Use of Doppler velocimetry in diagnosis and prognosis of intrauterine growth restriction (IUGR): A Review

2.1 Umbilical artery

The Doppler velocimetry of the umbilical artery (UA) is representative of the degree of perfusion to the fetoplacental unit [16]. Normally, there is continuous forward flow in the umbilical artery throughout the cardiac cycle, a characteristic that can be seen as early as 14 weeks [16]. Placental vascular resistance decreases during gestational development, and as a result the pulsatility index (PI) of the UA gradually decreases [16]. Generally, the UA-PI is considered abnormal if it is greater than 2 standard deviations above the mean for gestational age. An abnormal UA-PI is indicative of increased placental vascular resistance and ergo, a possible fetal abnormality [16]. In the earlier stages of IUGR, there is still continuous forward flow in the UA, but the end-diastolic velocity is diminished such that the pulsatility index becomes elevated [17]. In the later stages, absent or reversed end diastolic flow of the UA (UA-AREDV) is imminent. Clinically, the Doppler waveforms can be obtained anywhere along the umbilical cord, although the abdominal cord insertion is a preferred location. This preference is due to the observation that waveforms obtained from the placental end of the cord tend to show higher end diastolic velocities compared to the abdominal insertion[18].

The umbilical artery is the most frequently surveilled vessel in Doppler velocimetry due to its accessibility and the strength of its associations with fetal outcomes. An abnormal UA-PI is associated with an increased risk of low birth weight and early delivery [19, 20]. UA-AREDV is among the most sensitive indicators of acidemia, asphyxia, perinatal death, stillbirth, and neonatal death [6, 22]. UA-AREDV is also associated with intraventricular hemorrhage (IVH) [23]. UA abnormalities often occur in parallel with ductus venosus [DV] abnormalities [24]. As such, it has been found that the prediction of perinatal outcomes is improved when umbilical artery and ductus venosus Doppler waveform analysis is combined [6]. A randomized controlled trial of high-risk fetuses found that Doppler velocimetry of the UA offered a decreased incidence of Cesarean delivery due to fetal distress compared to non-stress testing [25].

Although a fetus may present with abnormal UA flow early in gestation, the progression of this abnormality over time is a much more accurate indicator of fetal outcome. Some pre-viable fetuses initially display an absent end diastolic flow in the UA at 20– 23 weeks [26]. For some of the fetuses, the abnormality persists or worsens. For others, the UA-PI gradually improves over time, eventually reaching a normal value. The latter fetuses had a better outcome than the former in terms of gestational age at delivery, birth weight, and fewer perinatal complications. Although the potentially abnormal indices may initially be high, a progressive decrease in the ratio is associated with improved prognosis. Conversely, an increasing ratio leading to absent or reversed end diastolic flow (AREDV) is indicative of worsening prognosis [26, 27].

A meta-analysis of sixteen randomized controlled trials showed that Doppler velocimetry of the umbilical and fetal arteries, coupled with the appropriate intervention, can reduce perinatal mortality by 29% (RR = 0.71, 95% CI (Confidence Interval) 0.52– 0.98) [28]. It was also shown to reduce the incidence of stillbirths by 35%, although this did not meet the criteria for statistical significance. The studies used similar methodologies and focused on the use of Doppler for ‘high risk’ pregnancies. A ‘high risk’ pregnancy was defined as singleton or twin pregnancies in which the maternal or fetal condition could be expected to lead to fetal compromise. These conditions included suspected IUGR, post-term pregnancies, previous pregnancy loss, and women with hypertension, diabetes or other maternal pathology.

A bivariate meta-analysis was conducted to determine the accuracy of UA Doppler in predicting SGA and adverse perinatal outcomes [29]. In predicting SGA, the UA Doppler had a sensitivity of 0.55 (0.48, 0.62) and a specificity of 0.85 (0.81, 0.88). Similar results were found for adverse perinatal outcomes, with a sensitivity of 0.54 (0.47, 0.61) and a specificity of 0.84 (0.79, 0.87). Hence, while the test may be useful for identifying true negatives in cases of suspected IUGR, it is only able to identify about half of IUGR fetuses.

Of the three major vessels, the Doppler velocimetry of the umbilical artery has the strongest evidence to support its use. Because the umbilical artery is usually the first vessel to become affected in IUGR fetuses, the early detection of its abnormality can provide advanced warning for the clinician to take the necessary management precautions, such as increasing the frequency of Doppler examinations. Hence, while UA Doppler may not be the strongest predictor of perinatal outcome, it can be used to identify fetuses that are at risk of adverse outcomes [14].

