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Evaluation of Neonatal Cardiopulmonary and Anthropometric Indices: A Key Predictive Clinical Biomarker for Neonatal Health Status

Neonatal mortality has been reported as a major societal health menace across the globe. Hence, this study, which adopted a hospital-based cross-sectional type of experimental research design, aimed at examining the clinical indication of some selected cardiopulmonary and anthropometric indices as key predictive clinical biomarkers for neonatal survival. The subjects were divided into three groups; experimental Group 1 consisted of 80 pre-term neonates within 28 weeks; experimental Group 2 consisted of 80 pre-term neonates within 33 weeks; and the control group, which consisted of 80 apparently healthy, term neonates. For each subject selected, cardio-pulmonary parameters and anthropometric variables were obtained daily and compared. ANOVA, correlation coecients, and linear regression were used to compare statistical measures. A discrimination accuracy test of previous records using cut points available from previous models was conducted for ease of estimating the possibility of neonatal survival from assayed variables. The target saturation was established to fall within the interquartile range of preductal saturations measured in healthy term babies following vaginal birth at sea level. 11 In this current study, there was a statistically signicant decrease OSL in preterm neonates compared to term neonates (p < 0.01). The mean time taken for the pre-ductal saturation to reach 90% was 7.4 minutes and for post-ductal 9.5 minutes. The mean time taken for equalization of pre and post- ductal saturation was 11.46 minutes with no signicant correlation with time. Furthermore, about 74% of the term neonates had equalization of pre and post ductal SpO2 values over time. It is however shown that preterm neonates have lower SpO2 values when compared to term neonates, and they take a longer time to attain SpO2 values of more than 85%. 24 Furthermore, this study shows that the time taken for a preterm neonate to reach maximum SpO2 delivery is more than that required for term neonates, corresponding to the explanation of on the subject matter. This study also supports the hypothesis that preterm babies may have lower SpO2 compared to term babies, and they take longer time to achieve normal saturation . It may be noted that the International Liaison Committee on Resuscitation (ILCOR) guidelines make no recommendations for using different time cut offs for these neonates . 26 However, we suggest that routine pulse oximetry is performed on neonates until weeks after birth for proper monitoring of the cyanosis and related condition.


