Fetal cerebroplacental Doppler in pregnancies complicated by

placental abruption

José Morales-Roselló*, Asma Khalil†, Farida Akhoundova*, Silvia Salvi††, Maddalena

Morlando**, Janani Sivanathan†, José Alberola-Rubio*§, David Hervas-Marín#, Victoria

Fornés-Ferrer#, Alfredo Perales-Marín*, Basky Thilaganathan†.

*Servicio de Obstetricia, Hospital Universitario y Politécnico La Fe, Valencia, Spain.

†Fetal Medicine Unit, St George’s Hospital, London, UK.

††Dipartimento di Ostetricia, Ginecologia e Pediatria, Università Cattolica del Sacro Cuore,

Rome, Italy

** Department of Neurosciences, Reproductive and Dentistry Sciences, High Risk Pregnancy

Unit, University Federico II, Naples, Italy.

§Grupo  Bioelectrónica  (I3BH),  Universidad  Politécnica, Valencia, Spain

#Unidad de Bioestadística, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.

Corresponding author:

Dr. José Morales-Roselló

Servicio de Obstetricia, Hospital Universitario y Politécnico La Fe

Avenida Fernando Abril Martorell 106, 46026 Valencia, Spain

E-mail: jose.morales@uv.es

Running Title:

Fetal Doppler and placental abruption

Word Count:

Word count: 2035, Table count: 2, Figure count: 5 (plus 2 supplementary figures).

ABSTRACT

Background: Placental abruption is a severe complication which affects 0.5-1% of

pregnancies and is frequently associated with perinatal mortality. Most of cases at the end of

pregnancy occur unexpectedly in the absence of risk factors and are difficult to predict.

Objective: Our aim was to evaluate whether changes in the cerebroplacental Doppler and

birth weight (BW) suggestive of chronic fetal hypoxemia, precede the development of late-

onset placental abruption after 32 weeks.

Study design: In a multicenter retrospective study, Doppler examinations of the fetal

umbilical artery (UA) and middle cerebral artery (MCA) recorded after 32 weeks were

collected in pregnancies subsequently developing placental abruption within 2 weeks of

examination. The BW centile and cerebroplacental ratio (CPR) were calculated and the MCA

pulsatility indices (PI), UA PI and CPR values were converted into multiples of the median

(MoM). Afterwards, using the described parameters a comparison was made with a group of

fetuses, which were delivered within 2 weeks of Doppler assessment and did not develop

placental abruption. Multivariate logistic regression was used to adjust for potential

confounders and evaluate the feasibility of the different prediction models.

Results: Pregnancies complicated by late-onset placental abruption (n=31) presented lower

MCA PI (p=0.015) and CPR MoM values (p=0.029), and were significantly smaller

(p<0.001) compared to those who did not (n=1294). Logistic regression analysis indicated

that while cerebral vasodilation was a crucial parameter in the explanation of placental

abruption (MCA PI MoM OR=0.008, p=0.001), the influence BW exerted was very small

(BW centile OR=0.99, p=0.15).

Conclusions: Fetuses developing late-onset placental abruption demonstrate significant

cerebral vasodilation with scarce placental dysfunction, suggesting the existence of some

kind of chronic fetal hypoxaemia – even in the absence of overt fetal growth restriction.

KEY WORDS

Fetal middle cerebral artery Doppler, umbilical artery Doppler, cerebroplacental ratio,

placental abruption, late-onset fetal growth restriction.

INTRODUCTION

Placental abruption complicates 0.5-1% of pregnancies and is associated with several adverse

outcomes such as stillbirth and neonatal death. It is known to occur more frequently in

pathological conditions such as preeclampsia and fetal growth restriction (FGR). Other

known risk factors include smoking, multiparity, premature rupture of membranes and

previous placental abruption1-3. However, most of cases, especially those at the end of

pregnancy, occur unexpectedly in the absence of these risk factors and are therefore more

difficult to predict3.