2.2 Ductus venosus

The ductus venosus [DV] shunts oxygenated blood from the umbilical vein directly to the inferior vena cava, bypassing the liver. The Doppler waveform of the DV is associated with the physiological status of the right atrium and right ventricle [30]. DV Doppler waveform is distinguished by two peaks (S and D for ventricular systole and diastole, respectively), followed by a trough during atrial systole, the a-wave [16]. In normal fetuses, there is a forward flow at the DV and the pulsatility index for veins (PIV) decreases with advancing gestation [16]. Abnormalities in the ductus venosus waveform can be indicative of increased resistance in the right atrium due to placental abnormalities. Increased resistance in placental blood-flow can lead to elevated cardiac afterload and subsequently elevated end-diastolic intracardiac pressures. The forward flow in the ductus venosus thus becomes compromised, particularly in the a-wave. DV abnormalities generally present in the later stages of IUGR, first with an increasing PIV, followed by an absent or reversed a-wave (DV-RAV), indicating imminent fetal cardiac compromise [17].

The severity of the reversal of the ductus venosus blood flow may be a potential indicator for optimal delivery time of the fetus. The current practice involves immediate delivery of the fetus if DV Doppler abnormalities are found before the 32nd week of gestation. Regardless of gestational age, the risk of stillbirth when there is an absence or reversal of the a-wave doubles with each passing day in utero [31]. For instance, a delay of 6 days between the initial detection of DV abnormalities and the delivery of the fetus can lead to a 50% chance of a stillbirth [31]. DV-RAV that persists for more than 7 days without intervention is able to predict stillbirth with an extremely high sensitivity and specificity. However, this view is challenged by Mari et al. [16] in their study. Based on their data, it was suggested that IUGR fetuses should only be delivered after 32 weeks of gestation if they present DV reversed flow. Their reports indicated a drop of 48% in perinatal delivery for each week the fetus remains in utero between 25 and 29 weeks. On its own, DV-RAV is stronger predictor of adverse perinatal outcomes than UA-AREDV [6, 17]. However, when used in combination with UA-AREDV, DV-RAV offers enhanced predictive power for adverse perinatal outcomes such as acidemia, asphyxia, stillbirth, perinatal and neonatal death [6].

According to a systematic review and meta-analysis conducted by Morris et al., abnormal DV Doppler was found to accurately predict perinatal mortality (n = 5) [29]. However, adverse perinatal outcome (n = 14), acidaemia (n = 6), and APGAR score at 5 min <7 (n = 5) were not predicted with utmost accuracy by abnormal DV Doppler. In its entirety, the meta-analysis indicated that DV Doppler is only a moderately accurate predictor of compromise of fetal/neonatal wellbeing. A study conducted by Picconi, J. L. et al. [32] also indicated the usefulness of DV Doppler in predicting fetal/neonatal outcomes. It was suggested that for a better prediction of fetal outcome, it is essential to assess both the isovolumetric relaxation velocity (IRV) and end-diastolic velocity (EDV), and absent/reversed end diastolic flow (A/REDF). The study looked at peak systolic velocity (PSV), IRV and EDV, and qualitatively assessed A/REDF. S-wave/isovolumetric A-wave (SIA) index (PSV/(IRV+EDV)) was calculated. The results suggested that SIA index values less than – 1.25 correlated with fetal death, and those with greater value correlated with live birth (100% sensitivity and 100% specificity). Also, SIA index values less than 2.07 correlated with neonatal survival and values greater than 2.07 with neonatal death (67% sensitivity and 94% specificity). The ductus venosus A/REDF also correlated with fetal death, neonatal death, and neonatal survival with sensitivity values of 88%, 78%, and 32%, respectively. However, this procedure is only good for assessing the fetal outcome of severely premature IUGR fetuses. Since DV abnormalities are presented towards the end of the gestation, the usefulness of its Doppler data might be limited to predicting fetal outcomes at birth.

2.3 Middle cerebral artery

IUGR fetuses redistribute the flow of blood to the brain in an effect known as “brain sparing” [33]. Placental vascular dysfunction limits the delivery of nutrients to the fetus through the umbilical veins as well as the elimination of wastes through the umbilical arteries. This increases the afterload in the right ventricle, resulting in a shift in cardiac output towards the left ventricle and hence the upper body. The brain can compensate for the nutrient deficiency by reducing cerebral blood flow resistance, which in turn decreases left ventricular afterload [33]. The increase in blood flow to the brain during end-diastole is marked by a decreased pulsatility index [PI] in the MCA. The simultaneous decrease in MCA-PI and increase in UA-PI can be quantified by the cerebroplacental ratio (MCA-PI/UA-PI). The MCA-PI/UA-PI ratio less than 1.08 is considered abnormal. In normal fetuses, this ratio is much higher due to a higher MCA-PI [34].

