Transcutaneous bilirubin level to predict hyperbilirubinemia in preterm neonates

Dewi Rahmawati; Mahendra Tri Arif Sampurna; Risa Etika; Martono Tri Utomo; Arend F. Bos

doi:10.12688/f1000research.22264.1

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Research Article

Transcutaneous bilirubin level to predict hyperbilirubinemia in preterm neonates

[version 1; peer review: 2 approved with reservations]

Dewi Rahmawati¹, Mahendra Tri Arif Sampurna ¹, Risa Etika¹, Martono Tri Utomo¹, Arend F. Bos²

Dewi Rahmawati¹, Mahendra Tri Arif Sampurna ¹, [...] Risa Etika¹, Martono Tri Utomo¹, Arend F. Bos²

PUBLISHED 28 Apr 2020

Author details Author details

¹ Department of Pediatrics, Dr. Soetomo Academic Teaching Hospital, Faculty of Medicine Universitas Airlangga, Surabaya, Indonesia
² Department of Pediatrics, Beatrix Children Hospital, Universitair Medisch Centrum Groningen, Groningen, 9713 GZ, The Netherlands

Dewi Rahmawati
Roles: Data Curation, Formal Analysis, Writing – Original Draft Preparation

Mahendra Tri Arif Sampurna
Roles: Conceptualization, Funding Acquisition, Methodology, Supervision, Validation, Writing – Review & Editing

Risa Etika
Roles: Supervision

Martono Tri Utomo
Roles: Supervision

Arend F. Bos
Roles: Supervision, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

Abstract

Background: Hyperbilirubinemia is common in neonates, with higher prevalence among preterm neonates, which can lead to severe hyperbilirubinemia. Assessment of total serum bilirubin (TSB) and use of a transcutaneous bilirubinometer (TcB) are existing methods to identify and predict hyperbilirubinemia. This study aimed to determine TcB cut-off values during the first day for preterm neonates to predict hyperbilirubinemia at 48 and 72 hours.
Methods: A total of 90 neonates born ≤35 weeks were included in the study. They were divided into two groups (Group I: 1000-1500 grams; Group II: 1501-2000 grams). The bilirubin level was measured on the sternum using TcB at the ages of 12, 24, and 72 h. TSB measurements were taken on the third day or if TcB level reached ± 1.24 mg/dL phototherapy threshold and if TcB showed abnormal results (Group I: 5.76-8.24 mg/dL; Group II: 8.76-11.24 mg/dL). Hyperbilirubinemia was defined as TSB ≥7 mg/dL for group I and >10 mg/dL for group II.
Results: In total, 38 group I neonates and 48 group II neonates were observed. Almost half of neonates in group I (44.7%) were suffering from hyperbilirubinemia at the age of 48 hours, with 45.8% of group II at the age of 72 hours. To predict hyperbilirubinemia at the age of 48 hours, the best 24-hour-age TcB cut-off values were calculated to be 4.5 mg/dL for group I and 5.8 mg/dL for group II. To predict hyperbilirubinemia at the age of 72 hours, we determined 24-hour-age TcB value of 5.15 mg/dL for group II.
Conclusion: TcB values in the early days of life can be used as hyperbilirubinemia predictors on the following days for preterm neonates. Close monitoring should be managed for those with TcB values higher than the calculated cut-off values.

Keywords

transcutaneous bilirubin, preterm neonates, predict, hyperbilirubinemia

Corresponding author: Mahendra Tri Arif Sampurna

Competing interests: No competing interests were disclosed.

Grant information: This research was funded by a research grant No. 886/UN3/2018 from the Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright: © 2020 Rahmawati D et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Rahmawati D, Sampurna MTA, Etika R et al. Transcutaneous bilirubin level to predict hyperbilirubinemia in preterm neonates [version 1; peer review: 2 approved with reservations]. F1000Research 2020, 9:300 (https://doi.org/10.12688/f1000research.22264.1) First published: 28 Apr 2020, 9:300 (https://doi.org/10.12688/f1000research.22264.1) Latest published: 08 Oct 2020, 9:300 (https://doi.org/10.12688/f1000research.22264.3)

Introduction

Hyperbilirubinemia is a common condition occurring in neonatal periods¹, with a prevalence of around 60% in term neonates and 80% in preterm neonates. Preterm neonates have greater risk of severe hyperbilirubinemia, which can lead to encephalopathy². This condition is preventable if early detection and prompt treatment can be arranged and managed properly^1,3,4.

Visual assessment is not reliable especially in the first 24–48 hours, since only 80% of jaundiced babies can be recognized visually if the bilirubin level reaches > 6 mg/dL^5–8. High bilirubin levels can be dangerous, since preterm neonates have a greater risk of low bilirubin kernicterus².

Total serum bilirubin (TSB) measurement remains the gold standard for diagnosing hyperbilirubinemia. The drawbacks of this procedure, however, are that it is painful, causes stress to the neonates, has a greater risk of infection, and needs a couple of hours to get the results^9–11.

Trancutaneous bilirubinometry (TcB) is a non-invasive procedure to identify hyperbilirubinemia. A number of studies have been conducted to validate TcB to assess whether it can be used safely. These found that TcB has good correlations with TSB. The use of TcB can also reduce the need for blooding sampling by 41–73%^10,12,13.

Due to the burdens of an occurrence of hyperbilirubinemia, its early detection and prediction are crucial. TSB or TcB is recommended to predict neonatal hyperbilirubinemia for neonates with >35 weeks of gestation^13–15. Some studies using TcB to predict hyperbilirubinemia have already been conducted, but all of them recruited only late preterm and term neonates^5,16. For preterm neonates, one study was already conducted using TSB measurement at the age of 6 until 24 hours to predict hyperbilirubinemia in the following hours or days⁴. As far as the researchers know, there has been no previous study using TcB to predict hyperbilirubinemia for preterm neonates. Therefore, the aim of this study was to use TcB to predict hyperbilirubinemia in preterm neonates to prevent complications since visual assessment is no longer reliable.

Methods

Study background and ethical approval

This was a cohort study conducted in the Neonatal Intensive Care Unit (NICU) at Dr Soetomo General Hospital for 5 months (September 2018–January 2019). This study was approved by Dr. Soetomo General Hospital Surabaya Ethics Committee (No. 0586/KEPK/Ix/2018). An informed consent was signed by parents after they understood the information for consent. Study size retrieved in this research used purposive sampling with inclusion and exclusion criteria (a flow diagram is available as Extended data)^17,18 during the research period. The sample size that we retrieved was estimated by applying Hulley et al.¹⁹ formulation of which confidence interval was at 95%, coefficient correlation at 0.84 and standard deviation of 1.8⁴. Therefore, we applied minimum sample of 20 samples for each group, classified by infants’ body weight in certain ranges. While staying in accord with the minimum sample size, we expanded our samples up to 45 infants for each group with total sample of 90 infants. Yet, we had excluded four data due to missing TSB measurement.

Race and thickness of melanin layer of skin tissue were taken into account as confounding variables, and as variables able to modify and differ the outcomes of others. Therefore, to control for study bias, the subjects addressed for this study were those subjects which had similar ethnic backgrounds, which were Malay Mongoloid.

Participant eligibility

The inclusion criteria were: 1) born at ≤35 weeks of gestational age and with a birth weight of <2000 g, and 2) parental consent by signing a form. The exclusion criteria were: 1) being diagnosed as hyperbilirubinemia at the age of 12 hours, 2) having any major congenital anomaly, 3) being discharged from hospital at an age of less than 3 days. Neonates who received phototherapy before the observation was done, missed TSB, or voluntarily resigned from this study were excluded from the study. The subjects recruited were divided into two groups, neonates with birth weights of 1001–1500 g (Group I) and 1501–2000 g (Group II).

Variables

The bilirubin level of each neonate was measured on the sternum by TcB (Dräger® Jaundice Meter 105) at the age of 12 hours, 24 hours, and 72 hours with ±3 hours tolerance (the TcB measurement could be taken within 3 hours before/after the exact time). The TSB measurement was taken for each neonate at the age of 3 days or if the TcB bilirubin level was ≥5.76 mg/dl for group I and TcB ≥8.76 mg/dl for group II and it had to be taken within 6 hours before/after the TcB measurement. The TSB measurement also had to be taken if the TcB measurement showed abnormal results. Hyperbilirubinemia was defined as TSB ≥7 mg/dl for preterm neonates with birth weights of 1000–1500 g and TSB >10 mg/dl for preterm neonates with birth weights of 1501–2000 g.

Statistical analysis

The data was analysis by Microsoft Office Excel, IBM SPSS Statistics Version 21. We performed receiver operating characteristic (ROC) curve analysis to determined cut off point of TcB level to predict hyperbilirubinemia at the age of 48 and 72 hours. We calculated the specificity, sensitivity, positive predicted value (PPV), negative predicted value (NPV), and likelihood ratio.

Results

There were 90 preterm neonates recruited for this study, 40 of whom weighed 1000–1500 grams (Group I) and 50 of whom weighed 1501–2000 grams (Group II). Only 38 neonates of group I and 48 neonates of group II were observed until the end of the study. Four neonates were excluded from the study due to missing TSB results.

