Changes in fetal Doppler indices as a marker of ... - Wiley Online Library

Ultrasound Obstet Gynecol 2014; 43: 303–310 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.13319

Changes in fetal Doppler indices as a marker of failure to reach growth potential at term ´ J. MORALES-ROSELLO*†, A. KHALIL*, M. MORLANDO*, A. PAPAGEORGHIOU*, A. BHIDE* and B. THILAGANATHAN* *Fetal Medicine Unit, Academic Department of Obstetrics and Gynaecology, St George’s University of London, London, UK; †Servicio de Obstetricia, Hospital Universitario y Polit´ecnico La Fe, Valencia, Spain

K E Y W O R D S: cerebroplacental ratio; failure to reach growth potential; fetal Doppler; fetal growth restriction; middle cerebral artery Doppler; small-for-gestational age; umbilical artery Doppler

ABSTRACT Objective To evaluate whether changes in the middle cerebral artery (MCA), umbilical artery (UA) and cerebroplacental ratio (CPR) Doppler indices at term might be used to identify those appropriate-for-gestational-age (AGA) fetuses that are failing to reach their growth potential (FRGP). Methods This was a retrospective cohort study of data obtained in a single tertiary referral center over a 10year period from 2002 to 2012. The UA pulsatility index (PI), MCA-PI and CPR were recorded between 37+0 and 41+6 weeks within 14 days before delivery. The Doppler parameters were converted into multiples of the median (MoM), adjusting for gestational age, and their correlation with birth-weight (BW) centiles was evaluated by means of regression analysis. Doppler indices were also grouped according to BW quartiles and compared using Kruskal–Wallis and Dunn’s post-hoc tests. Results The study included 11 576 term fetuses, with 8645 (74.7%) classified as AGA. Within the AGA group, fetuses with lower BW had significantly higher UA-PI, lower MCA-PI and lower CPR MoM values. Largefor-gestational-age (LGA) fetuses were considered as the group least likely to be growth-restricted. The CPR MoM < 5th centile (0.6765 MoM) in these fetuses was used as a threshold for diagnosing FRGP. Using this definition, in the AGA pregnancies the percentage of fetuses with FRGP was 1% in the 75–90th BW centile group, 1.7% in the 50–75th centile group, 2.9% in the 25–50th centile group and 6.7% in the 10–25th centile group. Conclusion AGA pregnancies may present with fetal cerebral and placental blood flow redistribution indicative of fetal hypoxemia. Fetal Doppler assessment may be of value in detecting AGA pregnancies that are subject

to placental insufficiency, fetal hypoxemia and FRGP. Future studies are needed to evaluate the appropriate threshold for the diagnosis of FRGP and the diagnostic performance of this new approach for the management of growth disorders. Copyright  2014 ISUOG. Published by John Wiley & Sons Ltd.

INTRODUCTION Fetal growth restriction (FGR) resulting from chronic placental insufficiency is associated with a significant increase in the risk of perinatal morbidity1 , with the risk of fetal death being increased 10-fold at term. FGR refers to a condition in which a fetus is unable to achieve its genetically determined size as a consequence of placental insufficiency. As the genetic growth potential of a fetus is difficult to predict2,3 , birth weight (BW) < 10th centile for gestation (small-for-gestational age (SGA)), is commonly used as a proxy with which to identify fetuses at risk of adverse outcome4 . This pragmatic clinical definition, which uses fetal size rather than growth to identify failure to reach growth potential (FRGP), is limited by the finding that the majority of SGA babies are not pathologically growth-restricted. It is uniformly acknowledged that the use of SGA to identify FGR has a high false-positive rate, as many babies in this group are simply constitutionally small and are not affected by placental insufficiency5,6 . In cases of FGR, SGA coexists with fetal Doppler indices indicative of placental insufficiency and/or fetal hypoxemia. This is characterized by redistribution of fetal blood flow to sustain function in vital organs, such as the central nervous system, heart and adrenal glands, at the expense of other organs7 . Although the terms FGR and SGA are often, incorrectly, used interchangeably in the medical literature, FGR fetuses have worse perinatal outcomes than do their SGA counterparts, presumably

Correspondence to: Prof. B. Thilaganathan, Fetal Medicine Unit, St George’s University of London, Cranmer Terrace, London SW17 0RE, UK (e-mail: [email protected]) Accepted: 27 January 2014

Copyright  2014 ISUOG. Published by John Wiley & Sons Ltd.

