Doppler Velocimetry for Fetal Surveillance: Adverse Perinatal Outcome and Fetal Hypoxia

The primary objective of fetal surveillance is to detect fetal compromise arising from nutritive and respira- tory deficiencies. A variety of obstetric complications, including fetal growth restriction and hypertension, may expose the fetus to such risks. There is emerging evidence that the growth-restricted human fetus suf- fers from chronic hypoxia and acidosis. Although an immense amount of information is available on acute and subacute fetal respiratory deficit, the mechanism of chronic nutritional and respiratory deficiency in the fetus has remained relatively ill-understood.

Encountering unfavorable circumstances, the fetus appears to mobilize a spectrum of compensatory re- sponses, including preferential preservation of fetal growth over placental growth, changes in fetal move- ment pattern, and eventual deceleration of the fetal growth rate (Fig. 24.1). In the face of deepening de- privation, compensation gives way to decompensa-

tion. It has also been shown that a central component of the fetal homeostatic response involves flow redis- tribution, which favors the vital organs (i.e., brain, heart, adrenals), whereas flow to muscle, viscera, skin, and other less critical tissues and organs de- clines [1]. Underlying this phenomenon are the di- verse changes in impedance in these vascular sys- tems.

The introduction of Doppler velocimetry has not only enabled us to investigate this phenomenon in the human fetus but it has opened up the potential of its use for detecting fetal compromise. A significant amount of information exists on the diagnostic effi- cacy of the Doppler method for identifying the fetus with adverse outcome as defined by various clinical parameters. What constitutes adverse perinatal out- come, however, is a highly controversial and proble- matic issue. It is well recognized that many of these

Doppler Velocimetry for Fetal Surveillance:

Adverse Perinatal Outcome and Fetal Hypoxia

Dev Maulik, Reinaldo Figueroa

Fig. 24.1. Summary of fetal sequential re- sponse to progressive stress. Note that the depicted sequence is an approxima- tion; the actual course may vary depend- ing on the characteristics of the chronic deprivation and the individual fetal ability to cope

clinical indicators do not necessarily reflect chronic respiratory or nutritive deficit of the fetus. It is im- portant therefore to consider the efficacy of fetal Doppler velocimetry also with regard to detecting fe- tal hypoxia or asphyxia, although it may not prognos- ticate the long-term neurologic outcome of the infant.

This chapter provides a general review of the effi- cacy of fetal Doppler velocimetry for predicting ad- verse perinatal outcome and identifying fetal hypoxia and acidosis in high-risk and unselected pregnancies.

The efficacy of the method in relation to specific pregnancy disorders is considered in other dedicated chapters in this book.

Doppler Velocimetry

and Adverse Perinatal Outcome

This section presents a critical appraisal of the effec- tiveness of fetal Doppler velocimetry for identifying the fetus at risk. During this inquiry it is important to ascertain whether the technique is used in compli- cated pregnancies or in an unselected obstetric popu- lation. Although such risk categorization is merely a relative distinction of high or low prevalence of ad- verse outcome in population, it significantly influ- ences the efficacy measures of a test. Thus for a given diagnostic test, the efficacy is greater among patients with a high prevalence of the disorder than among those with a low prevalence. The efficacy of the Dop- pler technique should therefore be appraised accord- ing to the risk category of the study population.

Table 24.1. Diagnostic efficacy of umbilical Doppler velocimetry for high-risk pregnancies Study,

first author No. of

patientsRisk Outcome Prev

(%) Design DI Sens

(%) Spec

(%) PPV

(%) NPV

(%) KI

Trudinger [2] 170 GHR SGA < 10th C,

AS5<7 31 ? S/D³3 60 85 64 83

Laurin^a 159 SGA IUGR<2SD

ODFD 47

19 Blind BFC II±III 50

83 97

90 93

66 69

96 0.48 0.66 Dempster^b 205 GHR Late

deceleration 16 Blind S/D³97th C 70 89 54 94

Berkowitz^c 172 Risk of

IUGR ODFD, AF, Mec, AS, PND, RDS, SGA

21 Blind S/D³3 47 84 57 86

43 SGA Complications 43 67 63 57 71

Chambers^d 145 SGA,

HTN CSFD 17 Blind RI ³2SD 100^f 77 46 100

Maulik [7] 350 GHR SGA<10th C, IPFD, AS5<7, UApH<7.2, NICU admission

28 Blind S/D³3 79 93 83 91 0.73

Devoe [3] 1,000 GHR PND, IPFD, AS5<7, UApH<7.2

19 Not

blind S/D³90th C,

AEDV 21 95 49 85

Pattinson^e 369 GHR Abnormal NST

CSFD 8

3 Blind RI ³95th C 93

92 78

89 8

22 100

100

Risk, risk characteristics of the study population; GHR, general high risk; SGA, small for gestational age; HTN, hypertension;

IUGR, intrauterine growth restriction; C, percentile; AS5, Apgar score at 5 min; SD, standard deviation; ODFD, operative de- livery for fetal distress; AF, amniotic fluid; Mec, meconium; PND, perinatal death; RDS, respiratory distress syndrome; CSFD, cesarean section for fetal distress; IPFD, intrapartum fetal distress; UApH, umbilical arterial pH; NICU, neonatal intensive care unit; NST, nonstress test; Prev, prevalence; DI, Doppler index; Sens, sensitivity; Spec, specificity; PPV, positive predic- tive value; NPV, negative predictive value; KI, kappa index.

aBr J Obstet Gynecol 69:895, 1987.

bEur J Obstet Gynecol Reprod Biol 29:21, 1988.

cObstet Gynecol 71:742, 1988.

dBr J Obstet Gynaecol 96:803, 1989.

eObstet Gynecol 78:353, 1991.

fAnalysis done with the sensitivity kept fixed at 100% (i.e., no cases of adverse outcome would be missed).

Diagnostic Efficacy of Doppler Velocimetry Among High-Risk Pregnancies

The efficacy of fetal Doppler investigations for pre- dicting adverse perinatal outcome in complicated pregnancies has been widely investigated. A selection of these studies is summarized in Table 24.1, some of which are also discussed later.

