Using Doppler sonography resistive index for the diagnosis of perinatal asphyxia: a multi-centered study

Multiple events during labor and delivery may lead to encephalopathy of the neonate which is generally termed perinatal asphyxia [1]. Asphyxia is one of the most common causes of mortality and morbidity among newborns and an estimated one to six from every one thousand full-term births are associated with some degrees of asphyxia [2].

The events that lead to asphyxia cause oxygen deprivation and finally may present as neurological deficit in the neonate. Asphyxia may present with different symptoms including abnormal level of consciousness, difficult respiration, decreased muscle tone and reflexes and etc. [3].

As asphyxia prolongs, cerebral blood flow is compromised and decreases through systemic hypotension and dysregulation within the cerebral regulatory system. This leads to hypoperfusion and ischemia, which may develop into hypoxic-ischemic encephalopathy and neurological impairment (blindness, hearing loss, cerebral palsy, motor and mental development problems) for the child [1, 4, 5].

Different modalities have been used to diagnose asphyxia among neonates, among which magnetic resonance imaging (MRI) is considered the gold standard imaging method used in clinical practice [6]. Other imaging modalities include ultrasonography, Doppler sonography (DS) of the cerebral arteries, and in some cases computed tomography (CT) [7].

Sonography based imaging, present a non-invasive, portable and safe method of evaluation for patients suspected of asphyxia [8]. A reduction in the Resistive index and an increase in the end-diastolic flow velocity have been associated with changes in cerebral blood flow and presents an effective method for evaluation of asphyxia [9].

In a recent study by Kudreviciene et al., children with asphyxia were studied using DS. They determined a cut-off based on DS index for the prediction of neuro-developmental injuries. Other studied have also studied the prognostic role of DS in children with ischemic brain damage [4, 10, 11], however at present, data on the diagnostic role of DS in asphyxia remains scarce and DS is not routinely used in the clinical assessment of asphyxia in neonates [9].

In this study we evaluated and compared DS and MRI findings in a sample of neonates suspected of asphyxia, we also determined an optimum cut-off point based on DS (index) of the cerebral arteries to differentiate between neonates with asphyxia and normal neonates.

Overall, 34 patients entered the study. One patient died before having MRI and was excluded from the study. Patients' baseline characteristics are shown in Table 1.

Pearson's correlation showed that, DS of the ACA, MCA, BA all had a significant and strong correlation with MRI findings (regarding severity of asphyxia) (r > 0.8; p < 0.001). DS of the ACA and the BA had the strongest correlation with MRI findings (r = 0.889 and p < 0.001) (Table 2).

In the ROC analysis, all the arteries were separately evaluated regarding their compatibility with MRI findings. DS of the ACA showed that the ideal cut-off point for diagnosing neonates with asphyxia was at a RI of ≤ 0.62 (AUC = 0.957 and 95% CI: 0.819–0.997; sensitivity = 95.65; specificity = 100; PPV = 100; NPV = 90.9 and NLR = 0.043).

Regarding the BA, the exact same results were recorded as the ACA (AUC = 0.957 and 95% CI: 0.819–0.997; sensitivity = 95.65; specificity = 100; PPV = 100; NPV = 90.9 and NLR = 0.043).

ROC analysis of the MCA showed that, similar to the ACA and BA, a cut-off of ≤ 0.62 was the ideal cut-off point for differentiating between normal neonates and those with asphyxia (AUC = 0.990 and 95% CI: 0.873–1; sensitivity = 91.30; specificity = 100; PPV = 91.2; NPV = 100 and NLR = 0.087) (Table 3) (Fig. 1).

Results of pairwise comparison of ROC curves, showed that the ROC curves between the ACA and BA (which were completely similar p > 0.99) did not have a significant difference with that of the MCA (p = 0.39).

In this study we evaluated DS of the ACA, MCA and BA among neonates clinically diagnosed with asphyxia and compared it with MRI findings, which is the gold standard tool for the diagnosis of neonatal asphyxia, furthermore we defined a cut-off point for RI at which DS is able to detect neonatal asphyxia. We found that a RI ≤ 0.62 in DS, is the optimum cut-off point for the diagnosis of perinatal asphyxia with an accuracy of 95% (for the ACA and the BA) and 99% (for the MCA).