ORIGINAL PAPER

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as a consequence of chronic placental insufficiency and prolonged fetal hypoxemia in the former group. It is less well recognized, however, that many FRGP fetuses are delivered with a BW that is appropriate-for-gestational age (AGA)8 . Hence, a baby with a BW on the 40th centile, but with a genetic potential to be born on the 80th centile, may have suffered more severe and protracted hypoxemia compared with a fetus born with a BW on the 5th centile that has met its growth potential. A recent study by ParraSaavedra et al. found placental histological abnormalities in 25.4% of the AGA group, suggesting the presence of an occult chronic placental insufficiency9 . Therefore, the standard definitions of both SGA and FGR unintentionally exclude apparently AGA infants that are growth-restricted or suffering from placental insufficiency10 . To date, it has not been possible to identify accurately or estimate the proportion of AGA fetuses that may be affected by occult chronic placental insufficiency, fetal hypoxemia and FRGP. Since fetal middle cerebral (MCA) and umbilical artery (UA) Doppler indices are used routinely to distinguish FGR from SGA fetuses, it is possible that these indices may also be of value in identifying FGR and placental insufficiency in AGA pregnancies11 – 14 . The aim of this study was to determine whether AGA fetuses at term exhibit changes in MCA and UA Doppler indices that may be of value in identifying those that are affected by placental insufficiency and FRGP.

METHODS This was a retrospective cohort study of data obtained in a single tertiary referral center over a 10-year period from 2002 to 2012. Inclusion criteria were: singleton pregnancy; morphologically normal, term fetus; ultrasound examination within 14 days before date of delivery. Pregnancies complicated by fetal abnormality, aneuploidy or antepartum stillbirth were excluded from analysis. Gestational age was determined according to crown–rump length in the first trimester. Data on ultrasound examinations were obtained from computerized records (Viewpoint) and only one (the last) examination per fetus was included in the analysis15 . Data on pregnancy outcomes were collected from the hospital maternity records. The UA and MCA were examined using color Doppler and the pulsatility index (PI) was measured according to a standard protocol16,17 . In brief, MCA-PI values were obtained at the point at which the artery passes by the sphenoid wing close to the circle of Willis, and UA-PI values were obtained in free loops of the umbilical cord. Ultrasound examinations were performed mainly with a Voluson GE (GE Medical Systems, Zipf, Austria) ultrasound machine equipped with a 2–8-MHz convex probe, during fetal quiescence, in the absence of fetal tachycardia, and keeping as small an insonation angle as possible with the examined vessels. The cerebroplacental ratio (CPR) was calculated as the simple ratio between the MCA-PI and the UA-PI18 . All Doppler indices were converted into multiples of the median (MoM), correcting for gestational age in weeks19 .


Doppler PI medians (50th centile) were calculated by means of polynomial regression of values from only AGA fetuses, and BW values were converted into centiles using the method described by Yudkin et al.20 . Doppler PI MoM values were represented in scattergrams according to BW centile, and linear regression analysis with 95% CIs were calculated to evaluate statistical significance. Doppler measurements were afterwards grouped according to BW quartiles and compared using the Kruskal–Wallis test plus Dunn’s post-hoc test for multiple comparisons. As the group of large-for-gestational age (LGA) (> 90th centile) fetuses was assumed to include those least likely to have FRGP, the CPR 5th centile from this group was established preliminarily as the threshold of normality for this condition; the proportion of fetuses with FRGP was estimated in each group by subtracting the proportion of fetuses with a CPR below this limit, and compared using chi-square test plus Holm’s correction for multiple comparisons. The statistical software packages PASW Statistics for Windows 18.0 (SPSS Inc, Chicago, IL, USA) and GraphPad Prism version 5a, for Apple Macintosh (GraphPad Software Inc, San Diego, CA, USA) were used for data analyses.