Most studies indicated that the Doppler results were efficacious for identifying the fetus at risk in complicated pregnancies. There are, however, wide variations in the performance of the technique, with the sensitivity ranging from 21% to more than 90%

and the specificity from 63% to 97%. This range may not be surprising, as the studies were heterogeneous in several ways, including the population selection criteria, the method of using Doppler surveillance (e.g., the frequency of examination), the diagnostic threshold value of the test result, and the outcome parameters. As is evident, the investigators were not uniform in their selection criteria of an adverse peri- natal outcome, which included fetal smallness for ges- tational age (SGA), operative delivery for fetal dis- tress, Apgar score, the need for admission to the neo- natal intensive care unit (NICU), and various other

conditions. These variations are not surprising as the criteria for morbid perinatal outcome remain contro- versial. Many of the traditional measures of morbid- ity are now known to be of little significance for long-term prognosis of the infant. Despite these lim- itations, traditional measures of perinatal morbidity have not yet been replaced by any more insightful al- ternatives.

In addition, some of these studies were deficient in their experimental approach. For example, many inves- tigators did not employ a blind technique, which might have compromised the studies' validity as the clini- cians' preconceived notion about the efficacy of the test would inevitably introduce bias. If the physician was al- ready favorably disposed toward the test, the results could be erroneously affirmative; on the other hand, the chances of obtaining false-negative results would increase if the physician had no confidence in the test.

Thus blind evaluations significantly enhance the valid- ity of the study results. In one of the first studies re- ported on the diagnostic efficacy of Doppler velocime- try, the investigators [2] did not state whether the clin- icians were blind to the Doppler results. Moreover, in one of the largest studies on Doppler efficacy, which also included a nonstress test (NST) and biophysical

Fig. 24.2. Principle of receiver operating characteristic (ROC) curve analysis for assessing the efficacy of a diagnos- tic test. D(±) disease-free, D(+) diseased, T(±) test negative, T(+) test positive, TP true positive, FP true negative. Top:

Distribution pattern of the diseased and disease-free popu- lations along the test value represented by the horizontal line in the middle of each panel. Bottom: ROC curves. Note that with a useless test there is an equal chance of being diseased or disease-free at any given value of the test (A1);

the corresponding curve (A2) is the diagonal from the low- er left to the upper right corner. In contrast, a perfect test completely discriminates between the two populations (B1). The arrow points to the most discriminatory value of

the test. The corresponding ROC curve (B2) is represented by the left and upper margins of the graph with no false positives. The upper left corner corresponds to only true- positive and no false-positive results and therefore repre- sents the absolute discriminatory value of the test. A use- ful, but less than perfect, test predominantly separates the two populations with some degree of overlap that contrib- utes to the false-positive and false-negative results (C1).

The arrow, as in the previous case, points to the most dis- criminatory value of the test. The ROC curve covers an area (black shaded) that is a measure of the test's overall effi- cacy (C2). The test value nearest to the upper left corner is the most efficacious

profile [3], the clinicians had ready access to the Dop- pler and other fetal monitoring results, which ob- viously compromised the reliability of the conclusions drawn from this investigation.

Despite such limitations, most investigators have confirmed that fetal Doppler velocimetry is an effective method for identifying fetal jeopardy in high-risk pregnancies with the significant exception of postdat- ism, for which it may not be a reliable discriminator of fetal status (see Chap. 23 for an in-depth discussion).

This affirmative conclusion remains valid irrespec- tive of whether the study utilized the Bayesian or sig- nal analytic approach or both. The Bayesian approach determines the probabilistic measures of efficacy, such as the sensitivity, specificity, or predictive val- ues, at a given test value. The signal analysis method measures the overall discriminatory performance of a test from its true- and false-positive rates for all available values and assists in determining its optimal threshold for a particular application. This technique is also known as the receiver operating characteristic (ROC) method [4] and is explained in Fig. 24.2. In addition to these two techniques, the kappa index [5]

has been used. The kappa index measures the degree of concordance between the test result and the diag- nosis beyond chance; the value of this index has been utilized to assess the magnitude of the test's efficacy [6]. A kappa index more than 0.8 is regarded as near perfect, at 0.6±0.8 as ªsubstantialº, at 0.4±0.6 as mod- erate, and less than 0.4 as fair to poor.

These analytic techniques were utilized by Maulik et al. [7] to evaluate the diagnostic efficacy of the umbilical arterial systolic/diastolic (S/D) ratio for pre- dicting adverse perinatal outcome. As indicated, the study was blind, so that those responsible for clinical management of the patient did not have access to the Doppler results. A free-standing continuous-wave Doppler device with a 4-MHz transducer and a fast Fourier analyzer was used. The criteria for abnormal perinatal outcome included (1) SGA at birth (<10th percentile); (2) 5-min Apgar score <7; (3) umbilical cord arterial pH below 7.2; (4) fetal distress during labor (late and severe variable deceleration, subnor- mal short-term variability, and fetal scalp pH <7.20);

(5) presence of thick meconium; and (6) NICU ad- mission. The ROC curve assisted in determining the optimal cutoff value of the S/D ratio (demonstrated in Fig. 24.3). The ROC analysis indicated that this test had an impressive but less than perfect capability of discriminating between an adverse and a normal out- come. Ratios of 2.9 and 3.0 exhibited the maximum inherent discriminatory power: The former of the two values exhibited greater sensitivity, and the latter, which is the more prevalent standard, showed greater specificity and a higher kappa index (Table 24.2).

Furthermore, when fetal SGA status was excluded

from the outcome, the S/D ratio had the best diag- nostic efficacy; in contrast, when small fetal size was the only outcome criterion, the test demonstrated the worst efficacy. This result further confirms that the umbilical arterial Doppler indices are more capable of identifying fetal compromise than small fetal size.

Fetal Doppler Velocimetry, Nonstress Test, and Biophysical Profile:

Comparative Efficacy for Predicting Adverse Perinatal Outcome

When appraising the diagnostic efficacy of fetal Dop- pler, an important consideration is to compare it with

diastolic ratio cutoff points (from [7] with permission) Cutoff

point Sensitivity Specificity PPV NPV KI

2.5 0.93 0.53 0.47 0.94 0.36

2.9 0.83 0.87 0.74 0.92 0.68

3.0 0.79 0.93 0.83 0.91 0.73

3.5 0.35 0.99 0.93 0.77 0.41

PPV, positive predictive value; NPV, negative predictive val- ue; KI, kappa index.