Introduction
Neonatal period is the most vulnerable time as they face the highest risk of dying in their rst month of life, with the majority dying in the rst week. 1 Expanded body of evidence have shown that about 14 million of the 130 million children born each year die within the rst 28 days of life. 2,3 The rst week accounts for three-quarters of neonatal deaths, with more than a quarter occurring within the rst 24 hours. 2 Neonatal deaths account for 40% of all deaths in children under the age of ve worldwide. 2 As a result, efforts in developed countries to meet the United Nations' development goals of halving childhood mortality by two-thirds by 2020 focused on reducing neonatal deaths. 1 Childhood mortality is frequently used as a broad indicator of social development or a particular indicator of a country's health conditions in this context. In the midst of this, child health programs, particularly neonatal health, are frequently overlooked. 1 Until early childhood, neonates' cardio-respiratory systems go through series of physiological changes. The cardiovascular and pulmonary anomalies are the most common congenital abnormalities in newborns. 4 As a result of this, cardiovascular and respiratory physiology in neonates differ from that of older children and adults. Deaths in the NICU (neonatal intensive care unit) due to cardio-pulmonary pathologies are found to be the greatest in developing and developed countries. 5 Despite this, there has been little quanti cation of predictive markers to predict neonatal survival and predictors that can actually suggest the neonate's state of health in terms of the amount of treatment that should be given. As a result, physiological functions in neonates must be investigated as potential tools for predicting neonatal survival using cardiopulmonary and anthropometric parameters. These markers include blood pressure, pulse rate, oxygen saturation level, and respiratory rate which are the regular cardio-pulmonary parameters in NICUs in developing countries, weight, length, and head circumference are the regular anthropometric parameters 6,5 in maternity clinics.
In this context, this study aimed at determining the changes in cardiopulmonary variables [SBP (Systolic Blood Pressure), DBP (Diastolic Blood Pressure), PR (Pulse Rate), RR (Respiratory Rate) and OSL (Oxygen Saturation Level)] in term and pre-term neonates, investigating the changes in anthropometric parameters [Weight, Length, HC (Head Circumference)] in term and pre-term neonates, establishing a relationship between cardiopulmonary and anthropometric variables in preterm and term neonates; and developing a multiple linear regression model from which neonatal survival can be predicted using cardio-pulmonary and anthropometric parameters. 2.2 Study Population and Sample Size determination: The study population was derived from the total number of neonates admitted in the NICU, Central Hospital Warri throughout the study duration. This was estimated at 3,750 neonates; this value comprised those on admission throughout their neonatal period and those discharged before they completed 28days of life for one reason or the other. From this number, a calculated sample was obtained using a single population proportion formula by considering p=50%, CI=95% and 5% margin of error. Finally, to compensate for non-response rate, 10% was added. Thus, to conduct this study a sample size of 240 was used 2.3 Study Design: A hospital-based cross-sectional type of experimental research design was adopted for this study within the period of six (6) months. Data were obtained from a cross section of neonates on admission in the NICU, Central Hospital Warri. The subjects were divided into three groups; Experimental Group 1 consisting of 80 pre-term neonates within 28-32weeks, Experimental Group 2 consisting of 80 pre-term neonates within 33-36weeks, and Control Group which consisted of 80 apparently healthy, term neonates. For each subject selected, cardio-pulmonary parameters (BP, PR, RR, and OSL) and Anthropometric variables (Weight, Length, and HC) were obtained daily and compared for changes across obtained data as earlier described in a previous study. 3 2.4 Sampling Technique: Using the simple random sampling technique, preterm neonates' of 28-36weeks gestation was drawn from the population of admitted neonates. As a rule, at least 10 events per potential predictor are required to build a prediction model. 31 Hence, the expected number of events was adequate to build a robust prediction model.

Eligibility Criterion: Only preterm neonates (28-36 weeks gestation) admitted into the NICU, Central
Hospital Warri, Delta State were eligible to participate in the study. Neonates of mothers who are under intra-partum antibiotics as well as babies with prior antibiotic therapy for present illness were excluded from this study. Neonates with respiratory distress, who manifested signs with di culty in breathing, were also excluded from this study. Resting systolic and diastolic blood pressure were measured using the electronic sphygmomanometer (Omron Intelli sense M6 Comfort, Japan) with a neonatal blood pressure cuff that covered up to 40% of the preferred limb (right arm). The cuff was applied to the upper arm (left or right) of the neonate at a lying position. 16 The heart rate was concomitantly recorded (in beats per minute) from the sphygmomanometer reading during blood pressure measurement. The neonates were required to rest in a quiet atmosphere for 30 minutes prior to assessment and recording as prescribed by. 9 Determination of Oxygen Saturation Level Oxygen Saturation level was measured with a pulse oximetry device as earlier described by, 10 which involves a non-invasive technique for measuring arterial oxygen saturation level. The device includes a sensor that measures light absorption of haemoglobin and represents arterial oxygen saturation, SpO 2 . It quanti es the "Relative amount of light absorbed by oxyhemoglobin and deoxyhemoglobin", comparing in any case the amount of light emitted. This comparison is then converted to a ratio and expressed in percentage of SpO 2 .

Determination of Respiratory Rate (RR)
A person's respiratory rate is the number of breaths he or she takes per minute. This was measured in the new-born when at rest by counting the number of breaths by counting how many times the chest rises in one minute as prescribed in a previous study. 11 2.6.2 Determination of Anthropometric Parameters Weight, length, and head circumference were calculated using the methods de ned by the American College of Sports Medicine. 12 Accordingly, all the anthropometric parameters were collected from the neonates in a supine position. The length and head circumference were measured with the aid of a exible rubber measuring tape. For head circumference, the tape was wrapped snugly around the circumference of the head from the most prominent part of the forehead (often 1-2 ngers above the eyebrow) to the widest part of the back of the head. With the subject dressed in light clothes without shoes, shoulder relaxed, the arms hanged loosely, the heels and occiput in contact with the hard lying oor, and the length was measured in centimeters from the head to the soles of the feet using a measuring tape. Still dressed as above, the weights of subjects were measured in grams (g) using an electronic weighing scale (Cardinal Scale Manufacturing Co., Webb Area, MO).To ensure speci city, each neonate was assessed three (3) times.