Maternal and neonatal characteristics are shown in Table 1. For group I, the mean gestational age of group I was 32.29 ± 1.84 weeks, with a mean birth weight of 1273.68 ± 177.34 grams. Meanwhile for group II the mean gestational age was 33.69 ± 1.26 weeks and a mean birth weight of 1792.70 ± 145.86 grams. Based on risk factors of ABO-incompatibility, one subject of group I who suffered hyperbilirubinemia at the age of 48 hours. Meanwhile, two subjects in group II suffered hyperbilirubinemia at the age of 48 hours and another two subjects at the age of 72 hours at the end of observation, the maximum bilirubin level was 15.2 mg/dl for group I and 16.33 mg/dL for group II. Most neonates of group I (44.7%) suffered hyperbilirubinemia at the age of 48 hours, while most neonates of group II (45.8%) at the age of 72 hours (Figure 1). We found the TSB mean in group I at the age of 24, 48, and 72 hours to be 7.9 mg/dL, 9.16 mg/dL, and 9.3 mg/dL respectively, and 11.01 mg/dL, 10.23 mg/dL, and 11.04 mg/dL respectively, in group II.

Table 1. Maternal and neonatal characteristics of subjects.

Maternal characteristics	Group I (n=38) n(%)	Group II (n=48) n(%)
Gestational Age (weeks) (mean ±SD)	32.29 ± 1.84	33.69 ± 1.26
Mode of delivery - spontaneous - c-section - vacuum	11(29) 26(68) 1(3)	9(19) 38(80) 1(1)
Maternal Blood Type A B O AB	7(18.4) 14(36.80) 16(42.10) 1(2.70)	12(25) 10(20.80) 19(39.60) 7(14.60)
Neonatal characteristics	Group I (n=38) n (%)	Group II (n=48) n (%)
Birth Weight (g) (mean ±SD)	1273.68 ± 177.34	1792.70 ± 145.86
Hematocrit (%) (mean ±SD)	48.04 ± 10.47	46.99± 8.48
Gender Male Female	19 (50) 19 (50)	30(62.50) 18(37.50)
Neonatal blood-type A B O AB	4(10.50) 11(28.90) 21(55.30) 2(5.30)	9(18.8) 10(20.8) 24(50) 5(10.4)

*Descriptive analysis was used.

Maternal and neonatal rhesus were positive.

Figure 1. Incidence of hyperbilirubinemia in preterm neonates.

TcB bilirubin level to predict hyperbilirubinemia at the age of 48 hours in group I preterm neonates

A ROC curve was constructed to determine a hyperbilirubinemia threshold based on the data collected. We found that the AUC (area under curve) of the TcB bilirubin level at the age of 12 hours to predict hyperbilirubinemia at the age of 48 hours for group I was 0.804 (p 0.002) with a cut-off point of 2.35 mg/dL (sensitivity 79.20% and specificity 71.40%). For the TcB bilirubin level at the age of 24 hours to predict hyperbilirubinemia at the age of 48 hours, we found an AUC 0.771 (p 0.06), with a cut-off point of 4.50mg/dl (sensitivity 87.50% and specificity 64.26%) (Figure 2a, Figure 2b, Table 2).

Figure 2. Transcutaneous bilirubinometer (TcB) level to predict hyperbilirubinemia at the age of 48 hours.

(a) Receiver operating characteristic (ROC) curve for TcB at the age of 12 hours to predict hyperbilirubinemia at the age of 48 hours for group I. (b) ROC curve for TcB at the age of 24 hours to predict hyperbilirubinemia at the age of 48 hours for group I. (c) ROC curve for TcB at the age of 12 hours to predict hyperbilirubinemia at the age of 48 hours for group II. (d) ROC curve for TcB at the age of 24 hours to predict hyperbilirubinemia at the age of 48 hours for group II.

Table 2. Transcutaneous bilirubinometer (TcB) bilirubin level cut-off point to predict hyperbilirubinemia at the age of 48 hours for group I.

TcB level Cut-off (mg/dl)		Group I
TcB level Cut-off (mg/dl)		Sn (%)	Sp (%)	PPV (%)	NPV (%)	LR
12 hours old	2.35	79.2	71.4	82.60	66.67	2.78
24 hours old	4.5	87.5	64.3	80.77	64.26	2.45

^†Receiver operative characteristic curve analysis was used. Sn, sensitivity; Sp, specificity; PPV, positive predictive value; NPV, negative predictive value; LR, likelihood ratio.

TcB bilirubin level to predict hyperbilirubinemia at the age of 48 hours in group II preterm neonates

We found the AUC of TcB bilirubin levels at the age of 12 hours to predict hyperbilirubinemia at the age of 48 hours for group II was 0.658 (p = 0.083), with a cut-off point of 3.05 mg/dL (sensitivity 66.7% and specificity 66.7%). The AUC of TcB bilirubin level at the age of 24 hours was 0.732 (p = 0.011), with a cut-off point of 5.80 mg/dL (sensitivity 80% and specificity 63.6%). (Figure 2c, Figure 2d and Table 3).

Table 3. TcB Bilirubin Level Cut-off Point to Predict Hyperbilirubinemia at the age of 48 hours for Group II.

TcB level Cut-off (mg/dl)		Group II
TcB level Cut-off (mg/dl)		Sn (%)	Sp (%)	PPV (%)	NPV (%)	LR
12 hours old	3.05	66.7	66.7	47.62	81.48	2.00
24 hours old	5.85	80	63.6	50.00	87.50	2.19

^†Receiver operative characteristic curve analysis was used. Sn, sensitivity; Sp, specificity; PPV, positive predictive value; NPV, negative predictive value; LR, likelihood ratio.

TcB bilirubin level to predict hyperbilirubinemia at the age of 72 hours in Group I preterm neonates

The TcB bilirubin level of group I at the age of 12 hours, 24 hours, and 48 hours to predict hyperbilirubinemia at the age of 72 hours showed a very weak AUC, which were 0.243 (p = 0.386); 0.297 (p = 0.494); 0.500 (p = 1.000) respectively, therefore no cut-off point could be determined.

TcB bilirubin level to predict hyperbilirubinemia at the age of 72 hours in Group II preterm neonates

The TcB bilirubin level of group II at the age of 12 hours to predict hyperbilirubinemia at the age of 72 hours showed a weak AUC (0.499; p = 0.991) with a cut-off point of 2.65 mg/dL (sensitivity 60% and specificity 46%). At the age of 24 hours, we found TcB AUC 0.751 (p = 0.008), with a cut-off point of 5.15 mg/dL (sensitivity 74.3% and specificity 76.9%). Meanwhile, at the age of 48 hours the TcB AUC was 0.731 (p = 0.015), with a cut-off point 8.65 mg/dL (sensitivity 67.6% and specificity 61%) (Figure 3a–c and Table 4).

Figure 3. Transcutaneous bilirubinometer (TcB) level to predict hyperbilirubinemia at the age of 72 hours.

(a) Receiver operating characteristic (ROC) curve for TcB at the age of 12 hours to predict hyperbilirubinemia at the age of 72 hours for group II. (b) ROC curve for TcB at the age of 24 hours to predict hyperbilirubinemia at the age of 72 hours for group II. (c) ROC curve for TcB at the age of 48 hours to predict hyperbilirubinemia at the age of 72 hours for group II.

Table 4. TcB Bilirubin Level Cut off Point to Predict Hyperbilirubinemia at the age of 72 hours for Group II.

TcB level Cut-off (mg/dl)		Group II
TcB level Cut-off (mg/dl)		Sn (%)	Sp (%)	PPV (%)	NPV (%)	LR
12 hours old	2.65	60	46	75.00	30.00	1.11
24 hours old	5.15	74.3	76.9	89.66	52.63	3.22
48 hours old	8.65	67.6	61	82.75	42.10	1.78

^†Receiver operative characteristic curve analysis was used. Sn, sensitivity; Sp, specificity; PPV, positive predictive value; NPV, negative predictive value; LR, likelihood ratio.

Discussion

This study has determined a TcB cut-off value of 4.5 mg/dL at the age of 24 hours in group I (1000–1500 grams) and 5.8 mg/dL in group II (1501–2000 grams) as predictive of hyperbilirubinemia at the age of 48 hours. To predict hyperbilirubinemia at the age of 72 hours, this study could not determine any TcB cut-off value for group I (1000–1500 gram) as a result of very weak correlation. The TcB cut-off value of 5.15 mg/dL at the age of 24 hours was determined as the best predictor for hyperbilirubinemia at the age of 72 hours in group II (1501–2000 grams). This cut-off level was established with a sensitivity value ranging from 74.3% to 87.5% at 24 hours after birth. Similar studies have already been conducted, but those studies recruited only late preterm neonates. Lavanya et al. found that TcB values measured in the first 24–48 hours of life can predict hyperbilirubinemia at an age of more than 48 hours²⁰. Bansal et al. determined that TcB values of >4.6 mg/dl at the age of 12–24 hours (sensitivity 83.09%; specificity 87.37%; PPV 90.4% and NPV 78.3%) and >7.4 mg/dl at the age of 24–48 hours (sensitivity 93.55%; specificity 82.11%; PPV 81.69% and NPV 95.35%) are predictors for hyperbilirubinemia in the first 48 hours of life⁵. Other studies conducted used TSB values to predict hyperbilirubinemia in the following days. Mayer recruited preterm neonates weighing 1000–1500 grams and determined a capillary TSB value of 3.55 mg/dl at the age of 12 hours as the best predictor of significant hyperbilirubinemia (sensitivity 94.4%, PPV 98.1%, and NPV 40%)⁴.

