Correlation between Transcutaneous Bilirubinemia and Blood Bilirubinemia in Screening Term Newborn for Neonatal Jaundice at the Essos Hospital Centre (EHC), Yaoundé, Cameroon ()
1. Introduction
Newborn jaundice refers to yellow coloration of the skin and/or eyes, and mucous membranes caused by an increase in the level of bilirubin in the blood with a deposit of bilirubin in these tissues. It affects about 60% of full-term newborn infants and 80% of preterm babies in the first week of life [1]. Most hyperbilirubinemia is physiological and heals spontaneously while others remain pathological and may evolve into nuclear jaundice causing severe and irreversible neurological lesions [2]. Screening and surveillance are critical for adequate management.
Jaundice surveillance may be done either through visual assessment, or measurement of bilirubin levels accumulated in skin sites (transcutaneous bilirubinemia) and through blood dosage (serum bilirubin). Clinical assessment may detect jaundice in the skin and mucous membranes, but is not very helpful in assessing the severity of hyperbilirubinemia. On the contrary, transcutaneous bilirubin levels introduced in clinical practice in 1980 by Yamanouchi et al. [3] are reliable screening tools in detecting newborn infants at risk for presenting clinically significant hyperbilirubinemia. Though TcB cannot replace blood sampling [4], it is yet an alternative screening test for pathological jaundice in remote areas.
In Africa, works on pathological jaundice in neonates are scarce, while literature shows that the rate of jaundice is high in developing countries [5]. As such, the first management component is early testing which should be part of the daily concerns of health staff in maternity wards and neonatology units. Some works describe a good correlation between transcutaneous bilirubin levels and total serum bilirubin as with Romagnoli et al. who led a comparative study in 2012 on the accuracy of the Bilicheck and JM103 bilirubin meters in Italy to assess total serum bilirubin [6]. In his works conducted in Rwanda in 2012, Uwurukundo et al. revealed a good correlation between transcutaneous bilirubin and serum bilirubin measurements for the detection of neonatal jaundice in dark-skin newborn babies [7]. Chimhini et al. assessed the use of the DRAEGER Jaundice Meter JM 103 in newborn babies in Zimbabwe in 2015 and declared that this device may be used to screen for neonatal jaundice in the Zimbabwean population [8].
No studies have been carried out in this field in our country. Therefore, we have started this study at the EHC to improve the management of neonatal jaundice by using TCB as the screening and surveillance tool for hyperbilirubinemia.
2. Methodology
2.1. Type of Study
We conducted a cross-sectional study at the neonatology Unit of the Essos Hospital Centre in Yaoundé from 28 January to 27 June 2019.
2.2. Inclusion Criteria
The following were involved in this study:
All full-term newborn infants (from 37 gestational weeks) aged between 0 - 7 days presenting clinical signs of jaundice, and whose parent or guardian agreed to participate in this study.
The following were excluded from this study:
Infants with prior phototherapy;
TcB measurements and /or sampling not done.
2.3. Sampling
We conducted a consecutive sampling. The sampling size was calculated using
the COCHRAN formula
with “N” representing the sample
size, “z” the confidence interval at 95% , “p” the estimated prevalence of severe neonatal jaundice estimated at 6% and “t” the margin error risk at 5%. Based on this formula our sample size stood at a minimal of 87 full term newborn babies.
2.4. Procedure
Recruitment and testing
Data was collected using a questionnaire designed by the main investigator and validated by the supervisor following testing amongst mothers for reliability and feasibility. After obtaining the parent or guardian’s informed consent, a short questionnaire was filled during face-to-face interview gathering information on each newborn prior clinical examination and screening.
➢ Clinical examination
This was a general physical examination to screen for physical signs of craniocaudal jaundice, in daylight or with a white radiation pocket torch.
Following a clinical evaluation of the newborn and confirmation of diagnosis by a paediatrician or health personnel neonatology unit, we carried out testing.
➢ Transcutaneous bilirubin measurement
All transcutaneous bilirubin measurements were done with a jaundice meter, the MBJ20® transcutaneous bilirubin meter by Beijing M & B Electronic Instrument Co. Ltd. (Beijing, China). Measurements were taken over the forehead and the sternum of the newborn in the supine position. The bilirubin level in each measuring site was clearly displayed on the digital screen in mg/dl. Both values were reported on our data collection sheet and the highest value was chosen for the study in mg/l.
➢ Total serum bilirubin (TsB) dosage
Blood samples were collected from a peripheral vein; two millilitres (2 ml) of venous blood within 5 - 10 minutes following the transcutaneous bilirubin measurement and transferred in heparinized sample tubes or bilirubin tubes in aseptic conditions.