The MCA is the most studied fetal cerebral artery and is able to detect cerebral blood flow and direction. [16]. Doppler measurements of the cerebral arteries are visualized around the Circle of Willis and waveforms are taken proximally [35]. It has been noted that MCA-PI/UA-PI ratio, or cerebroplacental ratio (CPR) is a better predictor of growth restricted fetuses and adverse perinatal outcomes than either the MCA-PI or UA-PI alone [34]. According to Tarzamniet al. [36], evaluation of the MCA Doppler waveform has greater efficacy in fetal intercranial assessment of at-risk fetuses in high-risk pregnancies in comparison to other fetal veins and arteries. In a study performed by Bano et al., CPR demonstrated a 100% specificity and positive predictive value (PPV) in diagnosing IUGR and predicting adverse perinatal outcome. However, the sensitivity of the ratio is questionable at a merely 44.4% and a negative predictive value (NPV) of 64.3%. Regardless, the sensitivity and NPV percentages of the ratio are still higher than that of MCA-PI and UA-PI alone [34].

In one of the studies conducted by Mari et al. [37], Doppler ultrasound was used to collect quantitative data from the MCA using its PI and peak systolic velocity (PSV). Using thirty IUGR fetuses, MCA-PI and MCA-PSV were recorded from initial diagnosis until the time of delivery. Ten fetuses followed longitudinally indicated an abnormal MCA-PI measurement prior to an abnormal MCA-PSV reading. The MCA-PSV reading followed a more consistent pattern of perinatal morbidity than the MCA-PI. In twelve fetuses where the MCA-PI was determined to be abnormal, none of the fetuses with normal MCA-PSV measurements died. Across the gestational age, MCA-PSV increases and then decreases during the period directly preceding time of delivery.

In a study by Cosmi et al. [38], the MCA-PI became progressively abnormal as days before delivery decreased. However, this pattern was not consistent. Arduini et al. [39] conducted a study in which a week prior to any recorded abnormalities, the MCA-PI did not experience any significant changes.

A study conducted by Van den Wijngaard et al. [40], compared the cerebral Doppler flow patterns of normal human fetuses to those with growth restricted anomalies. In this study, 14 fetuses with fetal growth retardation between the gestational ages of 27 and 37 weeks, and 55 normal pregnancies between 25 and 41 weeks were used. A Doppler system (Diasonics CV 400) was used to measure the blood flow velocities of basal internal arteries. A normal waveform in the basal internal arteries always produced a forward flow in the third trimester of pregnancy. The MCA-PI values in a normal pregnancy are higher than other intracranial arteries. This can be explained by an increased systolic upstroke in the waveform flow velocity and subsequent decline in velocity during diastole. There was a decrease in PI across all basal cerebral arteries in fetuses with IUGR which may occur as a result of a greater end-diastolic flow velocity. The redistribution of blood in the basal cerebralarteries may contribute to the brain sparing effect that is observed in IUGR fetuses [40].

MCA-PI is the most reliable diagnostic tool next to UA-PI for IUGR. Recent reports suggest that MCA-PSV is higher in fetuses affected with IUGR and may predict perinatal mortality more accurately than MCA-PI itself. In addition, evaluations of Doppler ultrasound measuring MCA peak systolic velocity has been used as a noninvasive procedure in detecting fetal anemia [41]. Alternatively, some studies suggest that the anterior cerebral artery (ACA) might be a better predictor of the brain sparing effect; a decrease in ACA-PI maximizes cerebral perfusion in fetuses with compromised growth [35].

2.4 Biophysical profile score and Doppler abnormalities

The biophysical profile score (BPS) is often used in combination with Doppler ultrasonography to detect fetal compromise in IUGR fetuses. The BPS consists of five parameters: fetal movement, fetal tone, fetal breathing, amniotic fluid volume and nonstress test. Each parameter is assigned a score of 0 (abnormal) or 2 (normal). The absence of any of these biophysical variables indicates that the central nervous system is in a state of hypoxemia or acidemia [42]. In general, a BPS score of greater than 6 suggests that the fetus is not compromised and acid-base balance is normal. On the other hand, a BPS score of less than 6 is an indication that immediate delivery is required in order to reduce the risk of intrauterine compromise. However, BPS tends to deteriorate abruptly and unexpectedly, prompting the need for immediate delivery [43].