Most neonates recruited in this study suffered hyperbilirubinemia before the age of 72 hours old. This study also showed that smaller babies suffered peak incidence earlier (at 48 hours) than larger babies (at 72 hours). Hyperbilirubinemia is more prevalent in preterm neonates^4,5,20) and is usually more severe and has longer duration compared to that in term neonates⁴. This is caused by increased bilirubin production, decreased bilirubin excretion, increased enterohepatic circulation, lower albumin level and a weak albumin-bilirubin bond^11,21. Early detection of hyperbilirubinemia will decrease its mortality and morbidity. The need for reliable methods to predict hyperbilirubinemia is important. The use of a noninvasive procedure, like TcB, in the first 6–24 hours of life is recommended as a marker of bilirubin production²² and it can decrease the need for blood sampling²³.

In group I at the ages of 24, 48, and 72 hours, we found TSB mean values of 7.9, 9.16, and 9.3 mg/dL, respectively; in group II, these values were 11.01, 10.23, and 11.04 mg/dL, respectively. This is similar to previous study which found that TSB mean values in the first 5 days of the lives of preterm neonates were 10–12 mg/dL²⁴. However, this study found there were preterm neonates who reached a TSB value >15 mg/dL in the first 72 hours. However, it is possible for preterm neonates to have high bilirubin levels in the first days of life, which can lead to hyperbilirubinemia complications if not recognized and treated properly. The previous study conducted by Bhutani et al. also indicated that neonates who suffer from hyperbilirubinemia in the following days had higher percentiles on the first day of life²⁵. Therefore, the American Academy of Pediatrics (AAP) recommends routine checks of TSB or TcB along with risk factor assessments in the first days of life¹⁴.

To the knowledge of the researchers, this was the first study conducted to predict hyperbilirubinemia in preterm neonates weighing 1000–2000 grams using TcB. One limitation of the study was that it could not determine TcB cut-off values to predict hyperbilirubinemia at the age of 72 hours for preterm neonates weighing 1000–1500 grams due to a lack of subjects able to complete the study, since most had already developed significant hyperbilirubinemia by this time. This, it is hoped that future similar studies will be able to recruit larger populations.

Conclusion

TcB values in the early days of life can be used as a predictor of hyperbilirubinemia in the following days for preterm neonates. It is possible for preterm neonates to have high bilirubin levels in the first few days of their lives. Therefore, daily measurement of TcB is important for early identification of hyperbilirubinemia, especially in order to prevent complications in certain more vulnerable preterm neonates. Close monitoring should be arranged for those who have TcB values higher than the cut-off values.

Data availability

Underlying data

Figshare: Datasheet TcB and TSB - Group 1. https://doi.org/10.6084/m9.figshare.11948490.v1²⁶.

This project contains data gathered for neonates in group 1 (those 1000–1500 grams).

Figshare: TcB Level and TSB-MTA - Group 2. https://doi.org/10.6084/m9.figshare.11948529.v1²⁷.

This project contains data gathered for neonates in group 2 (those 1500–2000 grams).

Extended data

Figshare: Supplemental File - Flow Chart Study of TcB and TSB. https://doi.org/10.6084/m9.figshare.12017586.v1¹⁸.

This project contains a study flow diagram.

Reporting guidelines

Figshare: STROBE checklist for ‘Transcutaneous bilirubin level to predict hyperbilirubinemia in preterm neonates’. https://doi.org/10.6084/m9.figshare.11991672.v2¹⁷.

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

Acknowledgements

We would like to thank neonatal unit at Dr. Soetomo Academic Teaching Hospital members who also gave contributions within the study progress, as follows:

1. Siti Annisa Dewi Rani, MD and Muhammad Pradhika Mapindra, MD as research assistants whom are employed in our Neonatal Unit for data editing

2. Spencer Lemaich who contributed to proofread the manuscript in English;

3. Head of each Neonatal Unit ward: Mrs. Pamiani, Mrs. Wahyu, and Mrs. Peni for supporting our study and coordinating each of their nursing team to collaborate with us;

4. All our colleagues in Neonatal Unit at Dr. Soetomo Academic Teaching Hospital.

Faculty Opinions recommended

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Version 3

VERSION 3 PUBLISHED 28 Apr 2020

Author details Author details

Dewi Rahmawati
Roles: Data Curation, Formal Analysis, Writing – Original Draft Preparation

Mahendra Tri Arif Sampurna
Roles: Conceptualization, Funding Acquisition, Methodology, Supervision, Validation, Writing – Review & Editing

Risa Etika
Roles: Supervision

Martono Tri Utomo
Roles: Supervision

Arend F. Bos
Roles: Supervision, Writing – Review & Editing

Competing interests

No competing interests were disclosed.

Grant information

This research was funded by a research grant No. 886/UN3/2018 from the Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Article Versions (3)

version 3

Revised

Published: 08 Oct 2020, 9:300

https://doi.org/10.12688/f1000research.22264.3

version 2

Revised

Published: 07 Sep 2020, 9:300

https://doi.org/10.12688/f1000research.22264.2

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Published: 28 Apr 2020, 9:300

https://doi.org/10.12688/f1000research.22264.1

© 2020 Rahmawati D et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Rahmawati D, Sampurna MTA, Etika R et al. Transcutaneous bilirubin level to predict hyperbilirubinemia in preterm neonates [version 1; peer review: 2 approved with reservations]. F1000Research 2020, 9:300 (https://doi.org/10.12688/f1000research.22264.1)

NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.

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Open Peer Review

Version 1

VERSION 1

PUBLISHED 28 Apr 2020

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Reviewer Report 21 May 2020

Tina M. Slusher, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA

Approved with Reservations

https://doi.org/10.5256/f1000research.24559.r62845

This study is an interesting study looking at the correlation between transcutaneous bilirubin (TcB) and serum bilirubin and the predictive value of subsequent clinically significant hyperbilirubinemia in neonates. However, there are some problems with the study that need to be ... Continue reading

They authors state that TcB has not been used in premature infants with the exception of late preterms. However, in a systematic review by Nager et al. most of the 22 articles they mention include very preterm infants. Perhaps the authors need to mean to say in their population but this needs to be clarified.
Each country does indeed need to develop their own criteria for diagnosis and treatment levels of hyperbilirubinemia based on risk in their environment, treatments available and other specifics related to their own country. However, authors do need to tell us where there cutoffs for each group came from---are the in country normal, standard cutoffs for their hospital or region or how were they selected.
Numbers too small to extrapolate widely to Indonesia or beyond.
Rhesus of mothers and infants missing; G6PD status missing if not done state that.
Although not a major problem or limitation this article could be improved by having a native English speaker read and make minor edits throughout.

Is the work clearly and accurately presented and does it cite the current literature?

Partly
Is the study design appropriate and is the work technically sound?

Partly
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Partly
Are all the source data underlying the results available to ensure full reproducibility?

Partly
Are the conclusions drawn adequately supported by the results?

Partly

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Pediatric Global Health, Neonatal Hyperbilirubinemia, Pediatric Critical Care

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

CITE

Report a concern

Author Response 07 Sep 2020

Mahendra Tri Arif Sampurna, Department of Pediatrics, Dr. Soetomo Academic Teaching Hospital, Faculty of Medicine Universitas Airlangga, Surabaya, Indonesia

07 Sep 2020

Author Response

1). Reviewer's comments:

This study is an interesting study looking at the correlation between transcutaneous bilirubin (TcB) and serum bilirubin and the predictive value of subsequent clinically significant hyperbilirubinemia ... Continue reading 1). Reviewer's comments:

This study is an interesting study looking at the correlation between transcutaneous bilirubin (TcB) and serum bilirubin and the predictive value of subsequent clinically significant hyperbilirubinemia in neonates. However, there are some problems with the study that need to be addressed.

The authors state that TcB has not been used in premature infants with the exception of late preterms. However, in a systematic review by Nager et al. most of the 22 articles they mention include very preterm infants. Perhaps the authors need to mean to say in their population but this needs to be clarified.

Author's response:
Dear Reviewer,
Thank you for your comments.

Yes, indeed you are right, thanks for your suggestion. What we meant here is similar with the study by Mayer (Mayer I, Gursoy T, Hayran M, Ovalı F. Value of twelfth-hour bilirubin level in predicting significant hyperbilirubinemia in preterms Infants. J Clin Med Res. 2014;6(3):190–6) but they used TSB to predict significant hyperbilirubinemia later on. Practice in our hospital so far is using Kramer and few TSB measurement to start phototherapy. So, we give another alternative which is non-invasive, easy to use, and applicable in our setting in Indonesia.

We added in our introduction as :

In a systematic review by Nagar et al.¹⁶, most of 22 articles studied the accuracy of TcB to estimate TSB, and TcB could be used in clinical practice to reduce blood sampling. Some studies have used TcB to predict significant hyperbilirubinemia in subsequent days, but all of them recruited only late preterm and term neonates ^5,17 . For preterm neonates, one study was already conducted using TSB measurements at 6- 24 hours to predict hyperbilirubinemia in the following hours or days ⁴ . As far as the researchers know, there have been no previous studies using TcB to predict subsequent, significant hyperbilirubinemia for older preterm neonates. Therefore, this study aimed to use TcB to predict hyperbilirubinemia in preterm neonates to prevent complications since visual assessment is unreliable.