RESULTS The study included 11 576 pregnancies that were scanned at term within 2 weeks before birth. The demographic characteristics of the study population are given in Table 1. There were six (0.05%) early neonatal deaths, six (0.05%) late neonatal deaths and no intrauterine deaths as per study inclusion criteria. The Doppler PI MoM values were calculated using the following equations derived from the AGA study population: MCA-PI 50th centile = 3.11 – (0.004131 × GA) – (0.0012105 × GA2 ), r2 = 0.199; UA-PI 50th centile = 3.034 – (0.089245 × GA) + 0.00084391 × GA2 ), r2 = 0.047; CPR 50th centile = −1.3841 + (0.22659 × GA) – (0.003743 × GA2 ), r2 = 0.051, where GA is gestational age in weeks. Table 1 Baseline demographics of the study population

Characteristic

Population (n = 11 576)

Maternal age (years) Gestational age at scan (weeks) Gestational age at delivery (weeks) Interval from scan to delivery (days) Male neonatal sex BW (g) BW centile < 10th BW centile 10–25th BW centile 25–50th BW centile 50–75th BW centile 75–90th BW centile > 90th

30.6 ± 5.7 40.1 ± 1.5 40.8 ± 1.3 4.7 (0–14) 5911 (51.1) 3445 ± 548 1637 (14.1) 1892 (16.3) 2760 (24.7) 2502 (21.6) 1491 (12.9) 1294 (11.2)

Data are given as mean ± SD, median (range) or n (%). BW, birth weight.

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Figure 1 Scattergrams of Doppler index multiples of the median (MoM) values in term fetuses according to their birth weight (BW) centile, with regression lines. (a) Middle cerebral artery (MCA) pulsatility index (PI) MoM (linear regression equation: y = 0.96401 + 0.0006769 × GA, where GA is gestational age in weeks; P < 0.0001, r2 = 0.0099). (b) Umbilical artery (UA) PI MoM (linear regression equation: y = 1.0787 – 0.0014502 × GA, P < 0.0001, r2 = 0.0528. (c) Cerebroplacental ratio (CPR) MoM (linear regression equation: y = 0.89699 + 0.0019601 × GA, P < 0.0001, r2 = 0.0485). Correlation of Doppler indices with BW centile was highly significant.

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Linear regression analysis showed that fetuses with lower BW centiles had significantly higher UA-PI MoM, lower MCA-PI MoM and lower CPR MoM at ultrasound examination (Figure 1). When BW was divided into quartiles, those AGA fetuses with lower BW had significantly lower MCA-PI MoM, lower CPR MoM and higher UA-PI MoM (Kruskal–Wallis test) (Figure 2 and Table 2). In LGA fetuses, considered as the group least likely to have FRGP, the 5th centile of CPR MoM was 0.6765. This optimal CPR limit was used as a threshold for diagnosing FRGP. The proportion of fetuses with CPR MoM below this threshold was not significantly different between the LGA group (4.9%, 64/1294) and the 75–90th BW centile group (6.0%, 90/1491; P = 0.241) or between the LGA group and the 50–75th BW centile group (6.7%, Copyright  2014 ISUOG. Published by John Wiley & Sons Ltd.

167/2502; P = 0.083). However, compared with the LGA group, the proportion with a CPR below this optimal level was significantly higher in the 25–50th BW centile (7.9%, 217/2760; P = 0.002), the 10–25th BW centile (11.6%, 220/1892; P < 0.001) and the 0–10th BW centile (22.2%, 364/1637; P < 0.001) groups. The percentage of fetuses with FRGP was calculated after subtracting the proportion of fetuses with CPR MoM < 5th centile in the BW centile groups from the proportion in the LGA group: thus, in the AGA centile groups, the percentage of fetuses with FRGP was 1% in the 75–90th BW centile group, 1.7% in the 50–75th centile group, 2.9% in the 25–50th centile group and 6.7% in the 10–25th centile group (Figure 3). A comparison between BW centile and CPR MoMs for the diagnosis of fetal growth disorders is illustrated in Figure 4. In the first, the SGA model, which is based on population centiles, cases were selected using as a cut-off the 10th BW centile. Many of the selected fetuses did not present changes in Doppler indices, suggesting that they were unlikely to be affected by placental insufficiency. In addition, despite a proportion presenting changes in Doppler indices, all fetuses with BW > 10th centile were classified as normal. In the second model, the FRGP model, which was based on the CPR MoMs, cases were selected using the 5th centile of the group in which the existence of changes in Doppler indices was unlikely (the LGA group), corresponding to a CPR of 0.6765 MoM. Ultrasound Obstet Gynecol 2014; 43: 303–310.