To the best of the author's knowledge this is the first study to compare DS findings with MRI findings in order to determine a cut-off point based on RI for the diagnosis of perinatal asphyxia. Up to this date, studies evaluating DS in asphyxia have been mostly old, have focused on prognosis (long term neuro-developmental outcome) and are less applicable in clinical practice for discriminating between neonates with asphyxia and normal neonates.

In a study by Kudreviciene et al. in 2014 [11], one year prognosis was evaluated among neonates with hypoxic brain injuries and normal neonates, using ultrasonography (US) and DS. They found that neonates with a RI ≤ 0.55 in the ACA on days 1–5 of birth, had significantly higher watershed border zone injury, thalamus, basal ganglia and cerebellar injuries.

Ilves et al. [20] also evaluated cerebral blood flow among infants with asphyxia in order to predict long term outcomes. They found that when evaluating cerebral arteries during the first 24 h of birth (similar to that of our study), infants with poor outcome or those with severe hypoxic ischemic encephalopathy had a lower RI in the BA, MCA and carotid arteries compared to a control group.

In another study [21], US indices were measured among 212 patients, in order to determine the validity of US in predicting three year adverse outcome among children with encephalopathy. In this study, US findings were evaluated during 24 and 72 h after birth. They found that among 39 neonates who had US during the first 24 h of life and had their RI measured, those with a RI < 0.56 had a 23.6 time higher chance (95% CI: 2.6–217.5, Sensitivity = 53%, specificity = 95%, PPV = 90% and NPV = 72%) of developing adverse outcomes.

A higher threshold for RI (< 0.60) in the ACA and the MCA was documented in an older study by Stark et al. (compared to similar studies) to be associated with poor five year clinical outcomes among 16 term asphyxiated neonates [22].

Some older studies have also evaluated the relationship between neurodevelopment of neonates and cerebral blood flow indices, and have mostly documented similar findings to the previously mentioned studies regarding decreased cerebral blood flow and its association with adverse long term outcomes [18, 23, 24].

In here we found that a cut-off of ≤ 0.62 for RI is a diagnostic threshold for asphyxia among full-term neonates. This is in coherence with previous literature, furthermore to date, studies that have evaluated RI cut-off points have all been based on clinical outcomes and prognosis among asphyxiated neonates and have all documented lower cut-off thresholds than that documented in our study. Perhaps a cause for the lower cut-off points documented in different studies from that documented in our study, is that not all asphyxiated children necessarily show poor long term neurodevelopmental outcomes (for example some milder forms of the disease) and so when evaluating cut-off points based on prognosis (as in the mentioned studies) a lower threshold is documented.

One of the main causes for the difference documented between studies regarding RI cut-off points, relates to the timing of the initial DS. A study documented no significant difference in RI when performing DS during specific hours of birth between children with asphyxia and normal infants, however this difference was mostly significant during the 24 h of birth between these two groups [20], thus pointing the importance of timing of DS for comparison among studies.

For facilities where MRI (as the gold standard diagnostic modality) is too expensive or is unavailable in perinatal care centers, based on our results a RI of ≤ 0.62 in DS performed on the first day of birth can be considered an appropriate diagnostic cut-off point for neonates suspected of asphyxia. This provides a tool for easy and less costly diagnosis of asphyxia and provides clinicians with an index with high precision for diagnosis of the condition.

Our study did have some limitations. Our cut-off points were based on DS performed on the first day of birth and for those neonates for whom DS is not performed on the first day, the reported cut-off points are not applicable. Another factor which is present in almost every study evaluating sonography findings, is the operator dependency and the subjective nature of sonography. This shows that for sonography to be considered an efficient tool for the evaluation of asphyxia, there is need for expert staff members to perform and evaluate sonography findings. Factors such as hypothermia and vasogenic edema are known to affect RI [25‐27], considering that all our patients received appropriate ICU care and were continuously monitored none of these caused any issue or bias in our measurements. Moreover, in our center that we lack facilities such as MRI, we refer patients for MRI only after obtaining clinical stability, thus DS during the first day can be helpful for diagnosing asphyxia in centers that have limited facilities such as MRI.

For evaluating neonates clinically suspected of asphyxia, especially in centers with limited facilities such as MRI, DS can be used as a first line diagnostic modality for the diagnosis of asphyxia. A RI of ≤ 0.62 is an appropriate cut-off to differentiate between normal and asphyxiated neonates with excellent accuracy.