2) Reviewer's comment: Each country does indeed need to develop their own criteria for diagnosis and treatment levels of hyperbilirubinemia based on risk in their environment, treatments available and other specifics related to their own country. However, authors do need to tell us where there cutoffs for each group came from---are the in country normal, standard cutoffs for their hospital or region or how were they selected

Author's response:
Thank you for your comments.
We added in our method à variables section as follows:

The bilirubin level of each neonate was measured on the sternum by TcB (Dräger® Jaundice Meter 105) at 12 hours, 24 hours, and 72 hours with ±3 hours tolerance (the TcB measurement could be taken within three hours before/after the exact time). The TSB measurement was taken for each neonate at the age of three days or if the TcB bilirubin level was ≥5.76 (7-1.24) mg/dL for Group I and TcB ≥8.76 (10-1.24) mg/dL for Group II and it had to be taken within six hours before or after the TcB measurement (assumption of TcB standard deviation being ±1.24 mg/dL). The TSB measurement also had to be taken if the TcB measurement showed abnormal results. Hyperbilirubinemia was defined as TSB ≥7 mg/dL for preterm neonates with birth weights of 1000–1500 g and TSB >10 mg/dL for preterm neonates with birth weights of 1501–2000 g as suggested by the Kaplan et al., in Martin’s Neonatal-Perinatal Medicine (2011).²¹

3). Reviewer's comment:
Numbers too small to extrapolate widely to Indonesia or beyond.

Author's response:
Dear Reviewer,
This is the study limitation and has been addressed in discussion section.
We added in the discussion section in the last paragraph:

A limitation of the study was that it could not determine TcB cut-off values to predict hyperbilirubinemia at the age of 72 hours for preterm neonates weighing 1000–1500 grams due to a lack of subjects able to complete the study, since most had already developed significant hyperbilirubinemia by this time.

4). Reviewer's comment:
Rhesus of mothers and infants missing; G6PD status missing if not done state that.

Author's response:
Dear Reviewer,
Thank you for your comments.

We even hardly measured Blood Group ABO and Rhesus of the mother and babies since the babies are not yellow. We have not used it as screening program. G6PD measurement is not affordable for our majority of citizen. We need to give consent first when the bilirubin is not yet decrease and rise again after intensive phototherapy, or there is sign of haemolysis

Thank you for your suggestion. Indeed, this is also our limitation that we added in the discussion section on the last paragraph

To the knowledge of the researchers, this was the first study conducted to predict significant hyperbilirubinemia in preterm neonates weighing 1000–2000 grams using TcB. A limitation of the study was that it could not determine TcB cut-off values to predict hyperbilirubinemia at the age of 72 hours for preterm neonates weighing 1000–1500 grams due to a lack of subjects able to complete the study, since most had already developed significant hyperbilirubinemia by this time. The mothers’ rhesus blood groups and the babies’ G6PD levels were not obtained. Hopefully, future similar studies will be able to recruit larger populations.

5) Reviewer's comment:
Although not a major problem or limitation this article could be improved by having a native English speaker read and make minor edits throughout

Author's response:
Dear Reviewer,
Thank you for your comments

We have already proofread this manuscript by Proofreading Service.

1). Reviewer's comments:

This study is an interesting study looking at the correlation between transcutaneous bilirubin (TcB) and serum bilirubin and the predictive value of subsequent clinically significant hyperbilirubinemia in neonates. However, there are some problems with the study that need to be addressed.

The authors state that TcB has not been used in premature infants with the exception of late preterms. However, in a systematic review by Nager et al. most of the 22 articles they mention include very preterm infants. Perhaps the authors need to mean to say in their population but this needs to be clarified.

Author's response:
Dear Reviewer,
Thank you for your comments.

Yes, indeed you are right, thanks for your suggestion. What we meant here is similar with the study by Mayer (Mayer I, Gursoy T, Hayran M, Ovalı F. Value of twelfth-hour bilirubin level in predicting significant hyperbilirubinemia in preterms Infants. J Clin Med Res. 2014;6(3):190–6) but they used TSB to predict significant hyperbilirubinemia later on. Practice in our hospital so far is using Kramer and few TSB measurement to start phototherapy. So, we give another alternative which is non-invasive, easy to use, and applicable in our setting in Indonesia.

We added in our introduction as :

In a systematic review by Nagar et al.¹⁶, most of 22 articles studied the accuracy of TcB to estimate TSB, and TcB could be used in clinical practice to reduce blood sampling. Some studies have used TcB to predict significant hyperbilirubinemia in subsequent days, but all of them recruited only late preterm and term neonates ^5,17 . For preterm neonates, one study was already conducted using TSB measurements at 6- 24 hours to predict hyperbilirubinemia in the following hours or days ⁴ . As far as the researchers know, there have been no previous studies using TcB to predict subsequent, significant hyperbilirubinemia for older preterm neonates. Therefore, this study aimed to use TcB to predict hyperbilirubinemia in preterm neonates to prevent complications since visual assessment is unreliable.

2) Reviewer's comment: Each country does indeed need to develop their own criteria for diagnosis and treatment levels of hyperbilirubinemia based on risk in their environment, treatments available and other specifics related to their own country. However, authors do need to tell us where there cutoffs for each group came from---are the in country normal, standard cutoffs for their hospital or region or how were they selected

Author's response:
Thank you for your comments.
We added in our method à variables section as follows:

The bilirubin level of each neonate was measured on the sternum by TcB (Dräger® Jaundice Meter 105) at 12 hours, 24 hours, and 72 hours with ±3 hours tolerance (the TcB measurement could be taken within three hours before/after the exact time). The TSB measurement was taken for each neonate at the age of three days or if the TcB bilirubin level was ≥5.76 (7-1.24) mg/dL for Group I and TcB ≥8.76 (10-1.24) mg/dL for Group II and it had to be taken within six hours before or after the TcB measurement (assumption of TcB standard deviation being ±1.24 mg/dL). The TSB measurement also had to be taken if the TcB measurement showed abnormal results. Hyperbilirubinemia was defined as TSB ≥7 mg/dL for preterm neonates with birth weights of 1000–1500 g and TSB >10 mg/dL for preterm neonates with birth weights of 1501–2000 g as suggested by the Kaplan et al., in Martin’s Neonatal-Perinatal Medicine (2011).²¹

3). Reviewer's comment:
Numbers too small to extrapolate widely to Indonesia or beyond.

Author's response:
Dear Reviewer,
This is the study limitation and has been addressed in discussion section.
We added in the discussion section in the last paragraph:

A limitation of the study was that it could not determine TcB cut-off values to predict hyperbilirubinemia at the age of 72 hours for preterm neonates weighing 1000–1500 grams due to a lack of subjects able to complete the study, since most had already developed significant hyperbilirubinemia by this time.

4). Reviewer's comment:
Rhesus of mothers and infants missing; G6PD status missing if not done state that.

Author's response:
Dear Reviewer,
Thank you for your comments.

We even hardly measured Blood Group ABO and Rhesus of the mother and babies since the babies are not yellow. We have not used it as screening program. G6PD measurement is not affordable for our majority of citizen. We need to give consent first when the bilirubin is not yet decrease and rise again after intensive phototherapy, or there is sign of haemolysis

Thank you for your suggestion. Indeed, this is also our limitation that we added in the discussion section on the last paragraph

To the knowledge of the researchers, this was the first study conducted to predict significant hyperbilirubinemia in preterm neonates weighing 1000–2000 grams using TcB. A limitation of the study was that it could not determine TcB cut-off values to predict hyperbilirubinemia at the age of 72 hours for preterm neonates weighing 1000–1500 grams due to a lack of subjects able to complete the study, since most had already developed significant hyperbilirubinemia by this time. The mothers’ rhesus blood groups and the babies’ G6PD levels were not obtained. Hopefully, future similar studies will be able to recruit larger populations.

5) Reviewer's comment:
Although not a major problem or limitation this article could be improved by having a native English speaker read and make minor edits throughout

Author's response:
Dear Reviewer,
Thank you for your comments

We have already proofread this manuscript by Proofreading Service.

Competing Interests: We declare that no competing interest Close
Report a concern
Respond or Comment

COMMENTS ON THIS REPORT

Author Response 07 Sep 2020

Mahendra Tri Arif Sampurna, Department of Pediatrics, Dr. Soetomo Academic Teaching Hospital, Faculty of Medicine Universitas Airlangga, Surabaya, Indonesia

07 Sep 2020

Author Response

1). Reviewer's comments:

This study is an interesting study looking at the correlation between transcutaneous bilirubin (TcB) and serum bilirubin and the predictive value of subsequent clinically significant hyperbilirubinemia ... Continue reading 1). Reviewer's comments:

This study is an interesting study looking at the correlation between transcutaneous bilirubin (TcB) and serum bilirubin and the predictive value of subsequent clinically significant hyperbilirubinemia in neonates. However, there are some problems with the study that need to be addressed.

The authors state that TcB has not been used in premature infants with the exception of late preterms. However, in a systematic review by Nager et al. most of the 22 articles they mention include very preterm infants. Perhaps the authors need to mean to say in their population but this needs to be clarified.

Author's response:
Dear Reviewer,
Thank you for your comments.

Yes, indeed you are right, thanks for your suggestion. What we meant here is similar with the study by Mayer (Mayer I, Gursoy T, Hayran M, Ovalı F. Value of twelfth-hour bilirubin level in predicting significant hyperbilirubinemia in preterms Infants. J Clin Med Res. 2014;6(3):190–6) but they used TSB to predict significant hyperbilirubinemia later on. Practice in our hospital so far is using Kramer and few TSB measurement to start phototherapy. So, we give another alternative which is non-invasive, easy to use, and applicable in our setting in Indonesia.