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Figure 2 Box-and-whiskers plots of Doppler index multiples of the median (MoM) values in term fetuses according to their birth weight (BW) centile group. (a) Middle cerebral artery (MCA) pulsatility index (PI) MoM. (b) Umbilical artery (UA) PI MoM. (c) Cerebroplacental ratio (CPR) MoM. *Appropriate-forgestational-age fetuses with lower BW had significantly lower MCA-PI MoM (P = 0.003), lower CPR MoM (P < 0.0001) and higher UA-PI MoM (P < 0.0001) (Kruskal–Wallis test).

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in the 10–25th BW centile (9.8%, 186/1892; P < 0.001) and the 0–10th (19.8%, 324/1637, P < 0.001) BW centile groups. In the AGA centile groups, the percentage of FRGP fetuses was 0.4% in the 50–75th BW centile group, 1.5% in the 25–50th BW centile group and 4.8% in the 10–25th BW centile group.

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Despite the fact that the proportion of fetuses with changes in Doppler indices increased with reducing BW centile, only fetuses with severe changes were selected, regardless of their growth centile. An alternative analysis, using the 75–90th BW centile to define ‘optimal CPR’ at term, is presented as supplementary material (Figures S1 and S2). In this analysis, the CPR MoM 5th centile (0.6568 MoM) in the 75–90th BW centile group was used as a threshold for diagnosing placental insufficiency, fetal hypoxemia and FRGP. The proportion of fetuses with CPR below this limit was not significantly different between the 75–90th BW centile group (5.0%, 75/1491), and the 50–75th BW centile (5.4%, 136/2502; P = 0.560) or the 25–50th BW centile (6.6%, 181/2760; P = 0.089) groups. Compared with the 75–90th BW centile group, the proportions were significantly different


CPR trend in AGA fetuses The data presented in this study demonstrate that in term AGA pregnancies, changes in Doppler indices suggestive of fetal hypoxemia are associated with lower, but normal, BW centiles. AGA fetuses on the lower BW centiles had significantly lower CPR values consistent with fetal blood flow redistribution as a result of high UA and low MCA indices. The most likely explanation for this finding is an increasing prevalence of fetal hypoxemia with lower neonatal BW within the AGA group. This novel finding challenges the conventional paradigm that ‘only SGA fetuses are at risk of placental insufficiency, fetal hypoxemia and FRGP’. The association between lower BW and lower CPR has been reported previously in postdates pregnancies21 . However, the authors included just 181 pregnancies and the association was only observed when comparing SGA with AGA infants, not being seen within the AGA group, presumably because of the small study size. Similarly, another group assessed 126 fetuses at term, but failed to show a relationship between


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Table 2 Comparison of fetal Doppler indices among appropriate-for-gestational age (AGA), small-for-gestational age (SGA) and large-for-gestational age (LGA) groups

Comparison within AGA groups Kruskal–Wallis test < 0.0001 Dunn’s multiple comparison test 10–25th vs 25–50th BW grp < 0.0001 10–25th vs 50–75th BW grp < 0.0001 10–25th vs 75–90th BW grp < 0.0001 NS 25–50th vs 50–75th BW grp 25–50th vs 75–90th BW grp < 0.0001 50–75th vs 75–90th BW grp < 0.001 Comparison including SGA and LGA Kruskal–Wallis test < 0.0001 Dunn’s multiple comparison test < 0.0001 10–25th vs < 10th BW grp 10–25th vs > 90th BW grp < 0.0001 25–50th vs < 10th BW grp < 0.0001 25–50th vs > 90th BW grp < 0.0001 50–75th vs < 10th BW grp < 0.0001 < 0.0001 50–75th vs > 90th BW grp 75–90th vs < 10th BW grp < 0.0001 NS 75–90th vs > 90th BW grp < 10th vs > 90th BW grp < 0.0001

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< 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 < 0.0001 NS < 0.0001

Multiple comparisons among AGA, SGA and LGA groups performed using Kruskal–Wallis and Dunn’s post-hoc test. BW grp, birth-weight centile group; CPR, cerebroplacental ratio; MCA, middle cerebral artery; MoM, multiples of the median; NS, not statistically significant; PI, pulsatility index; UA, umbilical artery.

fetal weight and Doppler indices22 . Notably, they used ultrasound estimated fetal weight (EFW) rather than BW and, furthermore, did not correct EFW for gestational age.