Abnormal uterine artery Doppler in the first and second trimester has been associated with

development of placental abruption in the context of early-onset fetal growth restriction

(FGR) and preclampsia4,5. However, fetal cerebroplacental hemodynamics prior to placental

abruption has not sufficiently been studied, especially after 32 weeks (late-onset placental

abruption). In addition, the evidence has been limited to case reports with contradictory

conclusions and the ultrasound assessment was frequently performed after the placental

abruption had already started6-11. The aim of this study was to investigate the cerebroplacental

Doppler, in the form of the umbilical artery pulsatility index (UA PI), middle cerebral artery

PI (MCA PI) Doppler, and the cerebroplacental ratio (CPR) in pregnancies complicated by

late-onset placental abruption. The secondary objective was to evaluate if the fetal Doppler

assessment in the late third trimester could predict which pregnancies will be complicated

with placental abruption.

MATERIAL AND METHODS

This was a retrospective case control study using databases from four tertiary university

centers belonging to three European countries. The study group consisted of 1325 Doppler

examinations of the MCA PI and UA PI obtained at or after 32 weeks. Of these, 31 cases

belonged to pregnancies that developed late-onset placental abruption and 1294 (the control

group) belonged to pregnancies that were not complicated by placental abruption. The

presence of placental abruption was evidenced according to clinical findings (vaginal

bleeding associated with uterine hypertonia, fetal bradycardia) plus the frequent observation

of a retroplacental blood clot during the cesarean section12. In order to standardize the interval

between the ultrasound and the outcome in both groups, only pregnancies where delivery

occurred within 2 weeks following the ultrasound assessment were included in this study.

The UA PI and MCA PI were examined in all fetuses using color Doppler according to a

standard protocol13,14 and the CPR was calculated as the simple ratio between the MCA PI

and the UA PI15. Only one examination per fetus (the last) was included. Ultrasound

examinations were performed with Voluson E8/E6/730 ultrasound machines using 2-8 MHz

convex probes, during fetal quiescence, in the absence of fetal tachycardia, and keeping the

insonation angle with the examined vessels as small as possible. Gestational age (GA) was

determined according to the crown-rump length in the first trimester. Pregnancies

complicated by congenital fetal abnormalities or aneuploidies were excluded.

In order to correct for GA in weeks, the Birthweight (BW) values were converted into BW

centiles16. Also, the UA PI, MCA PI and CPR values were converted into multiples of the

median (MoM) dividing values by the 50th centile at each gestational age.

Medians (50th centiles) were represented by the following equations17-18:

UA PI 50th centile = 2.2037 – 0.057955 * GA + 0.00053953*GA2

MCA PI 50th centile = –3.266164164+ 0.368135209*GA – 0.006318278*GA2

CPR 50th centile = –3.814786276+0.36363249 * GA – 0.005646672* GA2

The groups were subsequently evaluated with box and whiskers diagrams, and compared

using the Mann-Whitney U tests, as the data in the control group were found to follow non-

parametric distributions according to the Shapiro-Wilk test. Multivariable logistic regression

analysis was then applied to create prediction models in order to evaluate the individual

importance of BW centile, MCA PI MoM, UA PI MoM and CPR MoM in the explanation of

placental abruption. The results of the logistic regression were reported in the form of odds

ratios (OR) with their 95% confident interval (CI) and p-values. The results were shown in

effect plots with the 95% CI, which depicted the probability of placental abruption (in a 0 to 1

scale) according to the value of each individual parameter. Finally, ROC curve analyses with

the area under the curve (AUC) were used to evaluate the ability of the models to predict

placental abruption. The statistical analysis and graphs were performed using R-Software®

3.2.2 (http://www.r-project.org/), and SPSS 20® (IBM Corp®, Armonk, New York, USA).

The statistical significance was established at p<0.05.

RESULTS

Table 1 shows the demographics of the study population. The fetal sex and the interval

between ultrasound assessment and delivery were similar in the two study groups, but the

mothers in the group complicated by placental abruption were significantly younger

(p=0.019) and had significantly lower GA at delivery (p<0.001), when compared to the

controls. These pregnancies were also more frequently delivered by Cesarean section

(p<0.001) and had a higher perinatal mortality (p<0.001) than the control group. The BW

centile, MCA PI MoM and CPR MoM values were significantly lower in the pregnancies

complicated by placental abruption than in the controls (p<0.001, p=0.015 and p=0.029,

respectively). However, the UA PI MoM values were similar in the two study groups

(p=0.226) (Table 1, Figure 1).

Although several prediction models were calculated (table 2), the best one (model 1) included

the four studied parameters (MCA PI MoM, UA PI MoM, CPR MoM, and BW centile).