We added in our introduction as :

In a systematic review by Nagar et al.¹⁶, most of 22 articles studied the accuracy of TcB to estimate TSB, and TcB could be used in clinical practice to reduce blood sampling. Some studies have used TcB to predict significant hyperbilirubinemia in subsequent days, but all of them recruited only late preterm and term neonates ^5,17 . For preterm neonates, one study was already conducted using TSB measurements at 6- 24 hours to predict hyperbilirubinemia in the following hours or days ⁴ . As far as the researchers know, there have been no previous studies using TcB to predict subsequent, significant hyperbilirubinemia for older preterm neonates. Therefore, this study aimed to use TcB to predict hyperbilirubinemia in preterm neonates to prevent complications since visual assessment is unreliable.

2) Reviewer's comment: Each country does indeed need to develop their own criteria for diagnosis and treatment levels of hyperbilirubinemia based on risk in their environment, treatments available and other specifics related to their own country. However, authors do need to tell us where there cutoffs for each group came from---are the in country normal, standard cutoffs for their hospital or region or how were they selected

Author's response:
Thank you for your comments.
We added in our method à variables section as follows:

The bilirubin level of each neonate was measured on the sternum by TcB (Dräger® Jaundice Meter 105) at 12 hours, 24 hours, and 72 hours with ±3 hours tolerance (the TcB measurement could be taken within three hours before/after the exact time). The TSB measurement was taken for each neonate at the age of three days or if the TcB bilirubin level was ≥5.76 (7-1.24) mg/dL for Group I and TcB ≥8.76 (10-1.24) mg/dL for Group II and it had to be taken within six hours before or after the TcB measurement (assumption of TcB standard deviation being ±1.24 mg/dL). The TSB measurement also had to be taken if the TcB measurement showed abnormal results. Hyperbilirubinemia was defined as TSB ≥7 mg/dL for preterm neonates with birth weights of 1000–1500 g and TSB >10 mg/dL for preterm neonates with birth weights of 1501–2000 g as suggested by the Kaplan et al., in Martin’s Neonatal-Perinatal Medicine (2011).²¹

3). Reviewer's comment:
Numbers too small to extrapolate widely to Indonesia or beyond.

Author's response:
Dear Reviewer,
This is the study limitation and has been addressed in discussion section.
We added in the discussion section in the last paragraph:

A limitation of the study was that it could not determine TcB cut-off values to predict hyperbilirubinemia at the age of 72 hours for preterm neonates weighing 1000–1500 grams due to a lack of subjects able to complete the study, since most had already developed significant hyperbilirubinemia by this time.

4). Reviewer's comment:
Rhesus of mothers and infants missing; G6PD status missing if not done state that.

Author's response:
Dear Reviewer,
Thank you for your comments.

We even hardly measured Blood Group ABO and Rhesus of the mother and babies since the babies are not yellow. We have not used it as screening program. G6PD measurement is not affordable for our majority of citizen. We need to give consent first when the bilirubin is not yet decrease and rise again after intensive phototherapy, or there is sign of haemolysis

Thank you for your suggestion. Indeed, this is also our limitation that we added in the discussion section on the last paragraph

To the knowledge of the researchers, this was the first study conducted to predict significant hyperbilirubinemia in preterm neonates weighing 1000–2000 grams using TcB. A limitation of the study was that it could not determine TcB cut-off values to predict hyperbilirubinemia at the age of 72 hours for preterm neonates weighing 1000–1500 grams due to a lack of subjects able to complete the study, since most had already developed significant hyperbilirubinemia by this time. The mothers’ rhesus blood groups and the babies’ G6PD levels were not obtained. Hopefully, future similar studies will be able to recruit larger populations.

5) Reviewer's comment:
Although not a major problem or limitation this article could be improved by having a native English speaker read and make minor edits throughout

Author's response:
Dear Reviewer,
Thank you for your comments

We have already proofread this manuscript by Proofreading Service.

1). Reviewer's comments:

This study is an interesting study looking at the correlation between transcutaneous bilirubin (TcB) and serum bilirubin and the predictive value of subsequent clinically significant hyperbilirubinemia in neonates. However, there are some problems with the study that need to be addressed.

The authors state that TcB has not been used in premature infants with the exception of late preterms. However, in a systematic review by Nager et al. most of the 22 articles they mention include very preterm infants. Perhaps the authors need to mean to say in their population but this needs to be clarified.

Author's response:
Dear Reviewer,
Thank you for your comments.

Yes, indeed you are right, thanks for your suggestion. What we meant here is similar with the study by Mayer (Mayer I, Gursoy T, Hayran M, Ovalı F. Value of twelfth-hour bilirubin level in predicting significant hyperbilirubinemia in preterms Infants. J Clin Med Res. 2014;6(3):190–6) but they used TSB to predict significant hyperbilirubinemia later on. Practice in our hospital so far is using Kramer and few TSB measurement to start phototherapy. So, we give another alternative which is non-invasive, easy to use, and applicable in our setting in Indonesia.

We added in our introduction as :

In a systematic review by Nagar et al.¹⁶, most of 22 articles studied the accuracy of TcB to estimate TSB, and TcB could be used in clinical practice to reduce blood sampling. Some studies have used TcB to predict significant hyperbilirubinemia in subsequent days, but all of them recruited only late preterm and term neonates ^5,17 . For preterm neonates, one study was already conducted using TSB measurements at 6- 24 hours to predict hyperbilirubinemia in the following hours or days ⁴ . As far as the researchers know, there have been no previous studies using TcB to predict subsequent, significant hyperbilirubinemia for older preterm neonates. Therefore, this study aimed to use TcB to predict hyperbilirubinemia in preterm neonates to prevent complications since visual assessment is unreliable.

2) Reviewer's comment: Each country does indeed need to develop their own criteria for diagnosis and treatment levels of hyperbilirubinemia based on risk in their environment, treatments available and other specifics related to their own country. However, authors do need to tell us where there cutoffs for each group came from---are the in country normal, standard cutoffs for their hospital or region or how were they selected

Author's response:
Thank you for your comments.
We added in our method à variables section as follows:

The bilirubin level of each neonate was measured on the sternum by TcB (Dräger® Jaundice Meter 105) at 12 hours, 24 hours, and 72 hours with ±3 hours tolerance (the TcB measurement could be taken within three hours before/after the exact time). The TSB measurement was taken for each neonate at the age of three days or if the TcB bilirubin level was ≥5.76 (7-1.24) mg/dL for Group I and TcB ≥8.76 (10-1.24) mg/dL for Group II and it had to be taken within six hours before or after the TcB measurement (assumption of TcB standard deviation being ±1.24 mg/dL). The TSB measurement also had to be taken if the TcB measurement showed abnormal results. Hyperbilirubinemia was defined as TSB ≥7 mg/dL for preterm neonates with birth weights of 1000–1500 g and TSB >10 mg/dL for preterm neonates with birth weights of 1501–2000 g as suggested by the Kaplan et al., in Martin’s Neonatal-Perinatal Medicine (2011).²¹

3). Reviewer's comment:
Numbers too small to extrapolate widely to Indonesia or beyond.

Author's response:
Dear Reviewer,
This is the study limitation and has been addressed in discussion section.
We added in the discussion section in the last paragraph:

A limitation of the study was that it could not determine TcB cut-off values to predict hyperbilirubinemia at the age of 72 hours for preterm neonates weighing 1000–1500 grams due to a lack of subjects able to complete the study, since most had already developed significant hyperbilirubinemia by this time.

4). Reviewer's comment:
Rhesus of mothers and infants missing; G6PD status missing if not done state that.

Author's response:
Dear Reviewer,
Thank you for your comments.

We even hardly measured Blood Group ABO and Rhesus of the mother and babies since the babies are not yellow. We have not used it as screening program. G6PD measurement is not affordable for our majority of citizen. We need to give consent first when the bilirubin is not yet decrease and rise again after intensive phototherapy, or there is sign of haemolysis

Thank you for your suggestion. Indeed, this is also our limitation that we added in the discussion section on the last paragraph

To the knowledge of the researchers, this was the first study conducted to predict significant hyperbilirubinemia in preterm neonates weighing 1000–2000 grams using TcB. A limitation of the study was that it could not determine TcB cut-off values to predict hyperbilirubinemia at the age of 72 hours for preterm neonates weighing 1000–1500 grams due to a lack of subjects able to complete the study, since most had already developed significant hyperbilirubinemia by this time. The mothers’ rhesus blood groups and the babies’ G6PD levels were not obtained. Hopefully, future similar studies will be able to recruit larger populations.

5) Reviewer's comment:
Although not a major problem or limitation this article could be improved by having a native English speaker read and make minor edits throughout

Author's response:
Dear Reviewer,
Thank you for your comments

We have already proofread this manuscript by Proofreading Service.

Competing Interests: We declare that no competing interest Close
Report a concern

Views

Reviewer Report 11 May 2020

Claudio Tiribelli, University of Trieste, Trieste, Italy

Approved with Reservations

https://doi.org/10.5256/f1000research.24559.r62844

This is an interesting study investigating in preterm neonates (PTNs) the predictive value of the bilirubin level assessed by transcutaneous technique (TcB) for hyperbilirubinemia (HB). 90 PTNs were and divided into two groups according to the weight (1500 g as diving value). Bilirubin was prospectively measured at different time points (12, 24, 48, and 72 h). Bilirubin level was confirmed by serum bilirubin measurement (TSB) if the TcB was “increased”. ROC curves were used to assess a 24 h TcB value predicting 48 and 72 h HB. Although the data may be of interest, the study suffers several intrinsic weaknesses what must be addressed before being considered further.