Implications of study findings It is conventional to assume that only SGA fetuses are at risk of placental insufficiency and its perinatal consequences. If, indeed, AGA fetuses are immune to such stresses, fetal Doppler indices should not vary significantly between AGA babies in the various BW centile groups. These study findings imply that Doppler indices have the potential to identify AGA pregnancies that are complicated by placental insufficiency and fetal hypoxemia as evidenced by blood flow redistribution. Hence, fetal Doppler indices may have a role to play in identifying FRGP fetuses, regardless of their size. This last paradox, the lack of size restriction in term placental insufficiency, may be explained by the absence of sufficient influence in the late-onset disorder to decrease fetal growth significantly23 –25 . This is in direct contrast to preterm placental insufficiency, in which the chronic nature of the disease leads to an obvious diminution in size and, hence, a higher detection rate on the basis of fetal biometry alone26 – 28 . The supposition that Doppler indices may be more useful than is fetal biometry has been highlighted in a recent PORTO (Prospective Observational Trial to Optimize Pediatric Health in Intrauterine Growth


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Figure 3 Percentage of term fetuses with failure to reach growth potential (FRGP) according to their birth weight (BW) centile group (i.e. percentage of fetuses presenting a cerebroplacental ratio (CPR) multiple of the median (MoM) value below the established FRGP normality threshold (CPR MoM = 0.6765), calculated after subtracting those cases with CPR MoM < 5th centile observed in the group with BW > 90th centile). Appropriate-for-gestational-age (AGA) fetuses present a progressive decrease of CPR, which is especially important in the group with BW < 25th centile. *Chi-square test plus Holm’s correction for multiple comparisons.

Restriction (IUGR)) study, which also calls into question the current definition of IUGR29 . In this prospective study of 1200 pregnancies with EFW < 10th centile, 95% of those with abdominal circumference (AC) < 10th centile had a normal pregnancy outcome. However, the presence of abnormal UA Doppler was significantly associated with adverse outcome, irrespective of EFW or AC measurement. The relative importance of fetal Doppler parameters over biometry is further supported by the recent observations in term SGA and AGA fetuses of significantly impaired postnatal neurobehavioral performance in those with abnormal fetal brain perfusion30 – 32 . The association between being SGA and long-term neurodevelopment has been evaluated extensively, showing the expected association between BW < 10th centile and long-term impaired neurodevelopment compared with AGA infants. This is presumed to be the consequence of placental insufficiency and chronic fetal hypoxemia. It remains to be seen whether or not the degree of placental insufficiency leading to FRGP in AGA neonates has the same predictive value for perinatal complications and developmental problems as it does in the SGA group. The findings of the current study suggest that fetal Doppler indices may be a better marker than is fetal size for placental insufficiency, fetal hypoxemia and FRGP. It should be acknowledged that fetal Doppler indices have only limited utility in the prediction of intrapartum complications and short-term neonatal outcome, possibly because of the significantly confounding effect of the process of labor and birth33 .



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Figure 4 Graphical comparison between birth weight (BW) centile and cerebroplacental ratio (CPR) multiples of the median (MoM), for the diagnosis of fetal growth disorders. (a) Small-for-gestational age model, based on population weight centiles. Cases were selected using the 10th centile (p 10th ). Many of the selected fetuses do not present changes in Doppler indices, suggesting they are in reality, most likely, genetically small. In addition, despite a proportion presenting changes in Doppler indices, all fetuses with weight > p 10th are classified as normal. (b) Failure to reach growth potential model, based on CPR MoMs. Cases were selected using the 5th centile of the group in which changes in Doppler indices is unlikely, corresponding to a CPR of 0.6765 MoM. Although the proportion of fetuses with changes in Doppler indices increases with decreasing BW weight centiles, only fetuses with severe changes in Doppler indices are selected, regardless of their centile group.

