.7%, p<0.006). The women with hyper- fetal anomalies are present or AEDV cannot be tension and intrauterine growth restriction sustained explained by pregnancy complications such as pre- the greatest reduction in cesarean delivery for fetal eclampsia, then fetal karyotype should also be deter- distress. The neonatal morbidity between the two mined to rule out lethal aneuploidies. Although the groups was similar. benefits of emergency delivery for this phenomenon Some investigators have obtained more informa- remain controversial, randomized clinical trials have tion from the umbilical artery waveforms in cases of shown improved outcome from intervention in preg- reverse end-diastolic flow. This has been done to try nancies with absent end-diastolic velocity. This sub- to improve the timing of the delivery and to predict ject is discussed comprehensively in Chap. 26. the outcome of the pregnancy. Brodszki and associates [50] measured the highest amplitude and the area below the maximum velocity curve of forward and reverse flow; and they also measured the dura- References tion of forward and reverse flow in 44 fetuses with 1. Rochelson B, Schulman H, Framakides G et al (1987) reverse end-diastolic flow. They calculated three ra- The significance of absent end-diastolic velocity in um- tios: (1) the ratio of the highest amplitude of the for- bilical artery velocity waveforms. Am J Obstet Gynecol ward and reverse flow, (2) the ratio of the area of the 156:1213±1218 forward and reverse flow, and (3) the ratio of the 2. Woo JS, Liang ST, Lo RL (1987) Significance of an ab- duration of the forward and reverse flow. Then, they sent or reversed end diastolic flow in Doppler umbilical established cut-off values for each ratio for the pre- artery waveforms. J Ultrasound Med 6:291±297 3. Reuwer PJ, Sijmons EA, Rietman GW, van Tiel MW, diction of perinatal death. The ratio of the highest Bruines HW (1987) Intrauterine growth retardation: amplitude of the forward and reverse flow and the ra- prediction of perinatal distress by Doppler ultrasound. tio of the area of forward and reverse flow had the Lancet 2:415±418 best capacity to predict perinatal death. They found 4. Hackett GA, Campbell S, Gamsu H, Cohen-Overbeek T, that survivors had higher ratios than the nonsurvivors Pearce JM (1987) Doppler studies in the growth re- did. In addition, more fetuses with ratios below the es- tarded fetus and prediction of neonatal necrotising en- tablished cut-off values had pulsations in the venous terocolitis, haemorrhage, and neonatal morbidity. BMJ 294:13±16 system. The calculation of these ratios may provide ad- 5. Arabin B, Siebert M, Jimenez E, Saling E (1988) Obstet- ditional information when these fetuses are evaluated. ical characteristics of a loss of end-diastolic velocities in the fetal aorta and/or umbilical artery using Doppler ultrasound. Gynecol Obstet Invest 25:173±180 Summary 6. Hsieh FJ, Chang FM, Ko TM, Chen HY, Chen YP (1988) Umbilical artery flow velocity waveforms in fe- It is apparent from cumulative experience that the tuses dying with congenital anomalies. Br J Obstet Gy- naecol 95:478±482 end-diagnostic component of the umbilical arterial 7. Johstone FD, Haddad NG, Hoskins P et al (1988) Um- Doppler waveform is of crucial importance for fetal bilical artery Doppler flow velocity waveform: the out- prognostication. AREDV is known to be associated come of pregnancies with absent end diastolic flow. with an unusually adverse perinatal outcome. Most Eur J Obstet Gynecol Reprod Biol 28:171±178 a Chapter 25 Absent End-Diastolic Velocity in the Umbilical Artery and Its Clinical Significance 385

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