Major Critiques:

The indication when TSB was measured is unclear and confusing. In the abstract it is stated that TSB was assessed before 72 h if TcB showed “abnormal results”. What does this mean? Detailed numerical values must be provided to allow to understand why TSB was performed.
On what basis the TSB value of ≥ 7 mg/dL in group 1 and > 10 mg/dL HB in group 2 was selected? This needs to be scientifically substantiated. At what time this level was measured?
How TSB was measured? Were the lab values confirmed by internal calibration? This must be clarified.
Fig 1 shows that the time course of HB is different in the 2 groups being the bilirubin peak reached 24 h later in group 2. This difference accounts for the different TcB cutoff values. This needs to be considered and addressed in the discussion.
How was the correlation between TcB and TSB at 72h? This information is important to assess the reliability of the two techniques (see also point #3).
The abstract is inaccurate as data reported are different from those indicated in the text (see for example the lack of 48H values).

Is the work clearly and accurately presented and does it cite the current literature?

No
Is the study design appropriate and is the work technically sound?

No
Are sufficient details of methods and analysis provided to allow replication by others?

No
If applicable, is the statistical analysis and its interpretation appropriate?

Partly
Are all the source data underlying the results available to ensure full reproducibility?

No
Are the conclusions drawn adequately supported by the results?

Partly

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Bilirubin, Jaundice

CITE

Report a concern

Author Response 07 Sep 2020

Mahendra Tri Arif Sampurna, Department of Pediatrics, Dr. Soetomo Academic Teaching Hospital, Faculty of Medicine Universitas Airlangga, Surabaya, Indonesia

07 Sep 2020

Author Response
1). Reviewer's Comment: The indication when TSB was measured is unclear and confusing. In the abstract it is stated that TSB was assessed before 72 h if TcB showed “abnormal results”. ... Continue reading
1). Reviewer's Comment: The indication when TSB was measured is unclear and confusing. In the abstract it is stated that TSB was assessed before 72 h if TcB showed “abnormal results”. What does this mean? Detailed numerical values must be provided to allow to understand why TSB was performed.

Author's response:
Dear Reviewer,
Thank you for your comments.

We added in our method à variables section as follows:
The bilirubin level of each neonate was measured on the sternum by TcB (Dräger® Jaundice Meter 105) at 12 hours, 24 hours, and 72 hours with ±3 hours tolerance (the TcB measurement could be taken within three hours before/after the exact time). The TSB measurement was taken for each neonate at the age of three days or if the TcB bilirubin level was ≥5.76 (7-1.24) mg/dL for Group I and TcB ≥8.76 (10-1.24) mg/dL for Group II and it had to be taken within six hours before or after the TcB measurement (assumption of TcB standard deviation being ±1.24 mg/dL). The TSB measurement also had to be taken if the TcB measurement showed abnormal results. Hyperbilirubinemia was defined as TSB ≥7 mg/dL for preterm neonates with birth weights of 1000–1500 g and TSB >10 mg/dL for preterm neonates with birth weights of 1501–2000 g as suggested by the Kaplan et al., in Martin’s Neonatal-Perinatal Medicine (2011).

2). Reviewer's Comment: On what basis the TSB value of ≥ 7 mg/dL in group 1 and > 10 mg/dL HB in group 2 was selected? This needs to be scientifically substantiated. At what time this level was measured?

Author's response:
Dear Reviewer,
Thank you for your comments.

The cut off 7 and 10 mg/dl are based on the recommendation of Martin Fanaroff (Reference source: Kaplan M, Wong R, Sibley E, et al.: Neonatal Jaundice and Liver Disease. In: Martin’s Neonatal-Perinatal Medicine. 2011; 1443–90.) In this recommendation they use birth weight category regardless postnatal age in hours.

3). Reviewer's comment: How TSB was measured? Were the lab values confirmed by internal calibration? This must be clarified.

Author's response:
Dear Reviewer,

Thank you for your comments.
TSB measurements were performed by retrieving peripheral blood samples of each subject.
Added in methods à variables section :
Total serum bilirubin was measured in the central laboratory using SIEMENS Dimension® with a modified Doumas 22 reference method, which is a modification of the diazo method described by Jendrassik and Grof in 1938 23. Internal calibration was completed daily, with a quality control printout. The Indonesian External Quality Assurance Service performed external quality control.

4). Reviewer's comment: Fig 1 shows that the time course of HB is different in the 2 groups being the bilirubin peak reached 24 h later in group 2. This difference accounts for the different TcB cut-off values. This needs to be considered and addressed in the discussion.

Author's comment:
Dear Reviewer,
Thank you for the comment.

We added in the discussion:

It shows that that higher birth weight has opportunity to be hyperbilirubinemia later than the lower birthweight. The lower birthweight has lower threshold bilirubin, because they have higher chance to become encephalopathy in lower bilirubin level (high risk infants). The younger gestational age and lower birth weight, lead to a higher prevalence of infants developing hyperbilirubinemia. It is a result of excessive neonatal red cell hepatic and immaturity of the gastrointestinal system. Prematurely delivered infants have a likelihood of slower maturation of hepatic bilirubin uptake and conjugation.

5). Reviewer's comment: How was the correlation between TcB and TSB at 72h? This information is important to assess the reliability of the two techniques (see also point #3)

Author's response:
Dear Reviewer,
Thank you for your comments.
We actually did not assess the correlation between TcB and TSB at 72 hours of age. We would like to mention our reasons why we did not perform the assessment as the followings:

We were not specifically aiming at performing diagnostic test;

We only discovered fewer observed subjects who had reached observation at 72 hours of age thus the sample size at that age was not abundant in number. Most of the infants underwent phototherapy before 72 hours (group 1). Those infants were excluded from the study for further analysis.

6) Reviewer's Comment: The abstract is inaccurate as data reported are different from those indicated in the text (see for example the lack of 48H values).

Author's response:
Dear Reviewer,

Thank you for noticing. We adapted our abstract accordingly

We also found that there was an unsuitable data between those mentioned in the study abstract and the ones in figures. However, we would like to inform that the proportional data provided in the study abstract is correct already meanwhile the ones in figures were attained by integrating the data percentages. Therefore, we are going to amend and adjust the data provided in abstract.
1). Reviewer's Comment: The indication when TSB was measured is unclear and confusing. In the abstract it is stated that TSB was assessed before 72 h if TcB showed “abnormal results”. What does this mean? Detailed numerical values must be provided to allow to understand why TSB was performed.

Author's response:
Dear Reviewer,
Thank you for your comments.

We added in our method à variables section as follows:
The bilirubin level of each neonate was measured on the sternum by TcB (Dräger® Jaundice Meter 105) at 12 hours, 24 hours, and 72 hours with ±3 hours tolerance (the TcB measurement could be taken within three hours before/after the exact time). The TSB measurement was taken for each neonate at the age of three days or if the TcB bilirubin level was ≥5.76 (7-1.24) mg/dL for Group I and TcB ≥8.76 (10-1.24) mg/dL for Group II and it had to be taken within six hours before or after the TcB measurement (assumption of TcB standard deviation being ±1.24 mg/dL). The TSB measurement also had to be taken if the TcB measurement showed abnormal results. Hyperbilirubinemia was defined as TSB ≥7 mg/dL for preterm neonates with birth weights of 1000–1500 g and TSB >10 mg/dL for preterm neonates with birth weights of 1501–2000 g as suggested by the Kaplan et al., in Martin’s Neonatal-Perinatal Medicine (2011).

2). Reviewer's Comment: On what basis the TSB value of ≥ 7 mg/dL in group 1 and > 10 mg/dL HB in group 2 was selected? This needs to be scientifically substantiated. At what time this level was measured?

Author's response:
Dear Reviewer,
Thank you for your comments.

The cut off 7 and 10 mg/dl are based on the recommendation of Martin Fanaroff (Reference source: Kaplan M, Wong R, Sibley E, et al.: Neonatal Jaundice and Liver Disease. In: Martin’s Neonatal-Perinatal Medicine. 2011; 1443–90.) In this recommendation they use birth weight category regardless postnatal age in hours.

3). Reviewer's comment: How TSB was measured? Were the lab values confirmed by internal calibration? This must be clarified.

Author's response:
Dear Reviewer,

Thank you for your comments.
TSB measurements were performed by retrieving peripheral blood samples of each subject.
Added in methods à variables section :
Total serum bilirubin was measured in the central laboratory using SIEMENS Dimension® with a modified Doumas 22 reference method, which is a modification of the diazo method described by Jendrassik and Grof in 1938 23. Internal calibration was completed daily, with a quality control printout. The Indonesian External Quality Assurance Service performed external quality control.

4). Reviewer's comment: Fig 1 shows that the time course of HB is different in the 2 groups being the bilirubin peak reached 24 h later in group 2. This difference accounts for the different TcB cut-off values. This needs to be considered and addressed in the discussion.

Author's comment:
Dear Reviewer,
Thank you for the comment.

We added in the discussion:

It shows that that higher birth weight has opportunity to be hyperbilirubinemia later than the lower birthweight. The lower birthweight has lower threshold bilirubin, because they have higher chance to become encephalopathy in lower bilirubin level (high risk infants). The younger gestational age and lower birth weight, lead to a higher prevalence of infants developing hyperbilirubinemia. It is a result of excessive neonatal red cell hepatic and immaturity of the gastrointestinal system. Prematurely delivered infants have a likelihood of slower maturation of hepatic bilirubin uptake and conjugation.