True positive rate

False positive rate 1

0.8

0.6

0.4

0.2

0

0 0.2 0.4 0.6 0.8 1

3.5 3.2 3.1 3.0 2.9 2.8

2.7

2.5

2.3

Fig. 24.3. Receiver operating characteristic curve of the umbilical arterial systolic/diastolic (S/D) ratio. Note that the S/D ratio cutoff point (2.9) closest to the upper left corner of the graph has the best ability to discriminate between the normal and abnormal outcome groups. (Reprinted from [7] with permission)

that of the currently utilized fetal surveillance proce- dures. This section presents the comparative effective- ness of these modalities in relation to the prediction of adverse perinatal outcome. Other relevant aspects of this issue (i.e., the prediction of fetal asphyxia and the sequence of occurrence of abnormal tests) are discussed later in the chapter.

The effectiveness of the umbilical arterial A/B (S/D) ratio for predicting adverse outcome was investigated by Trudinger et al. [2] in 170 high-risk patients. The parameters of fetal compromise included birth weight below the 10th percentile or an Apgar score of less than 7 at 5 min. The fetal heart rate was assessed in terms of reactivity and a modified Fischer score. In this study, the umbilical arterial S/D ratio appeared to be more sensitive, but less specific, than electronic fetal heart rate monitoring. Farmakides et al. [8] investigated the diagnostic efficacy of the NST and the umbilical ar- terial S/D ratio in 140 pregnancies. The measures of outcome included intrauterine growth restriction (IUGR), fetal distress, cesarean section for fetal dis- tress, and admission to the NICU. Fetuses with a nor- mal NST but abnormal S/D ratio had an outcome worse than those with an abnormal NSTand a normal S/D ra- tio; those for whom both tests were abnormal experi- enced the worst outcome.

Further corroboration came from Arduini et al.

[9], who noted in a cross-sectional study involving 1,000 unselected pregnancies at 36±40 weeks' gesta- tion that umbilical velocimetry was more effective than NST for identifying fetuses at risk of adverse outcome (cesarean section for fetal distress, lower birth weight, 5-min Apgar score <7, admission to the NICU). The relative strengths of the individual and combined use of the various tests were investigated by Hastie et al. [10] in 50 pregnant patients. These investigators observed that the repeat nonreactive NST was highly sensitive (92%) and the S/D ratio highly specific (83%); they therefore suggested the ef- fectiveness of combining the two tests for predicting adverse perinatal outcome. The suggestion of a com- bined approach also came from Nordstrom et al.

[11], who determined the umbilical arterial S/D ratio and biophysical profile in 69 high-risk pregnancies within 10 days preceding the delivery. Intrapartum fe- tal distress and SGA occurred in 43% of the infants.

The S/D ratio demonstrated a higher sensitivity (37%), specificity (92%), positive predictive value (PPV) (79%), and negative predictive value (NPV) (66%) than the biophysical profile (27%, 82%, 53%, and 59%, respectively).

These observational studies, though highly infor- mative, do not provide evidence for a greater effec- tiveness of any of the tests in regard to altering out- come. Such conclusions can be achieved only by ran- domized trials. This issue is discussed in Chap. 26.

Fetal Doppler Sonography

and Neurodevelopmental Outcome

As indicated above, the currently utilized immediate measures of outcome may not effectively prognosti- cate the long-term effects of in utero fetal compro- mise on subsequent neurologic development. This point is particularly relevant when assessing the effi- cacy of antepartum surveillance, which is a relatively difficult area of investigation. Not surprisingly, there are few studies in this area, and those published so far are contradictory. Marɗl and Ley [12] in their long-term investigation found a significant correla- tion between the abnormalities of fetal aortic Doppler waveforms and deficient neurologic development of the infant assessed at 7 years of age. Similarly, Fouron et al. [13] measured the ratio of antegrade to retro- grade velocity integrals in the aortic isthmus of 44 fetuses with abnormal umbilical artery Doppler velocimetry and studied the neurodevelopmental con- dition of the children between the ages of 2 and 4 years. The investigators found a significant correla- tion between the flow patterns in the fetal aortic isth- mus and neurodevelopmental deficit, with a relative risk of 2.05 (95% CI 1.49±2.83) when predominantly retrograde flow was observed in the fetal aortic isth- mus. These findings are significant and require corro- boration. In a group of fetuses from high-risk preg- nancies delivered before 34 weeks Todd et al. [14]

found that when compared with umbilical Doppler velocimetry, antepartum fetal heart rate monitoring was more strongly associated with poor cognitive function of the infant at 2 years of age. Obviously, ad- ditional investigations are required before any defini- tive conclusions can be reached on this issue.

Efficacy of Doppler Sonography for Screening Low-Risk

and Unselected Pregnancies

Although the diagnostic efficacy of the Doppler tech- nique in a high-risk population is encouraging, its per- formance in a low-risk population is disappointing, as indicated by several studies summarized below.

In a prospective study involving 2,097 singleton

pregnancies, Beattie and Dornan [15] evaluated the

capability of umbilical arterial Doppler indices [pul-

satility index (PI), S/D ratio, resistance index (RI)] to

detect fetal growth restriction and perinatal compro-

mise. It was noted that the indices did not adequately

predict any of the parameters of adverse perinatal

outcome. It is noteworthy, however, that elevated

Doppler indices were the only abnormal findings in

three cases of unexplained fetal death in this popula-

tion. Moreover, although the investigators did not

find the indices to be useful for timing the death,

there were no indications that these fetuses under- went adequate surveillance after the abnormal Dop- pler findings, as up to 6 weeks transpired between the abnormal findings and the fetal death. There is an important methodologic issue related to the Dop- pler examination technique. The high-pass filter, which screens out low frequency components of the Doppler signal, was set at 200 Hz, thereby increasing the odds of a false-positive diagnosis of an absent end-diastolic velocity. Regrettably, such an inappro- priately high setting of the high-pass filter has been used by many other investigators, which may have compromised the validity of their results. Despite these limitations, the main finding that Doppler inso- nation of the umbilical arteries may not be effica- cious in a low-risk population has been corroborated by others [16±18].