Statistical Analysis
Statistical measure of Association (Correlation) was used to establish a relationship between measured variables. Con dence levels for all statistical based calculations were set at p < 0.05. Were applicable, one-way ANOVA was used to check differences in mean between groups. All statistical tests were automated, using the graph pad prison (version 8.0).

Changes in Cardiovascular status of Term and Pre-Term Neonates
The changes in cardiovascular variables of term and pre-term neonates are shown in Table 1.
Accordingly, pre-term of week 28-32 and Week 33-36 respectively revealed a signi cant (p < 0.05) increased in blood pressure as indicated by increased SBP (mmHg) and DBP (mmHg) level with corresponding decreased in PR (BPM) at week 28-32 when compared to term neonate. Notably, there was an increase in PR of pre-term neonate (Week 33-36) as related to term neonate

Changes in Anthropometric status of Term and Pre-Term Neonates
As shown in Table. 2, one-way ANOVA followed by post-hoc test showed that pre-term of week 28-32 and Week 33-36 respectively revealed a signi cant (p < 0.05) decreased in neonatal weight (kg), length (cm) and HC (cm) when compared to term neonate throughout the period of the study. As shown in Fig. 1a-b, one-way ANOVA followed by post-hoc test showed that pre-term of week 28-32 and Week 33-36 respectively revealed a signi cant (p < 0.05) decreased in RR (Cycle/Min) (1a), and OSL (%) (1b) when compared to term neonate. However, pre-term of week 28-32 shows a highly signi cant (p < 0.05) decreased in RR and OSL when compared pre-term of Week 33-36. \

Relationship between Cardiovascular status in Neonates
Pearson's correlation coe cient (R) between various neonatal cardiovascular measurements are presented in Fig. 2. All of the neonatal cardiovascular parameters such as systolic blood pressure (SBP), Diastolic blood pressure (DBP), and pulse rate (PR) had a positive correlation between each parameters (p<0.05). The correlation coe cient (R) value ranged from 0.16 to 1.00. The highest correlation was observed on both SBP (r=1.00), DBP (r=1.00), and PR (r=1.00).

Respiratory status in Neonates
Pearson's correlation coe cient (R) between various neonatal respiratory measurements are presented in Fig. 3. All of the neonatal respiratory parameters such as respiratory rate (RR), and oxygen saturation level (OSL) had a positive statistically signi cant correlation between each parameters (p<0.05). RR, and OSL had a positive statistically signi cant correlation when correlated with each other (p<0.05). The correlation coe cient (R) value ranged from 0.5 to 1.00. The highest correlation was observed on both RR (r=1.00), and OSL (r=1.00).

Relationship between Neonatal Anthropometric status in Neonates
Pearson's correlation coe cient (R) between various neonatal anthropometric measurements are presented in Fig. 4. All of the anthropometric parameters such as birth weight (Kg), length (cm) and head circumference (HC) from the neonates had a positive statistically signi cant correlation between each parameters (p<0.05). Weight, length and HC had a positive statistically signi cant correlation when correlated with each of the anthropometric measurement (p<0.05). The correlation coe cient (R) value ranged from 0.42 to 1.00. The highest correlation was observed on both BW (r=1.00), Length (r=1.00), and HC (r=1.00).