5). Reviewer's comment: How was the correlation between TcB and TSB at 72h? This information is important to assess the reliability of the two techniques (see also point #3)

Author's response:
Dear Reviewer,
Thank you for your comments.
We actually did not assess the correlation between TcB and TSB at 72 hours of age. We would like to mention our reasons why we did not perform the assessment as the followings:

We were not specifically aiming at performing diagnostic test;

We only discovered fewer observed subjects who had reached observation at 72 hours of age thus the sample size at that age was not abundant in number. Most of the infants underwent phototherapy before 72 hours (group 1). Those infants were excluded from the study for further analysis.

6) Reviewer's Comment: The abstract is inaccurate as data reported are different from those indicated in the text (see for example the lack of 48H values).

Author's response:
Dear Reviewer,

Thank you for noticing. We adapted our abstract accordingly

We also found that there was an unsuitable data between those mentioned in the study abstract and the ones in figures. However, we would like to inform that the proportional data provided in the study abstract is correct already meanwhile the ones in figures were attained by integrating the data percentages. Therefore, we are going to amend and adjust the data provided in abstract.
Competing Interests: we declare that no competing interests. Close
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Author Response 07 Sep 2020

Mahendra Tri Arif Sampurna, Department of Pediatrics, Dr. Soetomo Academic Teaching Hospital, Faculty of Medicine Universitas Airlangga, Surabaya, Indonesia

07 Sep 2020

Author Response
1). Reviewer's Comment: The indication when TSB was measured is unclear and confusing. In the abstract it is stated that TSB was assessed before 72 h if TcB showed “abnormal results”. ... Continue reading
1). Reviewer's Comment: The indication when TSB was measured is unclear and confusing. In the abstract it is stated that TSB was assessed before 72 h if TcB showed “abnormal results”. What does this mean? Detailed numerical values must be provided to allow to understand why TSB was performed.

Author's response:
Dear Reviewer,
Thank you for your comments.

We added in our method à variables section as follows:
The bilirubin level of each neonate was measured on the sternum by TcB (Dräger® Jaundice Meter 105) at 12 hours, 24 hours, and 72 hours with ±3 hours tolerance (the TcB measurement could be taken within three hours before/after the exact time). The TSB measurement was taken for each neonate at the age of three days or if the TcB bilirubin level was ≥5.76 (7-1.24) mg/dL for Group I and TcB ≥8.76 (10-1.24) mg/dL for Group II and it had to be taken within six hours before or after the TcB measurement (assumption of TcB standard deviation being ±1.24 mg/dL). The TSB measurement also had to be taken if the TcB measurement showed abnormal results. Hyperbilirubinemia was defined as TSB ≥7 mg/dL for preterm neonates with birth weights of 1000–1500 g and TSB >10 mg/dL for preterm neonates with birth weights of 1501–2000 g as suggested by the Kaplan et al., in Martin’s Neonatal-Perinatal Medicine (2011).

2). Reviewer's Comment: On what basis the TSB value of ≥ 7 mg/dL in group 1 and > 10 mg/dL HB in group 2 was selected? This needs to be scientifically substantiated. At what time this level was measured?

Author's response:
Dear Reviewer,
Thank you for your comments.

The cut off 7 and 10 mg/dl are based on the recommendation of Martin Fanaroff (Reference source: Kaplan M, Wong R, Sibley E, et al.: Neonatal Jaundice and Liver Disease. In: Martin’s Neonatal-Perinatal Medicine. 2011; 1443–90.) In this recommendation they use birth weight category regardless postnatal age in hours.

3). Reviewer's comment: How TSB was measured? Were the lab values confirmed by internal calibration? This must be clarified.

Author's response:
Dear Reviewer,

Thank you for your comments.
TSB measurements were performed by retrieving peripheral blood samples of each subject.
Added in methods à variables section :
Total serum bilirubin was measured in the central laboratory using SIEMENS Dimension® with a modified Doumas 22 reference method, which is a modification of the diazo method described by Jendrassik and Grof in 1938 23. Internal calibration was completed daily, with a quality control printout. The Indonesian External Quality Assurance Service performed external quality control.

4). Reviewer's comment: Fig 1 shows that the time course of HB is different in the 2 groups being the bilirubin peak reached 24 h later in group 2. This difference accounts for the different TcB cut-off values. This needs to be considered and addressed in the discussion.

Author's comment:
Dear Reviewer,
Thank you for the comment.

We added in the discussion:

It shows that that higher birth weight has opportunity to be hyperbilirubinemia later than the lower birthweight. The lower birthweight has lower threshold bilirubin, because they have higher chance to become encephalopathy in lower bilirubin level (high risk infants). The younger gestational age and lower birth weight, lead to a higher prevalence of infants developing hyperbilirubinemia. It is a result of excessive neonatal red cell hepatic and immaturity of the gastrointestinal system. Prematurely delivered infants have a likelihood of slower maturation of hepatic bilirubin uptake and conjugation.

5). Reviewer's comment: How was the correlation between TcB and TSB at 72h? This information is important to assess the reliability of the two techniques (see also point #3)

Author's response:
Dear Reviewer,
Thank you for your comments.
We actually did not assess the correlation between TcB and TSB at 72 hours of age. We would like to mention our reasons why we did not perform the assessment as the followings:

We were not specifically aiming at performing diagnostic test;

We only discovered fewer observed subjects who had reached observation at 72 hours of age thus the sample size at that age was not abundant in number. Most of the infants underwent phototherapy before 72 hours (group 1). Those infants were excluded from the study for further analysis.

6) Reviewer's Comment: The abstract is inaccurate as data reported are different from those indicated in the text (see for example the lack of 48H values).

Author's response:
Dear Reviewer,

Thank you for noticing. We adapted our abstract accordingly

We also found that there was an unsuitable data between those mentioned in the study abstract and the ones in figures. However, we would like to inform that the proportional data provided in the study abstract is correct already meanwhile the ones in figures were attained by integrating the data percentages. Therefore, we are going to amend and adjust the data provided in abstract.
1). Reviewer's Comment: The indication when TSB was measured is unclear and confusing. In the abstract it is stated that TSB was assessed before 72 h if TcB showed “abnormal results”. What does this mean? Detailed numerical values must be provided to allow to understand why TSB was performed.

Author's response:
Dear Reviewer,
Thank you for your comments.

We added in our method à variables section as follows:
The bilirubin level of each neonate was measured on the sternum by TcB (Dräger® Jaundice Meter 105) at 12 hours, 24 hours, and 72 hours with ±3 hours tolerance (the TcB measurement could be taken within three hours before/after the exact time). The TSB measurement was taken for each neonate at the age of three days or if the TcB bilirubin level was ≥5.76 (7-1.24) mg/dL for Group I and TcB ≥8.76 (10-1.24) mg/dL for Group II and it had to be taken within six hours before or after the TcB measurement (assumption of TcB standard deviation being ±1.24 mg/dL). The TSB measurement also had to be taken if the TcB measurement showed abnormal results. Hyperbilirubinemia was defined as TSB ≥7 mg/dL for preterm neonates with birth weights of 1000–1500 g and TSB >10 mg/dL for preterm neonates with birth weights of 1501–2000 g as suggested by the Kaplan et al., in Martin’s Neonatal-Perinatal Medicine (2011).

2). Reviewer's Comment: On what basis the TSB value of ≥ 7 mg/dL in group 1 and > 10 mg/dL HB in group 2 was selected? This needs to be scientifically substantiated. At what time this level was measured?

Author's response:
Dear Reviewer,
Thank you for your comments.

The cut off 7 and 10 mg/dl are based on the recommendation of Martin Fanaroff (Reference source: Kaplan M, Wong R, Sibley E, et al.: Neonatal Jaundice and Liver Disease. In: Martin’s Neonatal-Perinatal Medicine. 2011; 1443–90.) In this recommendation they use birth weight category regardless postnatal age in hours.

3). Reviewer's comment: How TSB was measured? Were the lab values confirmed by internal calibration? This must be clarified.

Author's response:
Dear Reviewer,

Thank you for your comments.
TSB measurements were performed by retrieving peripheral blood samples of each subject.
Added in methods à variables section :
Total serum bilirubin was measured in the central laboratory using SIEMENS Dimension® with a modified Doumas 22 reference method, which is a modification of the diazo method described by Jendrassik and Grof in 1938 23. Internal calibration was completed daily, with a quality control printout. The Indonesian External Quality Assurance Service performed external quality control.

4). Reviewer's comment: Fig 1 shows that the time course of HB is different in the 2 groups being the bilirubin peak reached 24 h later in group 2. This difference accounts for the different TcB cut-off values. This needs to be considered and addressed in the discussion.

Author's comment:
Dear Reviewer,
Thank you for the comment.

We added in the discussion:

It shows that that higher birth weight has opportunity to be hyperbilirubinemia later than the lower birthweight. The lower birthweight has lower threshold bilirubin, because they have higher chance to become encephalopathy in lower bilirubin level (high risk infants). The younger gestational age and lower birth weight, lead to a higher prevalence of infants developing hyperbilirubinemia. It is a result of excessive neonatal red cell hepatic and immaturity of the gastrointestinal system. Prematurely delivered infants have a likelihood of slower maturation of hepatic bilirubin uptake and conjugation.

5). Reviewer's comment: How was the correlation between TcB and TSB at 72h? This information is important to assess the reliability of the two techniques (see also point #3)

Author's response:
Dear Reviewer,
Thank you for your comments.
We actually did not assess the correlation between TcB and TSB at 72 hours of age. We would like to mention our reasons why we did not perform the assessment as the followings:

We were not specifically aiming at performing diagnostic test;

We only discovered fewer observed subjects who had reached observation at 72 hours of age thus the sample size at that age was not abundant in number. Most of the infants underwent phototherapy before 72 hours (group 1). Those infants were excluded from the study for further analysis.