Hanretty and coworkers [16] investigated the asso- ciation between the uteroplacental and umbilical ar- teries and the obstetric outcome in unselected preg- nant mothers. Only the results of the umbilical Dop- pler studies are discussed here. Their study utilized a prospective blind design and the populations of 326 women at 26±30 weeks' gestation and 356 women at 34±36 weeks' gestation. There was a significant (p<0.05±0.002) decrease in the birth weight of fetuses with an abnormal umbilical artery S/D ratio at either gestation. There were no statistically significant dif- ferences between the groups in relation to other ob- stetric outcomes, including antepartum admission, preeclampsia, preterm delivery, antepartum and intra- partum cesarean section, Apgar score, and NICU ad- mission.

Newnham and associates [17] evaluated the umbil- ical arterial S/D ratio as a screening tool in a pro- spective double-blind study of 535 pregnancies at me- dium risk for fetal compromise. Ultrasound biometry and Doppler measurements were performed at 18, 24, 28, and 34 weeks' gestation. Umbilical artery S/D ra- tios at 24, 28, and 34 weeks' gestation were found to be predictive of IUGR. This predictive capability was enhanced in the growth-restricted fetuses in whom hypoxia developed but was weak when umbilical ar- tery S/D ratios were evaluated as primary screening tests for fetal hypoxia. The results confirm a role for Doppler-determined S/D ratios in the evaluation of high-risk pregnancies but do not support a role as primary screening tests in low-risk obstetric popula- tions.

Sijmons and colleagues [18] conducted a prospec- tive blind assessment of the efficacy of umbilical arte- rial PI screening for predicting infants with SGA (birth weight <2.3rd and 10th percentile) and a low ponderal index (<3rd and 10th percentile). The pop- ulation consisted of 400 women at 28 and 34 weeks' gestation attending a university tertiary medical cen-

ter. The prevalence of the outcome varied between 3.3% and 22.1%. For the different outcome parame- ters, the test sensitivity ranged from 6.9% to 41.7%, specificity from 91.5% to 99.7%, the PPV from 10.0%

to 52.9%, and the NPV from 79.1% to 97.8%.

Doppler Velocimetry

and Fetal Hypoxia-Asphyxia

In this section we examine the efficacy of Doppler ve- locimetry of the various fetal circulations to detect fe- tal hypoxia and acidosis.

Fetal Asphyxia and Umbilical and Aortic Doppler Indices

A number of clinical studies have been reported on the efficacy of umbilical arterial and aortic Doppler measurements for detecting fetal hypoxia and asphyx- ia (Table 24.3). The studies employed two distinct approaches for assessing fetal asphyxia. In four stud- ies, umbilical cord blood sampling was performed at the time of elective cesarean section. Blood gases measured in this manner, however, may not reflect the antepartum acid-base status of the fetus. In the remaining five studies, blood gases in fetal blood samples were determined by cordocentesis. Most studies used Doppler assessment of the umbilical ar- tery, although one used the aortic mean velocity and another added aortic and carotid Doppler assess- ments. In three studies the efficacy of umbilical arte- rial Doppler and biophysical profile was compared, and one included a comparison with fetal heart rate monitoring. All studies measured pH, most deter- mined the PO

, and some also measured PCO

and lactate. There was also a considerable variability in the patient populations, ranging from those with so- nographic diagnosis of fetal growth compromise to those without recognized risks. Most investigators found a significant association between fetal acid- base compromise and Doppler indices from the um- bilical and aortic circulations. As expected, the higher the risk category of the pregnancy, the greater the as- sociation of the Doppler results with fetal asphyxia.

The association between fetal hypoxia and the umbili- cal artery Doppler index was less impressive. These studies are discussed below according to whether the investigations were restricted to the Doppler method or included other methods of fetal surveillance.

Efficacy of Doppler Method

Soothill et al. [19] were the first to use cordocentesis to

assess the efficacy of fetal Doppler velocimetry for re-

flecting fetal oxygenation and acidosis. Umbilical ve-

nous blood PO

, PCO

, pH, and plasma lactate were measured in 29 fetuses with growth restriction (ab- dominal circumference <5th percentile for gestational age). A duplex Doppler device was used to determine the mean velocity of aortic blood flow, which demon- strated significant negative correlations with the sever- ity of fetal hypoxia (r=±0.73, p<0.0001), hypercapnia (r=±0.48, p<0.02), and hyperlactemia (r=±0.54, p<0.005) and a positive correlation with fetal venous acidemia (r=0.58, p<0.001). These investigators sub- sequently demonstrated the efficacy of the continu- ous-wave Doppler interrogation, a simpler, more cost- effective technique for indirectly reflecting fetal blood gas status [20]. Umbilical venous blood gases were de- termined by cordocentesis in 59 fetuses with abdom- inal circumferences below the 5th percentile for gesta- tional age who also suffered from the absence of umbi- lical artery end-diastolic flow. In 88% of the cases the blood gases were abnormal; 42% were hypoxic, 37%

were asphyxiated, and 9% were acidotic. Furthermore, there was poor correlation between the degree of fetal smallness and the acidosis or severity of hypoxia.

Additional support for the efficacy of umbilical ar- tery Doppler indices for detecting fetal hypoxia and acidosis has come from other investigators. Ferrazzi et al. [21] used cord blood sampling at cesarean sec- tion on 14 high-risk pregnant patients, 10 of whom also underwent cordocentesis. A significant relation was found between the umbilical artery PI and the fe- tal blood pH, PCO

, and lactate concentrations. Um-

bilical venous oxygen content failed to show this as- sociation. A noteworthy observation was the sharp rise in umbilical venous lactate concentration when the umbilical arterial PI exceeded 1.5. Tyrrell et al.

[22] observed a significant association between the absence of end-diastolic flow in the umbilical artery and hypoxia and acidosis. The absent end-diastolic velocity detected hypoxia with a sensitivity of 78%, specificity 98%, PPV 88%, and NPV 98%. Similarly, acidosis was detected with a sensitivity of 90%, speci- ficity 92%, PPV 53%, and NPV 100%. When umbili- cal artery Doppler sonography revealed the presence of the end-diastolic velocity, an S/D ratio elevated be- yond 4.5 was diagnostic of hypoxia (sensitivity 89%, specificity 97%, PPV 40%, NPV 98%) and acidosis (sensitivity 100%, specificity 88%, PPV 20%, NPV 100%). Although the authors were confident about the method's diagnostic efficacy for both fetal hypox- ia and acidosis, it should be noted that the umbilical arterial response was greater with acidosis than with hypoxia.