Prediction of RR from Neonatal cardiovascular Parameters in Preterm Neonates using multiple linear regression
In predicting or estimating RR from neonatal cardiovascular measurements in pre-term neonates, a multiple linear regression analyses were carried out and the report is shown in (

Predictive Accuracy Measure of the Regression Model
Based on the predictive biomarkers of the regression model, the individual parameters (e.g. MAP and OSL) as indicated in model 1 had better predictive potential for pre-term neonate survival whereas the best predictor for term neonate are SBP and OSL (Model 2) as statistically correlated with RR (Table 9).  Blood pressure is classi ed as "high" (HBP) when the mean SBP exceeds 120 mmHg or the DBP exceeds 80 mmHg. 13 The average systolic and diastolic blood pressures of each participant neonate was within normal limits at baseline. This was expected as it was one of the selection criteria to exclude new born babies with any cardiovascular health complications and/or anomalies.
This study also showed a signi cant decrease (p < 0.05) in average body weight of pre-term neonates compared with term neonate. This could be due to intra-uterine growth. Thus term neonates might have gained more weights due to long period of stay in-utero as earlier explained by . 14 Throughout the monitoring period, the drop in preterm newborn weight became more gradual when compared to the term neonates, as a signi cant increase in average body weight was noticed at some period in the normal term neonate used in present study. Newborn infants whose developments in-utero occasioned by intrauterine growth restriction (IUGR) are usually small-for gestational-age (SGA), a body weight < 3rd centile. 15 Most IUGR infants are the consequence of utero-placental insu ciency that occurs during the third trimester. 14 Consequently, the weight was affected so that the neonate appears wasted. These gestational insults often cause critical under-nutrition and impair musculoskeletal growth, resulting in a stunted neonate with reduced weight and length. 14 Therefore the observed reduced body weight noted in preterm neonates in this study could have been as a result of utero-placental insu ciency also noted in an earlier study. 15 Blood pressure is one of the commonest clinical methods of assessing circulatory status of humans. 16 In this study, the Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) were assessed and a comparison was made in these values in term and preterm neonates. Accordingly, there was a statistically signi cant increase (p < 0.05) in the blood pressure parameters (SBP and DBP) for pre-term compared to term neonates. Thus, this current study deduced SBP as a key cardiovascular health marker which is revealed to be higher in preterm than term neonates. The DBP is apparently more crucial, and therefore having this lowering ability is more bene cial. Hence, modi cation for the prevention and management of high blood pressure is needed in preterm than term neonate. Considering all these, preterm neonates could be assumed to have a more chaotic (or less linear) cardiovascular function behavior than term neonates. The preterm neonates, who have no well-balanced sympatheticparasympathetic systems, can also be considered "less healthy" within the concept of health and disease. This logic is explained easily due to some intrinsic or extrinsic factors that must occur to justify delivery before the term (<37 weeks of gestation). It is also expected that differences in age and the presence or absence of co morbidities changes the results of the assayed variables (SBP and DBP) used in assessing the standard cardiovascular patterns in this study. This nding corroborate previous study by. 17 The pulse rate (PR) signi cantly affects cardiovascular function, and it is a vital marker for neonatal cardiovascular risk assessment. 9 In this study, the PR was seen to have signi cantly increased (p < 0.05) in preterm than term neonates upon comparison. This depicts its immense bene t in reducing cardiovascular risk in term than preterm babies. This nding agrees with that from a similar study by 18 where there was no signi cant difference in PR with time for term babies.
In clinical practice, preterm neonates are closely monitored for diseases and related complications. As long as the "low-risk" neonates born at term appear well, they are subjected to the bare minimum of standardized observations. 19 Unexpected diseases in term neonates, on the other hand, are normal and can quickly become life-threatening shortly after birth. 20,21,11 Tachypnea, a condition characterized by respiratory rate higher than normal (RR) is used a symptoms of various diseases in the immediate neonatal period. 22 Results from this study shows a statistically signi cant increase in RR of preterm compared with term neonates. By implication, this is suggestive of a high risk factor for preterm babies, speci cally in the respiratory system. The increased work of breathing seen in preterm neonates in this study may be attributed to mismatched pulmonary mechanics. It may also be due to increased airway resistance (Pressure/Volumetric Flow), decreased lung compliance (Volume/Pressure), or both as earlier explained by 23 Naturally, neonates undergo key physiologic changes during transition from intrauterine to extra-uterine life. 10 In most cases, this transition is smooth. About 5-10% reportedly requires breathing supports, and about 1% requires absolute resuscitation. 