Doppler ultrasonography can be used to provide advance warning of BPS deterioration and to allow for preparation for delivery. In contrast to the BPS, Doppler indices of the arterial and venous vessels tend to deteriorate gradually, over a period of two weeks prior to delivery. Baschat et al. observed that the UA PI and MCA PI gradually increased over the two-week period while the DV and inferior vena cava (IVC) remained relatively stable until approximately four days before delivery [43]. Since deterioration of the precordial veins reflects direct cardiac compromise, this could be used to anticipate a deterioration of BPS within 4 days.

The cross-sectional observation of the last Doppler indices and BPS prior to delivery revealed unexpected results [44]. It had been hypothesized that the extent of hemodynamic deterioration would be reflected in the BPS. That is, fetuses with only an abnormal UA would exhibit a normal BPS, while those with abnormal DV would register an abnormal BPS. Fetuses with an equivocal BPS score of 6 would exhibit brain sparing. While concordance between Doppler abnormalities and BPS was present in 44% of fetuses, over half of the fetuses showed disagreement between the two surveillance systems. This suggests that while both cardiovascular and behavioral deterioration has associations with the perinatal outcome of the IUGR fetus, they are independent of each other. Hence, this provides an opportunity for the complementary use of Doppler and BPS in order to stratify IUGR fetuses into distinct risk categories. A fetal risk assessment score (FRAS) was recently developed to integrate BPS and Doppler velocimetry [45]. Although the score has only been tested on a retrospective cohort, ROC analysis has suggested that FRAS offers superior predictive power over the BPS alone for poor perinatal outcome in growth-restricted fetuses [45].

2.5 Progression of Doppler abnormalities

The longitudinal analysis of Doppler changes in IUGR has revealed several distinct patterns of progression. These changes reflect the ongoing deterioration of the fetal and placental vasculature. Ferrazzi et al. stratified Doppler changes into ‘early’ and ‘late’ stage abnormalities [46]. Early stage abnormalities included an elevated UA PI and brain sparing. These abnormalities reflected the increasing resistance in the placental and redirection of blood flow to the brain. Late stage changes primarily affected the venous systems, including the ductus venosus, inferior vena cava, and umbilical vein. These late changes reflected central cardiovascular deterioration. In a prospective study of 236 IUGR fetuses, three patterns of Doppler deterioration were observed [43]. The most common pattern began with a worsening UA-PI followed by brain sparing and finally venous deterioration. Six fetuses demonstrated abnormal precordial venous flow before the advent of brain sparing. Four fetuses developed an abnormal flow in the DV without ever undergoing brain sparing. Turan et al. further observed that the gestational age at which Doppler abnormalities first appear can have a profound influence on the outcome of the fetus [15]. For fetuses with mild placental insufficiency, Doppler abnormalities appeared significantly later in gestation (median = 31.5 weeks) and only progressed to the brain sparing stage with no venous abnormalities. Fetuses with more severe placental insufficiency developed Doppler abnormalities much earlier (median = 27.1 weeks) and exhibited a more rapid deterioration of Doppler indices. The latter fetuses were delivered at a significantly earlier gestation age.

While there is much evidence that correlates individual Doppler abnormalities with adverse perinatal outcomes, the prognostic accuracy of single-vessel Doppler has not been promising. Odibo et al. [47] found that the area under the ROC curve for the UA and MCA in predicting adverse perinatal outcomes was 70% and 48%, respectively. This suggests that using the MCA Doppler to discriminate between fetuses with abnormal and normal perinatal outcomes provides the same accuracy as random guessing. Hence, more sensitive and specific prognostic markers are required in order to be used in clinical practice. Multivessel longitudinal Doppler has the potential to accomplish this.

2.6 Timing of delivery

One of the major challenges in the management of IUGR is to determine the optimal timing of delivery. This decision is made by weighing the risks of prematurity against the risks of the intrauterine environment. Ideally, the pregnancy should be safely prolonged for as long as possible to allow for fetal maturation. Because of the aforementioned associations between Doppler findings and adverse perinatal outcomes, Doppler can be used to guide the decision for delivery. Rather using a cross-sectional approach to the interpretation of Doppler indices, the progression of these indices longitudinally should be considered. As previously discussed, Doppler deterioration tends to precede the decline in BPS, and hence Doppler can be used to anticipate biophysical deterioration.