Comparative Efficacy of Doppler Velocimetry and Other Methods of Fetal Surveillance The diagnostic efficacy of umbilical arterial Doppler velocimetry has been compared with that of other modalities of antepartum fetal surveillance. Pardi and colleagues [23] studied SGA fetuses (abdominal cir- cumference <5th percentile) regarding the umbilical

Study,

first author No. of

patients Patient risk

category Cord blood

sampling Doppler

assessment Acid-base

parameters Association correlation

Soothill [19] 29 SGA Cordocentesis Aortic MVpH, PO2, PCO2 Present

Nicolaides [20] 59 SGA Cordocentesis UA AEDVpH, PO2 Present

Ferrazzi [31] 14 High risk C/S UA PI pH, PCO2,

lactate Present

Tyrrell [22] 112 Unselected C/S UA AEDVpH, PO2 Present

Bilardo [27] 51 SGA

AGA Cordocentesis UA, aortic,

carotid PI, RI, MV

pH, PO2 Present

Vintzileos [24]^a 62 High risk C/S UA S/D pH Absent

Yoon [25]^a 105 Unselected C/S UA PI pH, PO2,

PCO2

Present

Pardi [22]^b 21 SGA Cordocentesis UA PI pH, PO2,

PCO2, lactate Present

Yoon [25]^a 24 High risk Cordocentesis UA PI pH, PO2,

PCO2

Present SGA, small for gestational age; AGA, appropriate for gestational age; C/S, cesarean section; UA, umbilical artery; AEDV, ab- sent end-diastolic velocity; MV, mean velocity; PI, pulsatility index; RI, resistance index; S/D, systolic/diastolic ratio.

aStudies compared the Doppler method with the biophysical profile.

bStudy compared fetal heart rate monitoring with the Doppler method.

artery PI and by cardiotocography to detect cordo- centesis-derived fetal blood gas abnormalities. Fetuses with normal cardiotocography and a normal PI did not demonstrate hypoxia or acidemia. In contrast, when both tests were abnormal, two-thirds of the fetuses had lactic acidosis, low blood oxygen content, and low pH values. These observations indicate that the combination of Doppler indices and cardiotocog- raphy is a powerful tool for identifying asphyxia in the SGA fetus. Use of this approach should improve management of this condition by identifying the in- fants who are not only small but also compromised, which in turn should promote more timely interven- tion and at the same time minimize unnecessary pro- cedures.

More extensive investigations exist regarding the comparative efficacy of Doppler velocimetry and the biophysical profile in recognizing fetal asphyxia.

Among these studies the report by Vintzileos and co- investigators [24] is the only one that contradicts the rest of the investigations discussed in this chapter.

They found no association between the Doppler results and cord arterial and venous pH. Fetal biophysical as- sessment was made and the umbilical artery S/D ratio determined in 62 patients with pregnancy complica- tions (mostly preeclampsia or SGA) within 3 h of deliv- ery by cesarean section, which was performed before the onset of labor. Cord blood gases were measured on samples collected immediately after delivery of the baby. The relation between the cord arterial and venous pH and the biophysical profile score and NST were sta- tistically significant (p<0.05±<0.0005), whereas that between the S/D ratio and cord arterial or venous pH was not significant. Furthermore, the NST had the best sensitivity (100%) and NPV (100%). The fetal biophy- sical profile had the best specificity (91%), PPV (62%), and overall efficiency (90%). The S/D ratio had the lowest sensitivity (66%), specificity (42%), PPV (16%), NPV (88%), and overall efficiency (45%). The authors concluded that the umbilical arterial S/D ratio, as determined by continuous-wave Doppler velocime- try, is inferior to the biophysical profile and the NST, and it has no value for antepartum surveillance for fetal acidosis.

These findings, however, were contradicted by Yoon et al., who used both approaches of cord blood sampling: collection from the cord vessels at cesarean section or from the umbilical vein by antepartum cor- docentesis. In the first study [25] the comparative ef- ficacy of Doppler umbilical velocimetry and the bio- physical profile for identifying fetal acidosis was in- vestigated in 105 singleton pregnancies in which um- bilical blood gases were determined at cesarean sec- tion performed before the onset of labor. The bio- physical profile and Doppler velocimetry showed comparable effectiveness for detecting fetal acidosis.

Patients with abnormal Doppler results showed a sig- nificantly higher prevalence of fetal acidosis, and all the fetuses with abnormal Doppler results were either acidotic or growth-restricted. Upon recognizing the limited validity of cord blood gases sampled at cesar- ean section for reflecting antepartum fetal acid-base status, the investigators conducted a second study [26], which used cordocentesis to assess fetal acide- mia, hypoxemia, and hypercarbia in 24 patients (at 26±40 weeks' gestation). Umbilical arterial PI was de- termined using pulsed Doppler equipment. The prev- alence of fetal acidemia (pH at 2 SD below the mean for gestational age) was 41.7%. A statistically signifi- cant relation was noted between the change in umbil- ical artery PI and fetal acidemia (p<0.001) and hy- percarbia (p<0.001) but not hypoxemia (p>0.1).

Similarly, a significant relation was noted between the biophysical profile score and fetal acidemia (p<0.001) and hypercarbia (p<0.005) but not hypoxemia (p>0.1). Stepwise multiple logistic regression and ROC analyses demonstrated that umbilical artery Doppler velocimetry was a better predictor for acide- mia and hypercarbia than the biophysical profile score.

Fetal Asphyxia

and Cerebral Doppler Sonography

In contrast to the umbilical artery Doppler indices, the cerebral artery Doppler indices demonstrate a consistent relation with fetal hypoxia. The human fe- tal cerebral circulation is uniquely sensitive to a de- cline in PO

and a rise in PCO

. As hypoxia develops, vasodilation and a concomitant fall in the middle ce- rebral arterial Doppler index occur. When hypoxia becomes severe, the Doppler index tends to rise, sug- gesting increasing cerebral vascular impedance, which is probably caused by cerebral edema. It is also ap- parent that the umbilical artery Doppler indices are sensitive to acidosis but not to the partly compen- sated respiratory acidosis.