TsB dosages were carried out in the hospital’s clinical chemistry laboratory. The proportioning principle was calibrated daily based on the Diazo method (use of diazonium ion) with the Biotechnical 1500 biochemistry Automate.
2.5. Data Processing and Statistical Analysis
Statistical method: the statistical analysis was carried out with the R 3.6.0 version software. Our results were presented in form of tables, plots and figures expressed per frequency, per enrolment for qualitative variables, per mean and standard deviation for quantitative variables. The R package EpiR was particularly useful. The association between the two measurements was evaluated by the Pearson correlation coefficient r, the Student test for paired data was used to compare the means of samples, the concordance correlation coefficient (CCC), and Bland and Altman plots were used to assess the agreement between TsB and TcB. In all statistical analysis, a significance threshold of 5% was retained.
Ethical Considerations
Ethical clearance was obtained from the Institutional Human Health Ethics and Research Committee of the University of Douala (CEI-UD) under the number 1878 CEI-UDo/05/2019/T, as well as a research authorisation from the administrative authorities of the EHC of Yaoundé. Participants were enrolled after written consent following the reading of the information sheet of the study. The identity of participants was kept confidential and the results obtained during the study were used for scientific purposes alone. The participants were involved after reading.
3. Results
We recruited 88 new-born infants with jaundice.
3.1. Characteristics of the Population
Table 1 summarizes the distribution of newborn infants per clinical and socio-demographic patterns. The sex ratio of the babies included was 1.25 favouring
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Table 1. Sociodemographic and clinical characteristics of the studied population.
male. Median Postnatal age was 3 days and 75% of the newborn had a birth weight ranged between 2500 and 4000 g, mostly full term (Mean gestational age was 38 weeks) and predominantly breastfed.
3.2. Distribution of Transcutaneous and Serum Bilirubin Measurements
The mean TcB corresponding to the maximum average between frontal and sternal measurement was 153 mg/dl ± 48 and the average Tsb was 123.80 mg/dl ± 50.48 (Table 2).
The population under observation was concentrated in 100 - 150 mg/l and 150 - 200 mg/l ranges. For the Tsb variable, the population under observation was highly concentrated in the <100 mg/l and 100 - 150 mg/l range.
As a reminder, the threshold value was 100 mg/l for diagnosis of hyperbilirubinemia as suggested by the National Institute for Health and Care Excellence (NICE). The highest average bilirubin level was obtained with transcutaneous bilirubin from sternum) (TcBs) 149.25 ± 47.64 mg/l, followed by transcutaneous bilirubin from forehead (TcBf) 143.32 ± 45.31 mg/l. The lowest average bilirubin level was found in total serum bilirubin, Tsb 123.80 ± 50.48 mg/l. The bilirubin intervals measured with these methods were 45 - 327 mg/dl for Tsb, 61 - 328 mg/dl and 59 - 329 mg/dl for TcBs and TcBf, respectively.
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Table 2. Frequency distribution of bilirubin concentration according to the different types of measurements.
3.3. Study of the Correlation and Agreement between TcB and TsB Values
Table 3 presents the correlation coefficient between Tsb, TcBf and TcBs for all paired measurements. We have noted a strong correlation between the two TcB measurement sites (forehead and sternum) r = 0.91 (95% CI = [0.86 - 0.94]). A positive correlation was observed between Tsb and TcBf (r = 0.78, 95% CI = [0.68 - 0.85]) and Tsb and TcBs (r = 0.86, IC at 95% = [0.79 - 0.90]). Figure 1 shows a scatter plot between TcB values and Tsb. The right linear regression line is also represented. The Pearson’s linear correlation between TcB and Tsb was r = 0.86 [0.80; 0.91] showing a good linear correlation. The concordance correlation coefficient estimates in the general sample was 0.2 [0.05, 0.33]. Even though its 95% confidence interval does not contain 0, one would conclude on a poor agreement between TsB and TcB measurements.
3.4. Bland and Altman Test Deviation Graph
Figure 2 represents the Bland and Alman Plot of TsB measurements versus TcB. The dotted lines (red and green) represent the upper and lower limits of the deviations 21.14 mg/l and −80.50 mg/l respectively. The blue line represents the bias = −29.68 mg/l. It is observed that the limits are wide and the bias −29.68 mg/l is statically significant (p < 0.01). This result indicates systematic bias, as TcB measurement overestimates the TsB mesurements.