Their OR for placental abruption were as following: MCA PI MoM OR 0.008 (95% CI

[0.0004, 0.1536], p=0.001); UA PI MoM OR 9.33 (95% CI [1.381, 53.29], p=0.013); CPR

MoM OR 19.48 (95% CI [1.22, 200.4], p=0.02) and BW centile OR 0.99 (95% CI [0.973,

1.003], p=0.15). According to the multivariable analysis, the most important individual

parameter was the MCA PI MoM, followed by the UA PI MoM. Furthermore, the importance

of BW centile was negligible, and the importance of CPR MoM was between that of UA PI

MoM and MCA PI MoM. MCA PI MoM and BW centile behaved as protective factors from

placental abruption with high values meaning lower risk. Conversely, UA PI MoM behaved

as risk factors with the opposite effect. A counterintuitive exception was the CPR MoM,

which showed lower values for placental abruption in the univariate analyses and a positive

association in the multivariable model. This apparent paradox was statistically explained by

the high collinearity between the MCA PI MoM and the CPR MoM. Since both variables

were highly correlated (Pearson’s correlation, r=0.73) the coefficient of the CPR MoM was

influenced by the presence of the MCA PI MoM in the model. In fact, when the MCA PI

MoM was removed from the model, the CPR MoM coefficient became negative

(Supplementary figure 1).

Figure 2 shows the ROC curve of the best model (model 1) according to the logistic

regression analysis. This included the four variables MCA PI MoM, UA PI MoM, CPR MoM

and BW centile. The area under the curve (AUC) was modest: 0.68, although better than any

AUC belonging to the above-mentioned individual parameters (0.56, 0.63, 0.61 and 0.64

respectively). At the optimum threshold, the model achieved a sensitivity of 58% and a

specificity of 73%, and the detection rate was nearly 60% for a false positive rate of nearly

25%.

Also, model 1 presented an Akaike Information Criteria (AIC) of 286.13 (table 2). This value

was 2.35 units lower than that of the best model with 3 parameters (model 2), which showed

an AIC of 288.48 (an AIC difference of 2-3 units indicates a substantial difference between

both parameters)19. However, in order to assess this difference exhaustively, a likelihood-ratio

test for nested models comparison was also performed between model 1 and 2. The

likelihood-ratio test showed a p=0.037 indicating that the difference between both models

was statistically significant.

Figure 3 shows the effect plots with the probability of placental abruption expressed in a 0-1

scale according to the values of the studied parameters. The grey area shows the 95%

confidence intervals. While no clear threshold was seen in case of BW centile, the risk of

placental abruption increased as the MCA PI MoM reached values <0.8, the UA PI MoM

reached values >1.3 and the CPR MoM reached values >1.2 (the explanation for this

counterintuitive value has been mentioned above). The increase in the risk of placental

abruption was stronger for the MCA PI MoM and CPR MoM than for the UA PI MoM. The

increase in the risk of placental abruption according to BW centile was minimal and no

threshold was observed.

As indicated above, models that included 3 parameters like model 2 showed poorer prediction

abilities with higher AIC, and less clear thresholds in the effect plots than model 1 (Figure 4

and 5 and table 2). And this performance decreased even more when one of the included

parameters was the CPR MoM (model 3) (supplementary figure 1 and table 2) or when the

model included just two parameters (model 4) (Supplementary figure 2 and table 2). It is

important to underline that although the AUC of model 1 was similar to that of model 2, the

AUC is not a good method to compare models, a procedure for which a statistical parameter

like AIC is better suited.

DISCUSSION

Summary of the findings

Fetuses belonging to pregnancies that developed placental abruption showed significantly

lower MCA PI and CPR MoM values, and were significantly smaller. While the cerebral

vasodilatation was a crucial parameter in the explanation of placental abruption, the influence

BW exerted was very small. The combination of fetal size and cerebroplacental Doppler had

a moderate predictive accuracy for placental abruption.

Interpretation of the study findings

Studies investigating the association between fetal UA Doppler and placental abruption

reported controversial results as some present high UA PI values typical of early-onset FGR,

while others show UA PI values within the normal range. Furthermore, early and late-onset

placental abruption cases are frequently reported as one group, making it difficult to draw

significant conclusions. Studies examining both the MCA and UA Doppler in cases of late-

onset placental abruption are very scarce; we found just one report describing normal UA PI

and MCA PI values in a 34 weeks fetus with BW below the third centile, in which the

ultrasound measurements were taken after the placental abruption had already developed20.