Bilardo et al. [27] performed multiple ultrasound

biometric and pulsed Doppler measurements in

41 SGA and 10 appropriate-for-gestational-age (AGA)

fetuses at 19±37 weeks' gestation. Fetal asphyxia was

assessed from umbilical venous blood sampled by

cordocentesis. In addition to the PO

, PCO

, and pH

measurements, an asphyxia index was formulated

from the three blood gas parameters by principal

component analysis. Of the various ultrasonographic

biometric and Doppler parameters, those encompass-

ing the hemodynamic changes in the vascular supply

to the fetal brain (internal carotid) and abdominal

viscera (aorta) were the best predictors of fetal as-

phyxia. A more specific study on the middle cerebral

artery PI and fetal oxygenation [28], which utilized

cordocentesis for fetal blood sampling, showed a sig- nificant quadratic relation between fetal hypoxemia and the degree of reduction in the PI. The maximum fall in PI occurred when the fetal PO

was 2±4 SD be- low the normal mean for gestation. When the oxygen deficit increased, the PI tended to rise. The authors speculated that this increase reflected the develop- ment of fetal brain edema.

The fetal cerebral and umbilical circulatory re- sponses to hypoxia, hypercapnia, and acidosis were investigated by Chiba and Murakami [29] in 17 SGA fetuses. Cordocentesis was performed to determine umbilical venous blood gases and pH. The fetal circu- latory response was evaluated by gestation-adjusted RI values from the middle cerebral and umbilical ar- teries. The middle cerebral artery demonstrated de- creased impedance in the presence of hypoxia and acidosis. In contrast, the umbilical artery impedance increased with acidosis but was insensitive to hypoxia and hypercapnia. These observations were corrobo- rated by Akalin-Sel et al. [30], who found a low PO

and pH and a high PCO

in the umbilical venous blood sampled by cordocentesis from the SGA fetuses compared to the gestation-related normal values. The cerebral circulation was responsive to hypoxia and hypercapnia, whereas the aortic and umbilical circu- lations were responsive to hypercapnia and acidosis but not to hypoxia. Decreased impedance in the cere- bral arterial system was associated with increased im- pedance in the aortic, umbilical, and uteroplacental arteries.

These findings have significant clinical implica- tions for managing high-risk pregnancies. Although some animal studies suggest that fetal Doppler velo- cimetry may not be efficacious for identifying fetal asphyxia, it may not be applicable to the human situ- ation, as indicated by the results of clinical research summarized above. Obviously, the fetal cardiovascular response to chronic and progressive hypoxia and acidosis is complex. Doppler investigation helps us to elucidate this phenomenon and may contribute to im- proving the perinatal outcome. The differential re- sponse of the umbilical and cerebral hemodynamics to hypoxia and acidosis may be utilized to sequence the progression of fetal compromise, which may sig- nificantly enhance the diagnostic efficacy of the Dop- pler technique. Moreover, integration of the current modes of fetal surveillance, such as antepartum cardiotocography or biophysical profile scoring with the Doppler mode, offers exciting possibilities for im- proving the clinical value of this diagnostic approach.

Sequence of Changes

in Fetal Surveillance Parameters with Progressive Antepartum Fetal Compromise

Although comparisons have been made between Dop- pler velocimetry and other prevalent modes of fetal surveillance, no single testing modality should be re- garded as the exclusive choice for fetal surveillance, as these tests reveal different aspects of fetal patho- physiology, often in a complementary manner. Ob- viously, more work is needed to determine the optimal integration of the various surveillance methods for improving the perinatal outcome in a cost-effective manner: It is important to establish the sequence in which the various signs of fetal compromise manifest during surveillance of the fetus at risk. It is known that not all of these signs appear simultaneously. We have witnessed a variable chronology of falling cerebral Doppler indices, rising umbilical arterial Doppler in- dices, eventual disappearance of the end-diastolic flow, and the occurrence of ominous cardiotocographic pat- terns. It is also critical to examine the prognostic sig- nificance of the pattern of these occurrences. A few studies have systematically addressed this issue.

Arduini et al. [31] followed 36 SGA fetuses with an abnormal elevation of the umbilical and middle cere- bral artery PI ratios (>95th percentile) until the onset of antepartum late deceleration of the fetal heart rate.

Comprehensive Doppler evaluation of the fetal circu- lation was performed along with fetal cardiotoco- graphic examination. Statistically significant changes in PI occurred in all the vessels (umbilical artery, des- cending aorta, renal artery, internal carotid artery, middle cerebral artery). The most significant fall in the middle cerebral PI occurred 2 weeks before the onset of late deceleration, indicating the maximum compensatory vasodilatory response of the cerebral circulation. In contrast, significant increases in the peripheral and umbilical PI occurred close to the on- set of abnormal fetal heart rate patterns. James et al.

[32] evaluated the chronology of abnormalities of: (1) umbilical artery Doppler results; (2) fetal growth as indicated by ultrasound measurement of the fetal ab- dominal circumference; and (3) biophysical profile score. The retrospective study of 103 fetuses at risk of chronic fetal asphyxia revealed that the umbilical ar- tery Doppler result deteriorated first, followed by the abdominal circumference, and then the biophysical profile score. Whereas an abnormality of one of these parameters in isolation did not result in any adverse consequences, abnormality of all three ultrasono- graphic features led to the worst outcome.

A prospective longitudinal investigation was con-

ducted by Ribbert et al. [33] that included the follow-

ing indicators of fetal well-being: fetal heart rate variability, body movements, breathing movements, and Doppler hemodynamic evaluation of the umbili- cal and internal carotid arteries. The study popula- tion consisted of 19 SGA fetuses who eventually re- quired delivery by cesarean section because of fetal distress. In 14 of 19 fetuses, abnormal velocity wave- forms were present from the beginning of the study.

The heart rate variability was initially marginal but declined further during the last 2 days preceding de- livery. Decreased body and breathing movements oc- curred subsequently and less frequently. The worst outcome was in fetuses with reversed end-diastolic velocities and a rapid fall in the variability. The authors concluded that with the progressive decline of the fetal condition fetal test abnormalities occur in the following sequence: Abnormal velocity waveform patterns occur first followed by a progressive de- crease in the heart rate variability; fetal general body and breathing movements are the last to decline.