10 The indications and timing of supplemental oxygen therapy to assist the newborn in this transition has been a matter of debate. 11 The 2010 International Liaison Committee on Resuscitation (ILCOR) recommendations states resuscitation can be initiated with room air or blended oxygen, but it should be guided by measurement of oxygen saturation using pulse oximetry. 11 The target saturation was established to fall within the interquartile range of preductal saturations measured in healthy term babies following vaginal birth at sea level. 11 In this current study, there was a statistically signi cant decrease OSL in preterm neonates compared to term neonates (p < 0.01). The mean time taken for the pre-ductal saturation to reach 90% was 7.4 minutes and for post-ductal 9.5 minutes. The mean time taken for equalization of pre and post-ductal saturation was 11.46 minutes with no signi cant correlation with time. Furthermore, about 74% of the term neonates had equalization of pre and post ductal SpO2 values over time. It is however shown that preterm neonates have lower SpO2 values when compared to term neonates, and they take a longer time to attain SpO2 values of more than 85%. 24 Furthermore, this study shows that the time taken for a preterm neonate to reach maximum SpO2 delivery is more than that required for term neonates, corresponding to the explanation of on the subject matter. 24 This study also supports the hypothesis that preterm babies may have lower SpO2 compared to term babies, and they take longer time to achieve normal saturation . 25 It may be noted that the International Liaison Committee on Resuscitation (ILCOR) guidelines make no recommendations for using different time cut offs for these neonates . 26 However, we suggest that routine pulse oximetry is performed on neonates until weeks after birth for proper monitoring of the cyanosis and related condition.
In terms of anthropometric measurements, the current study found that birth weight, length, and head circumference all correlated positively with neonate survival, which is consistent with earlier studies. 27, 3, 28, 29, 30, Based on the predictive biomarkers of the regression model, the MAP and OSL had better predictive potential for pre-term neonate survival whereas the best predictor for term neonate are SBP and OSL which are statistically correlated with RR as shown in the results. Interestingly, signi cant correlation was observed for all the cardiopulmonary and anthropometric variables. Thus, all the parameters in this study are reliable to predict neonatal survival. This study formulated regression modeling equations from cardiopulmonary and anthropometric parameters to predict neonatal survival. Notably, statistically signi cant regression equation was derived with MAP and OSL as independent variables in preterm neonates, while SBP and OSL are independent variables in term neonates. However, RR seems to be the most reliable dependent variable for both preterm and term neonates. The calculated RR within normal limit in both term and preterm neonates predicts a higher chance of survival, while calculated RR outside normal limits in both term and preterm neonates predicts lower chances of survival. To the best of our knowledge, no research work has formulated a regression model predictive accuracy measurements for neonatal survival using a combination of neonatal cardiopulmonary and anthropometric parameters. Hence, this nding could be useful by community health workers to provide insight into the extent of compromise in the newborn health. More so, prediction of neonatal cardiopulmonary and anthropometric status is crucial to ensuring better treatment protocol/regimen

Conclusions
The study concluded that anthropometric measurements as well as cardiopulmonary indices are good predictors of neonatal survival. There was a decrease in RR and SpO2 in preterm neonates, indicating increased work of breathing and cyanosis, respectively. As a result, the knowledge of newborn cardiopulmonary and anthropometric variables may be effective predictive markers for early discovery of neonates that are at high risk of neonatal death, triggering earlier and more drastic care. A corroborative study with an event-driven approach that assays more molecular or other non-physiological variables is recommended.

Declarations
Ethics approval and consent to participate Availability of data and materials Data obtained from this study is available on request from the corresponding author and Olowe G.T.

Competing interests
The authors declare that there is no con ict of interest of any form and oxygen saturation level, OSL (b). Bars represent the mean ± S.E.M (n = 80). One way ANOVA followed by Bonferroni's post-hoc test revealed that there are signi cant differences between various neonatal groups. *--= statistically signi cant decrease in OSL among pre-term neonates 28-32 weeks gestation compared to term (control) neonates at p-value < 0.05; #--= statistically insigni cant decrease in OSL among pre-term neonates 33-36weeks gestation compared to term (control) neonates at p-value < 0.05