This study describes CPR assessment in pregnancies before the clinical onset of late-onset

placental abruption. Our data proved the existence of cerebral vasodilation indicating prior

hypoxaemia amenable to Doppler detection. Two other observations may be drawn from our

data. One observation is that in comparison with cerebroplacental Doppler, BW centile is

likely to be a worse predictor, which is consistent with our recent findings at term21,22. The

other observation is that cerebral vasodilation occurred without a significant increase in the

UA PI. This might suggest that these fetuses experience a state of nutritional imbalance than

just a pure placental dysfunction23-26.

Clinical and research implications

The ability to predict placental abruption would enable us to schedule delivery an appropriate

time, reducing perinatal mortality and morbidity caused by sudden fetal hypoxia. Recent

studies investigating how to predict placental abruption have evaluated abnormal uterine

Doppler in the context of early preeclampsia and FGR27. However, complications in late

gestation are better characterized by anomalies of the cerebroplacental Doppler28 and the

importance of the uterine flow decreases in comparison with the CPR when it comes to

evaluating late-onset pregnancy events.

Study strengths and limitations

The strengths of this study include firstly the novel findings, as this was the first study

evaluating the cerebroplacental Doppler in late-onset placental abruption, secondly, the short

interval between the ultrasound assessment and delivery, and thirdly, evaluating the fetal

Doppler prior to the clinical onset of placental abruption. The main limitation of this study

was the retrospective nature of the study and the lack of uterine artery Doppler data. Another

limitation is the inclusion of a small number of preterm and small-for-gestational-age (SGA)

fetuses in the comparison group. However, as a proportion of these pregnancies complicated

by SGA and preterm delivery demonstrate cerebral vasodilation29,30, the exclusion of these

pregnancies would increase the observed differences.

Conclusion

In summary, fetuses developing late-onset placental abruption demonstrate significant

cerebral vasodilation with scarce placental dysfunction, suggesting the existence of chronic

fetal hypoxaemia31 – even in the absence of fetal growth restriction. Future prospective

studies are needed to evaluate the use of fetal Doppler recorded in the third trimester in the

screening for placental abruption and related adverse outcomes.

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LEGENDS

Table 1.

Characteristics of the study population.

Table 2.

Characteristics of the models for the prediction of placental abruption.

Figure 1. Box and whiskers comparisons of the UA PI MoM, MCA PI MoM, CPR MoM and

BW centile in the study groups.

Figure 2. ROC curve of the logistic regression model including MCA PI MoM, UA PI MoM,

CPR MoM and BW centile.

Figure 3. Effect plots describing the probability of the placental abruption according to the

values of the 4 studied parameters. The risk of placental abruption increased as the MCA PI

MoM reached values <0.8, the UA PI MoM reached values >1.3 and the CPR MoM reached

values >1.2. For the BW centile no threshold was observed and the increase in the risk of

placental abruption was minimal.

Figure 4. ROC curve of the logistic regression model including MCA PI MoM, UA PI MoM

and BW centile.

Figure 5. Effect plots describing the probability of the placental abruption according to the

values of the 3 studied individual parameters (MCA PI MoM, UA PI MoM and BW centile).

The risk of placental abruption increased very slightly as MCA PI MoM reached values <1

MoM. For the UA PI MoM and BW centile, no clear threshold was observed and the increase

in the risk of placental abruption was minimal.

Supplementary figure 1. Effect plots describing the probability of placental abruption

excluding the MCA PI MoM values from the model. The coefficient became negative. Since

both variables, CPR MoM and MCA PI MoM, were highly correlated (Pearson’s correlation,

r = 0.73) the coefficient of the CPR MoM was influenced by the presence of the MCA PI

MoM changing the sign of the CPR MoM coefficient with an apparent paradoxical positive

OR (see figure 3).

Supplementary figure 2. Effect plots describing the probability of placental abruption using

a model that included only the CPR MoM and the BW centile. Unfortunately, this model was

much less predictive than the other models (table 2, figure 3 and 5 and supplementary figure

1) and the risk increased progressively with no clear thresholds.