Weiner et al. [34], studying hemodynamic changes in the middle cerebral artery and the aortic and pul- monic outflow tracts, correlated these changes with the computerized fetal heart rate pattern in fetuses with absent end-diastolic velocity in the umbilical ar- tery. They observed that with progressive deteriora- tion of the fetal status the cerebral circulation loses its autonomic reactivity first, followed within a few days by a similar response in the heart, as shown by the decreased fetal heart rate variability. This study is discussed in greater detail in Chap. 25.

A prospective longitudinal study was conducted by Hecher et al. [35] that included short-term variation of the fetal heart rate, PIs of fetal arterial and venous waveforms, and the amniotic fluid index. The study population included 110 singleton pregnancies with growth-restricted fetuses after 24 weeks of gestation and was divided into two groups: pregnancies deliv- ered at 32 weeks or less and pregnancies delivered after 32 weeks. The first variables to become abnor- mal were the amniotic fluid index and the umbilical artery PI. Abnormalities of the middle cerebral artery, aorta, fetal heart rate short-term variation, ductus ve- nosus, and inferior vena cava then followed. The de- crease in PI of the middle cerebral artery followed the abnormalities in the umbilical PI, and became progressively abnormal until delivery in the pregnan- cies delivered before 32 weeks. In pregnancies deliv- ered after 32 weeks the authors found a normaliza- tion of the middle cerebral artery PI before abnor- malities in the fetal heart rate. In the pregnancies de- livered before 32 weeks of gestation, the increase in the ductus venosus PI and the decrease in short-term variation were more pronounced than the changes in the other variables and became abnormal a few days before delivery. In addition, perinatal mortality was

significantly higher if the short-term variation and ductus venosus PI were abnormal compared to only one or neither being abnormal.

Baschat et al. [36] examined longitudinally 44 growth-restricted fetuses with elevated umbilical ar- tery PI (>2 standard deviations above mean) and birth weight below the 10th percentile who required delivery for abnormal scores in the biophysical pro- file. Fetal well-being was assessed serially using all five components of the biophysical profile and con- current Doppler evaluations of the umbilical artery, middle cerebral artery, ductus venosus, inferior vena cava, and free umbilical vein. The majority of the fe- tuses did not have reactivity of the fetal heart rate.

The investigators observed significant deterioration of the biophysical profile and Doppler studies between the first examination and time of delivery. First, there was a change in the Doppler variables. In 42 (95.5%) fetuses one or more of the Doppler variables were ab- normal. The umbilical artery and ductus venosus PI abnormalities progressed rapidly a median of 4 days before the biophysical profile worsened. Fetal breath- ing movement began to decline 2±3 days before deliv- ery, followed by a decrease in the amniotic fluid vol- ume. Loss of fetal movement and tone were observed on the day of delivery. Additionally, in 31fetuses dete- rioration in the Doppler parameters was complete 23 h before a worsening of the biophysical profile, while in 11 fetuses deterioration of the Doppler pa- rameters and the biophysical profile occurred simul- taneously.

The above studies indicate that Doppler velocime- try and existing fetal monitoring techniques can be integrated to provide greater pathophysiologic insight into the mechanism of progressive fetal decompensa- tion. Such integration may provide a rational, effec- tive alternative to the current standards of fetal sur- veillance.

Summary

There is ample evidence that Doppler indices from

the fetal circulation can reliably predict adverse peri-

natal outcome in an obstetric patient population with

a high prevalence of complications, such as fetal

growth restriction and hypertension. This efficacy is

not evident, however, in populations with a low prev-

alence of pregnancy complications. It is also apparent

that fetal Doppler indices are capable of reflecting fe-

tal respiratory deficiency with varying degrees of effi-

ciency. The umbilical arterial Doppler indices are

more sensitive to asphyxia than to hypoxia, whereas

cerebral Doppler indices demonstrate significant sen-

sitivity to hypoxia. Compared to fetal heart rate mon-

itoring and the biophysical profile, umbilical artery

Doppler velocimetry shows mostly similar and often superior efficacy. Furthermore, progressive fetal dete- rioration manifests in sequential abnormalities of the various fetal assessment parameters, starting with middle cerebral artery vasodilation and eventual pro- gression to disappearance of the fetal heart rate varia- bility, late deceleration, and the absence or reversal of the end-diastolic velocity in the umbilical artery. Evi- dently, no single testing modality should be regarded as the exclusive choice for fetal surveillance, as these tests reveal different aspects of fetal pathophysiology, often in a complementary manner. Clearly, more work is needed to determine the optimal integration of the various surveillance methods for improving perinatal outcome in a cost-effective manner.

References

1. Cohn H, Sachs E, Heymann M, Rudolph A (1974) Car- diovascular responses to hypoxemia and acidemia in fetal lambs. Am J Obstet Gynecol 120:817±823

2. Trudinger BJ, Cook CM, Jones L, Giles WB (1986) A comparison of fetal heart rate monitoring and umbili- cal artery waveforms in the recognition of fetal com- promise. Br J Obstet Gynaecol 93:171±175

3. Devoe LD, Gardner P, Dear C, Castillo RA (1990) The diagnostic values of concurrent nonstress testing, am- niotic fluid measurement, and Doppler velocimetry in screening a general high-risk population. Am J Obstet Gynecol 163:1040±1047

4. Swets JA, Pickett RM (1982) Evaluation of diagnostic systems: methods from signal detection theory. Aca- demic Press, Orlando, FL

5. Cohen J (1960) A coefficient of agreement for nominal scales. Educ Psychol Meas 20:37±44

6. Landis JR, Koch GG (1977) The measurement of obser- ver agreement for categorical data. Biometrics 33:159±

7. Maulik D, Yarlagadda P, Youngblood JP, Ciston P160 (1990) The diagnostic efficacy of the umbilical arterial systolic/diastolic ratio as a screening tool: a prospective blinded study. Am J Obstet Gynecol 162:1518±1523 8. Farmakides G, Schulman H, Winter D et al (1988) Pre-

natal surveillance using non-stress testing and Doppler velocimetry. Obstet Gynecol 71:184±189

