Discussion
This is the largest study on reference ranges for newborn PPI values. Since all babies born in public sector hospitals were included in the screening, the study is representative of the population and the risk of bias is low. The fact that the same protocol was followed by all screening units and that the same type of device was used is a major strength of the study. This allows for the extrapolation of these reference values in other settings by calibrating other machines to the reference machine.
The median values of preductal as well as postductal PPI from this study are higher than those reported previously. There is a high degree of heterogeneity in PPI values reported thus far. The corresponding values from 3952 neonates, between 24 and 48 hours of age from China were 2.10 (IQR 1.60–3.30) and 2.30 (IQR 1.70–3.40), respectively.13 Lower values were reported from 241 newborns in Turkey on day 1, preductal 1.35 (IQR 1.02–1.91) and postductal 0.88 (IQR 0.62–1.22)5 ; preductal 1.68 (IQR 1.18–2.46) and postductal 1.71 (IQR 1.20–2.50) from Sweden at age 0–120 hours.2 When day-wise stratified median values from the current study were reviewed, values on each day through days 1–7 were consistently higher than previously reported values mentioned above. This heterogeneity merits further investigation.
The current study was done in Kerala, which has a tropical climate. South Asian population is known to be genetically different from other populations with respect to various diseases including cardiovascular diseases.14 In this context, whether the heterogeneity may be explained by factors like ambient temperature and genetic variability needs further exploration. In addition to factors that influence the differences in PPI value between populations, there is also a list of factors that are known to influence PPI values at an individual level. These include circadian rhythm, feeding, jaundice, sleep/awake state, prone/supine position, ongoing intravenous treatments, skin colour and site of measurement.5 15 16 The distribution of preductal and postductal PPI is skewed to the left, from the extremely high values in a small subset of patients. As the focus from a newborn screening perspective is primarily on lower PPI, the higher values may not be of relevance.
The study also brings to light the challenges faced by population screening of such a large number of newborns. UPOS was recommended after 24 hours of life and before 48 hours. However, 39.8% were conducted on day 1 and 25.2% on day 3 of life or later. This resulted from the fact that the sheer numbers demanded workflow to be distributed between the initial few days of life. Considering the timing of ductal closure, this may not meet the goal of detecting CCHD before ductal closure in the later screens. This may also result in higher false-positive UPOS rates from day 1. Age at the measurement of PPI holds relevance from CCHD screening perspective.
On the other hand, when it comes to screening for other new born illnesses, day of measurement of PPI may not hold great relevance. However, this is yet to be systematically investigated. The current study has identified minor differences in PPI values from day 1–7 that have achieved statistical significance, the clinical relevance of which may also need further investigation. Previous studies have shown no significant difference in the PPI of term babies in the early days of life.3 The minor variations in the early newborn period found in this study can be attributed to the transitional physiology. On the other hand, in preterm babies, a significant increase in PPI values from day 1 to day 3 has been noted in previous studies, attributed to maturation of the sympathetic system during the first few days of life.13
Another practical challenge was the lack of postductal measurements in a large number of newborns. This was because babies are uncomfortable when unwrapped for screening and may not allow the completion. Time and staffing constraints setting make repeat screens challenging. Based on this, the UPOS protocol of the state of Kerala was changed to record the postductal measurements first. From the Bland Altman plot (figure 2), agreement between preductal and postductal PPI measurements was better in the lower range. Since PPI screening is done primarily to identify lower values, screening either the foot or arm may have provided adequate information to identify CCHD.
The few studies that have examined the influence of gender on PPI in newborns have not found any association.2 5 11 Therefore, a noteworthy finding from this large database is the effect of birth weight and gender on PPI, as represented in table 1. For the same weight, boys tend to have higher values for both preductal and postductal PPI. Since the median difference adjusted for weight is only 0.1, the effect is relatively small (table 1). This effect may have been missed by previous studies with smaller sample sizes. This difference in PPI values between genders may necessitate deriving gender-based threshold values to define abnormality. This would be important in designing research protocols for outcome studies. Further significance of these differences and reasons thereof is yet to be explored and understood.
The absence of association between PPI and SPO2 values suggests that they measure different aspects of the physiology. Moreover, low PPI values less than 0.7 could not be predicted well from SPO2. Therefore, PPI may have complementary value to SPO2 in population screening for CCHD.
Limitations
This retrospective study benefits from a large data collected using a predefined screening protocol. Despite the substantial database enabling meaningful analysis, numerous postductal PPI values were absent. Furthermore, measurements were spread over the first week of life, as opposed to the recommended time frame for UPOS. Other demographic and clinical variables like prenatal care, comorbidities, gestational age, maternal age were unavailable. The retrospective nature of the study precluded scheduled follow-up visits to assess outcomes. This paper does not investigate the predictive value and clinical utility of UPOS or PPI.
Future directions
PPI distributions from diverse populations are necessary to account for the impact of factors such as ambient temperature. Gender and birth weight’s overlooked influence on PPI should be studied across various demographics. Prospective studies, designed to encompass all live births, would add significant value. Outcome-based studies from large populations are imperative before PPI can be recommended for population screening for early detection of CCHD.