Using ‘optimal CPR’ to define FRGP

Other strategies to diagnose FRGP

The LGA group was used to define ‘optimal CPR’ at term. While this group is at slightly higher risk of adverse perinatal outcome, this is related mainly to relative macrosomia, prolonged labor and intrapartum trauma. Even though it is possible to argue that these pregnancies may be affected by genetic or metabolic conditions, these fetuses, by virtue of their increased size, are the least likely to be affected by placental insufficiency and hypoxemia. In this regard, it is reassuring to find that the proportion of LGA infants with a CPR < 5th centile (4.9%) was not significantly different from the proportion in the 75–90th BW centile group (6.0%). Hence, if a proportion of AGA fetuses are affected by placental insufficiency and fetal hypoxemia, changes in the MCA- and UAPI might be used to identify those at higher risk of adverse outcome. Assuming low CPR is a reflection of fetal hypoxemia, the excess proportions of fetuses with a CPR < 5th centile (0.6765 MoM) in the lower BW centile groups are likely to represent fetuses that are affected by placental insufficiency. The estimates from the current data are that the proportion of fetuses affected by placental insufficiency with FRGP in the 50–75th , 25–50th and 10–25th BW centile groups are 1.7%, 2.9% and 6.7%, respectively. Given these data, it is possible to estimate that in a population of 10 000 pregnancies, approximately 180 of the 1000 SGA fetuses and 230 of the 8000 AGA infants would have a suboptimal CPR just prior to term delivery.

When compared with traditional population-based norms, placental insufficiency leading to fetal hypoxemia and FRGP is a better predictor of short-term adverse pregnancy outcomes, such as stillbirth, neonatal mortality and morbidity, as well as long-term neonatal outcomes, such as neonatal encephalopathy, cerebral palsy and impaired cognitive ability34 . Although definitive interventional trials to validate the clinical value of fetal growth potential have not, as yet, been conducted, many observational studies indicate that it shows significant promise in this respect. The use of customized growth standards instead of population-based reference charts has been proposed in an attempt to better identify growth-restricted fetuses35 – 37 . However, the benefits of customized growth charts are not established and those benefits that they confer seem to be confined to preterm growth-restricted infants38 – 40 . At term, the use of customized charts appears to offer little benefit over the use of population-based standards41 .


Conclusion We have shown that even AGA pregnancies may present with fetal cerebral and placental blood flow redistribution indicative of fetal hypoxemia. Fetal Doppler assessment may be of value in detecting AGA pregnancies that are subject to placental insufficiency, fetal hypoxemia and FRGP. Future studies are needed to evaluate the


Fetal Doppler to identify failure to reach growth potential performance of this approach in the prediction of neonatal neurodevelopmental impairment, with the aim of optimizing the timing of delivery and reducing long-term neonatal disability.

ACKNOWLEDGMENT ´ We wish to thank Dr David Hervas-Mar´ ın for his help in reviewing the statistical analysis of this manuscript.

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SUPPORTING INFORMATION ON THE INTERNET The following supporting information may be found in the online version of this article: Figure S1 Percentage of fetuses presenting a cerebroplacental ratio (CPR) multiples of the median (MoM) value below the established failure to reach growth potential (FRGP) normality threshold (CPR MoM = 0.6568). The percentage of fetuses with FRGP were calculated after subtracting those cases with CPR MoM < 5th centile observed in the group with birth weight between 75th and 90th centiles. Figure S2 Graphical comparison between birth weight (BW) centile and cerebroplacental ratio (CPR) multiples of the median (MoM), for the diagnosis of fetal growth disorders. (a) Small-for-gestational age model, based on population BW centiles. Cases are selected using the 10th centile. Many of the selected fetuses do not present changes in Doppler indices, suggesting they are in reality, most likely, genetically small. In addition, despite a proportion presenting changes in Doppler indices, all fetuses with BW > 10th centile are classified as normal. (b) Failure to reach the growth potential model, based on the CPR MoMs. Cases were selected using the 5th centile of the AGA group in which the existence of changes in Doppler indices is unlikely (the 75–90th centile group), corresponding to a CPR of 0.6568 MoM. Despite the proportion of fetuses with changes in Doppler indices increasing with reducing BW centiles, only fetuses with severe changes are selected, regardless of their centile.