Fetuses with early-onset IUGR experience a rapid and extensive deterioration of Doppler indices, with all three vessels affected by 30 weeks of gestation [14]. Most deliveries of these fetuses occur before 34 weeks [15]. A hallmark of early-onset IUGR is the absence or reversal of the DV a-wave, and thus Doppler surveillance of this vessel is important. DV-RAV is highly associated with stillbirth and neonatal death [6, 48]. From a clinical standpoint, the detection of DV-RAV indicates the need for immediate delivery, since each additional day in utero doubles the risk of stillbirth [49]. Due to the strong association between DV-RAV and adverse outcomes, delivery should be considered before ductus venosus flow deteriorates to that point. However, the DV-PIV does not increase at a steady rate and tends to remain at normal values until about five days before delivery [49]. Cruz-Martinez et al. identified several markers that could indicate the onset of decline in DV flow. The aortic isthmus PI was shown to surpass the 95th-percentile a week earlier than the DV. Furthermore, the myocardial performance index (MPI) was observed to increase in parallel to the DV-PIV, but crossed the 95th percentile an average of 3 weeks earlier [50]. These markers could be used to anticipate the decline in DV flow and make preparations for delivery.

In late-onset IUGR, the cardiovascular deterioration is slower and less extensive. As such, delivery should occur after 34 weeks, when the risks of prematurity are much less [51, 52]. However, a systematic review composed of 3 prospective and 7 retrospective cohort studies provided evidence that late pre-term infants (34– 36 weeks) are at elevated risk of harmful developmental outcomes [53]. These discoveries question the current status of what is characterized as both ‘pre-term’ and ‘term’, as adverse fetal outcomes are noted in the later stages. According to the other studies mentioned, once a patient has reached 34 weeks, delivery may actually still not be ideal. So, we propose in our algorithm that one may consider delivery after 34 weeks of gestation as there may be some changes in the future planning of delivery of babies of 34– 39 weeks.

In general, deterioration in late-onset IUGR only progresses to the brain sparing stage, with minimal changes in venous systems [15]. The cerebroplacental ratio can provide a measure of the degree of brain sparing. In a longitudinal study of 171 late-onset IUGR fetuses, it was found that while changes in the UA-PI were minimal after 30 weeks, but the CPR and MCA-PI exhibited a steady decrease from 30 weeks to delivery [54]. Thus, a threshold value must be identified for the CPR that would allow for a sensitive and specific prediction of adverse perinatal outcome, should the CPR fall below that value. Odibo et al. [47] assessed the screening efficiency of the CPR in the prediction of adverse perinatal outcomes in IUGR fetuses and found that using either a categorical threshold of CPR <1.08 or a gestational age-specific value of CPR <10th percentile yielded a similar test efficacy of 67%. Vergani et al. examined a cohort of IUGR fetuses delivered > =34 weeks and developed a probability formula for the prediction of adverse neonatal outcome using the variables of gestational age, abdominal circumference centile, and UA-PI centile [55]. It was found that a score of > =25 was able to predict adverse neonatal outcome with a sensitivity of 75% and specificity of 82%.

2.7 Conclusion and future directions

As previously mentioned, SGA is not synonymous with IUGR, which is greatly increasing the diagnostic uncertainty for growth-restricted fetuses. Hence, we propose a novel algorithm that integrates the indices of multivessel Doppler with BPS (Fig. 1). The diagnostic properties of the proposed algorithm also reflect on the prognosis of IUGR fetuses, especially the perinatal outcomes. The aim of the proposed algorithm is to integrate Doppler velocimetry with biophysical profiling in order to determine the optimal timing of delivery and hence reduce the risks of adverse perinatal outcomes. Once IUGR is suspected due to an abnormal EFW or HC/AC ratio, the UA Doppler can be used to ascertain whether placental insufficiency is imminent. If the UA Doppler is abnormal, Doppler testing frequency should be increased, and CPR can be used to monitor fetal well-being and to indicate the onset of brain sparing. Once the CPR declines past the threshold for abnormality (1.08), Doppler studies and BPS should be performed daily with particular attention to the DV. Delivery should be considered if either the DV-SIA or BPS becomes abnormal. Hence, we propose that for the diagnosis of IUGR, UA-PI and CPR should be considered, while the DV-SIA or BPS should be used for the timing of delivery to improve prognosis.

Further validation of the proposed algorithm in a retrospective manner is required. In addition, a novel index or a formula that can encapsulate the different aspects of multivessel Doppler is also needed. These means of diagnosis and prognosis of IUGR can greatly enhance the utilization of Doppler technology to minimize perinatal outcomes. The findings of this review point to the idea that identifying the appropriate fetal vessels will allow us to find the ideal time to deliver the fetus. Some vessels, like the aortic isthmus, have more importance than others with regards to IUGR, so when we start observing conditions like isthmus flow reversal, it will serve as a trigger for delivery. Each of these forms of velocimetry may not have same intervals, which is why we propose a mathematic model in order to effectively determine the optimal time for delivery of thebaby.