9. Arduini D, Rizzo G, Soliani A, Romanini C (1991) Dop- pler velocimetry versus nonstress test in the antepar- tum monitoring of low-risk pregnancies. J Ultrasound Med 10:331±335

10. Hastie SJ, Brown MF, Whittle MJ (1990) Predictive val- ues of umbilical artery waveforms and repeat cardioto- cography in pregnancies complicated by nonreactive cardiotocography. Eur J Obstet Gynecol Reprod Biol 34:67±72

11. Nordstrom UL, Patel NB, Taylor DJ (1989) Umbilical artery waveform analysis and biophysical profile: a comparison of two methods to identify compromised fetuses. Eur J Obstet Gynecol Reprod Biol 30:245±251 12. Marɗl K, Ley D (1992) Intrauterine blood flow and

postnatal neurological development in growth-retarded fetuses. Biol Neonate 62:258±264

13. Fouron JC, Gosselin J, Amiel-Tison C et al (2001) Cor- relation between prenatal velocity waveforms in the aortic isthmus and neurodevelopmental outcome be- tween the ages of 2 and 4 years. Am J Obstet Gynecol 184:630±636

14. Todd AL, Trudinger BJ, Cole MJ, Cooney GH (1992) Antenatal tests of fetal welfare and development at age 2 years. Am J Obstet Gynecol 167:66±71

15. Beattie RB, Dornan JC (1989) Antenatal screening for intrauterine growth retardation with umbilical artery Doppler ultrasonography. BMJ 298:631±635

16. Hanretty KP, Primrose MH, Neilson JP, Whittle MJ (1989) Pregnancy screening by Doppler uteroplacental and umbilical waveforms. Br J Obstet Gynaecol 96:1163±1167

17. Newnham JP, Patterson LL, James IR, Diepeveen DA, Reid SE (1990) An evaluation of the efficacy of Doppler flow velocity waveform analysis as a screening test in pregnancy. Am J Obstet Gynecol 162:403±410

18. Sijmons EA, Reuwer PJ, van Beek E, Bruinse HW (1989) The validity of screening for small-for-gesta- tional-age and low-weight-for-length infants by Dop- pler ultrasound. Br J Obstet Gynaecol 96:557±561 19. Soothill PW, Nicolaides KH, Bilardo K, Campbell S

(1986) Relation of fetal hypoxia in growth retardation to mean blood velocity in the fetal aorta. Lancet 2:1118±1120

20. Nicolaides KH, Bilardo CM, Soothill PW, Campbell S (1988) Absence of end diastolic frequencies in umbili- cal artery: a sign of fetal hypoxia and acidosis. BMJ 297:1026±1127

21. Ferrazzi E, Pardi G, Bauscaglia M (1988) The correla- tion of biochemical monitoring versus umbilical flow velocity measurements of the human fetus. Am J Ob- stet Gynecol 159:1081±1087

22. Tyrrell S, Obaid AH, Lilford RJ (1989) Umbilical artery Doppler velocimetry as a predictor of fetal hypoxia and acidosis at birth. Obstet Gynecol 74:332

23. Pardi G, Cetin I, Marconi AM et al (1993) Diagnostic value of blood sampling in fetuses with growth retar- dation. N Engl J Med 328:692±696

24. Vintzileos AM, Campbell W, Rodis J et al (1991) The relationship between fetal biophysical assessment, um- bilical artery velocimetry, and fetal acidosis. Obstet Gy- necol 77:622±627

25. Yoon BH, Syn HC, Kim SW (1992) The efficacy of Doppler umbilical velocimetry in identifying fetal acidosis: a comparison with fetal biophysical profile. J Ultrasound Med 11:1±6

26. Yoon BH, Romero R, Roh CR et al (1993) Relationship between the fetal biophysical profile score, umbilical ar- tery Doppler velocimetry, and fetal blood acid-base sta- tus determined by cordocentesis. Am J Obstet Gynecol 169:1586±1594

27. Bilardo CM, Nicolaides KH, Campbell S (1990) Doppler measurements of fetal and uteroplacental circulations:

relationship with umbilical venous blood gases mea- sured at cordocentesis. Am J Obstet Gynecol 162:115±

28. Vyas S, Nicolaides KH, Bower S, Campbell S (1990)120 Middle cerebral artery flow velocity waveforms in fetal hypoxaemia. Br J Obstet Gynaecol 97:797±803

29. Chiba Y, Murakami M (1992) Cerebral blood flow dy- namics in fetus. No To Hattatsu 24:136±142

30. Akalin-Sel T, Nicolaides KH, Peacock J, Campbell S (1994) Doppler dynamics and their complex interrela- tion with fetal oxygen pressure, carbon dioxide pres- sure, and pH in growth-retarded fetuses. Obstet Gyne- col 84:439±446

31. Arduini D, Rizzo G, Romanini C (1992) Changes of pulsatility index from fetal vessels preceding the onset of late decelerations in growth-retarded fetuses. Obstet Gynecol 79:605±611

32. James DK, Parker MJ, Smoleniec JS (1992) Comprehen- sive fetal assessment with three ultrasonographic char- acteristics. Am J Obstet Gynecol 166:1486±1491

33. Ribbert LS, Visser GH, Mulder EJ, Zonneveld MF, Morssink LP (1993) Changes with time in fetal heart rate variation, movement incidences and haemody- namics in intrauterine growth retarded fetuses: a longi- tudinal approach to the assessment of fetal well being.

Early Hum Dev 31:195±208

34. Weiner Z, Farmakides G, Schulman H, Penny B (1994) Central and peripheral hemodynamic changes in fe- tuses with absent end-diastolic velocity in umbilical artery: correlation with computerized fetal heart rate pattern. Am J Obstet Gynecol 170:509±515

35. Hecher K, Bilardo CM, Stigter RH et al (2001) Monitor- ing of fetuses with intrauterine growth restriction: a longitudinal study. Ultrasound Obstet Gynecol 18:564±

36. Baschat AA, Gembruch U, Harman CR (2001) The se-570 quence of changes in Doppler and biophysical param- eters as severe fetal growth restriction worsens. Ultra- sound Obstet Gynecol 18:571±577