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Figure 1. Linear regression scatter plot of TSB versus TCB, and the Pearson correlation coefficient estimate r.
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Table 3. Correlation matrix between TcB forehead, TcB sternum and TsB.
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Figure 2. Bland and Altman plot of the difference between measurements of serum bilirubin (TSB) and transcutaneous Bilirubin (TCB) concentration.
3.5. Differential Analysis of the Tsb-TcB and Factors Associated with This Difference
In Table 4, it is presented CCC and bias estimates according to the levels of TcB measurements. Basically, for TcB measurements <100 mg/l, there is a fair agreement between TcB and TsB measurements as the CCC estimate was 0.59 [0.11, 0.85] and the bias (12.33, p = 0.08) was not significant. For TcB measurements > 100 mg/l, the bias was significant and a poor agreement was observed. At postnatal age more than 2 days, it is observed a fair agreement between TcB and TsB as the CCC estimate was 0.61 [0.47, 0.73], although the bias was significant. However, for postnatal age of 1 day and 2 days the CCC confidence interval estimates contains 0, indicating poor agreement for newborns with these postnatal ages. Basically, Table 4 indicates poor agreement between TcB and TsB, and that the TcB would overestimate the true TsB measurements.
4. Discussion
The aim of this work was to study the correlation between TcB and TsB values in testing for neonatal jaundice in full-term newborn infants at the EHC.
4.1. Characteristics of the Sample
The sample of this study was mostly constituted of male infants at 55.6%. This profile is similar to those of Oyapero et al. [9] and Madubuike [10] who had a high incidence of male infants in Nigeria.
4.2. Correlation and Agreement
We found a strong correlation between the two TcB testing sites (forehead and sternum) r = 0.91; our data are consistent with similar studies and protocols [8] [11] [12]. Conversely, for others, transcutaneous bilirubin measurements on the forehead had a better correlation with serum bilirubin [9] [13] [14]. The correlation
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Table 4. Estimation of the concordance correlation (CCC) estimates and the bias according to TcB thresholds.
between TcB/TsB in this study is consistent with other sites, which, although using other devices, have indicated a strong association between TcB and TsB measurements, with correlation coefficients ranging from 0.75 to 0.95 [9] [14] [15].The correlation coefficient as used in many literature works to investigate agreement between TsB and TcB may be unappropriated to decide which tools to use. In fact, correlation does not imply agreement, and that constitute a pitfall for many research works [16] [17]. This study is among the firsts investigating the agreement between TsB and TcB in dark skinned population.
4.3. Bland and Altman
The average difference between mean TsB and TcB according to the Bland and Altman method was −29.68 mg/l [14]. This inaccuracy was greater than the observation of Oyapero, Raimondi, Romagnoli [6] [9] [18]. It is worth noting that we worked with a black population and previous studies have shown that the bias between TcB and TsB values was higher in black subjects [15].
4.4. Differential Analysis
Based on concordance correlation coefficient estimate for different levels of TcB thresholds, for TcB values below 100 mg/l, a fair agreement was observed. This finding is similar to those found in similar studies [14] [15] [19] [20] [21].
4.5. Potential Applications
In this setting, the majority of the babies aged more than 3 days at inclusion, the potential applications of our findings may be scarce for early screening. However, as the agreement was higher after 2 days of life, a recommendation of systematic screening of jaundice using TcB in case of early discharge can be raised [22] [23]. In addition, this strategy could also target and prioritize all the babies at risk of hyperbilirubinemia born from mothers of O+ blood group and those mothers with a past story of babies having suffered of neonatal jaundice.
5. Study Limitations
Though this study provides some information on the usefulness of transcutaneous bilirubin measurement on dark skinned neonates, we acknowledge some limitations. The first question is whether taking into account or not the different color tones declined on black skin for the sensitivity of transcutaneous bilirubinemia. As this point is still controversial, in our study, we considered that the whole population had a homogeneous skin tone through visual observation [22]. Our hypothesis could thus limit the validity of our results and suggest further studies on the different categories of black skin tones of our newborns. The second point is around the optimal delay to use this method; the age of our screened population, not homogenous, may have reduced the sensitivity of this method for babies aged less than 72 hours of life.
6. Conclusion
This study revealed a strong linear correlation between transcutaneous bilirubin (TcB) and total serum bilirubin (TsB), but a poor agreement between the two measurements. Moreover, the TcB overestimates the TsB measurements, therefore, if used, the threshold should be adjusted. To this stage, we can recommend the use of TcB in our context, for screening of jaundice during home follow-up of neonates after two days of life in case of early discharge.