6) Reviewer's Comment: The abstract is inaccurate as data reported are different from those indicated in the text (see for example the lack of 48H values).

Author's response:
Dear Reviewer,

Thank you for noticing. We adapted our abstract accordingly

We also found that there was an unsuitable data between those mentioned in the study abstract and the ones in figures. However, we would like to inform that the proportional data provided in the study abstract is correct already meanwhile the ones in figures were attained by integrating the data percentages. Therefore, we are going to amend and adjust the data provided in abstract.
Competing Interests: we declare that no competing interests. Close
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VERSION 3 PUBLISHED 28 Apr 2020

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Version 3 (revision) 08 Oct 20
Version 2 (revision) 07 Sep 20	read	read
Version 1 28 Apr 20	read	read

Claudio Tiribelli, University of Trieste, Trieste, Italy
Tina M. Slusher, University of Minnesota, Minneapolis, USA

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Reviewer Report

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17 Sep 2020 | for Version 2

Tina M. Slusher, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA

10 Views Cite this report Responses(1)

Approved

Language in places is still awkward and could be improved on but message is clearer and concerns have been addressed.

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Pediatric Global Health, Neonatal Hyperbilirubinemia, Pediatric Critical Care

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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Reviewer Report

12 Views

08 Sep 2020 | for Version 2

Claudio Tiribelli, University of Trieste, Trieste, Italy

12 Views Cite this report Responses(1)

Approved

Authors have addressed my concerns.

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Bilirubin, Jaundice

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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Author Response

21 Sep 2020

Mahendra Tri Arif Sampurna, Department of Pediatrics, Dr. Soetomo Academic Teaching Hospital, Faculty of Medicine Universitas Airlangga, Surabaya, Indonesia

Dear Prof. Claudio Tiribelli,

Thank you very much for the review of our manuscript entitled: "Transcutaneous bilirubin level to predict hyperbilirubinemia in preterm neonates."

We sincerely appreciate all the valuable comments and suggestions, which helped us to improve the quality of the article.

Looking forward to working with you in the future

Thank you for your kind attention.

Warm regards,
On behalf of all authors
Mahendra

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No competing interests were disclosed.

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Reviewer Report

16 Views

21 May 2020 | for Version 1

Tina M. Slusher, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA

16 Views Cite this report Responses(1)

Approved With Reservations

They authors state that TcB has not been used in premature infants with the exception of late preterms. However, in a systematic review by Nager et al. most of the 22 articles they mention include very preterm infants. Perhaps the authors need to mean to say in their population but this needs to be clarified.
Each country does indeed need to develop their own criteria for diagnosis and treatment levels of hyperbilirubinemia based on risk in their environment, treatments available and other specifics related to their own country. However, authors do need to tell us where there cutoffs for each group came from---are the in country normal, standard cutoffs for their hospital or region or how were they selected.
Numbers too small to extrapolate widely to Indonesia or beyond.
Rhesus of mothers and infants missing; G6PD status missing if not done state that.
Although not a major problem or limitation this article could be improved by having a native English speaker read and make minor edits throughout.

Is the work clearly and accurately presented and does it cite the current literature?

Partly
Is the study design appropriate and is the work technically sound?

Partly
Are sufficient details of methods and analysis provided to allow replication by others?

Yes
If applicable, is the statistical analysis and its interpretation appropriate?

Partly
Are all the source data underlying the results available to ensure full reproducibility?

Partly
Are the conclusions drawn adequately supported by the results?

Partly

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Pediatric Global Health, Neonatal Hyperbilirubinemia, Pediatric Critical Care

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Author Response

07 Sep 2020

Mahendra Tri Arif Sampurna, Department of Pediatrics, Dr. Soetomo Academic Teaching Hospital, Faculty of Medicine Universitas Airlangga, Surabaya, Indonesia

1). Reviewer's comments:

This study is an interesting study looking at the correlation between transcutaneous bilirubin (TcB) and serum bilirubin and the predictive value of subsequent clinically significant hyperbilirubinemia in neonates. However, there are some problems with the study that need to be addressed.

The authors state that TcB has not been used in premature infants with the exception of late preterms. However, in a systematic review by Nager et al. most of the 22 articles they mention include very preterm infants. Perhaps the authors need to mean to say in their population but this needs to be clarified.

Author's response:
Dear Reviewer,
Thank you for your comments.

Yes, indeed you are right, thanks for your suggestion. What we meant here is similar with the study by Mayer (Mayer I, Gursoy T, Hayran M, Ovalı F. Value of twelfth-hour bilirubin level in predicting significant hyperbilirubinemia in preterms Infants. J Clin Med Res. 2014;6(3):190–6) but they used TSB to predict significant hyperbilirubinemia later on. Practice in our hospital so far is using Kramer and few TSB measurement to start phototherapy. So, we give another alternative which is non-invasive, easy to use, and applicable in our setting in Indonesia.

We added in our introduction as :

In a systematic review by Nagar et al.¹⁶, most of 22 articles studied the accuracy of TcB to estimate TSB, and TcB could be used in clinical practice to reduce blood sampling. Some studies have used TcB to predict significant hyperbilirubinemia in subsequent days, but all of them recruited only late preterm and term neonates ^5,17 . For preterm neonates, one study was already conducted using TSB measurements at 6- 24 hours to predict hyperbilirubinemia in the following hours or days ⁴ . As far as the researchers know, there have been no previous studies using TcB to predict subsequent, significant hyperbilirubinemia for older preterm neonates. Therefore, this study aimed to use TcB to predict hyperbilirubinemia in preterm neonates to prevent complications since visual assessment is unreliable.

2) Reviewer's comment: Each country does indeed need to develop their own criteria for diagnosis and treatment levels of hyperbilirubinemia based on risk in their environment, treatments available and other specifics related to their own country. However, authors do need to tell us where there cutoffs for each group came from---are the in country normal, standard cutoffs for their hospital or region or how were they selected

Author's response:
Thank you for your comments.
We added in our method à variables section as follows:

The bilirubin level of each neonate was measured on the sternum by TcB (Dräger® Jaundice Meter 105) at 12 hours, 24 hours, and 72 hours with ±3 hours tolerance (the TcB measurement could be taken within three hours before/after the exact time). The TSB measurement was taken for each neonate at the age of three days or if the TcB bilirubin level was ≥5.76 (7-1.24) mg/dL for Group I and TcB ≥8.76 (10-1.24) mg/dL for Group II and it had to be taken within six hours before or after the TcB measurement (assumption of TcB standard deviation being ±1.24 mg/dL). The TSB measurement also had to be taken if the TcB measurement showed abnormal results. Hyperbilirubinemia was defined as TSB ≥7 mg/dL for preterm neonates with birth weights of 1000–1500 g and TSB >10 mg/dL for preterm neonates with birth weights of 1501–2000 g as suggested by the Kaplan et al., in Martin’s Neonatal-Perinatal Medicine (2011).²¹

3). Reviewer's comment:
Numbers too small to extrapolate widely to Indonesia or beyond.

Author's response:
Dear Reviewer,
This is the study limitation and has been addressed in discussion section.
We added in the discussion section in the last paragraph:

A limitation of the study was that it could not determine TcB cut-off values to predict hyperbilirubinemia at the age of 72 hours for preterm neonates weighing 1000–1500 grams due to a lack of subjects able to complete the study, since most had already developed significant hyperbilirubinemia by this time.

4). Reviewer's comment:
Rhesus of mothers and infants missing; G6PD status missing if not done state that.

Author's response:
Dear Reviewer,
Thank you for your comments.

We even hardly measured Blood Group ABO and Rhesus of the mother and babies since the babies are not yellow. We have not used it as screening program. G6PD measurement is not affordable for our majority of citizen. We need to give consent first when the bilirubin is not yet decrease and rise again after intensive phototherapy, or there is sign of haemolysis

Thank you for your suggestion. Indeed, this is also our limitation that we added in the discussion section on the last paragraph

To the knowledge of the researchers, this was the first study conducted to predict significant hyperbilirubinemia in preterm neonates weighing 1000–2000 grams using TcB. A limitation of the study was that it could not determine TcB cut-off values to predict hyperbilirubinemia at the age of 72 hours for preterm neonates weighing 1000–1500 grams due to a lack of subjects able to complete the study, since most had already developed significant hyperbilirubinemia by this time. The mothers’ rhesus blood groups and the babies’ G6PD levels were not obtained. Hopefully, future similar studies will be able to recruit larger populations.

5) Reviewer's comment:
Although not a major problem or limitation this article could be improved by having a native English speaker read and make minor edits throughout

Author's response:
Dear Reviewer,
Thank you for your comments

We have already proofread this manuscript by Proofreading Service.

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Competing Interests

We declare that no competing interest

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Reviewer Report

20 Views

11 May 2020 | for Version 1

Claudio Tiribelli, University of Trieste, Trieste, Italy

20 Views Cite this report Responses(1)

Approved With Reservations

The indication when TSB was measured is unclear and confusing. In the abstract it is stated that TSB was assessed before 72 h if TcB showed “abnormal results”. What does this mean? Detailed numerical values must be provided to allow to understand why TSB was performed.
On what basis the TSB value of ≥ 7 mg/dL in group 1 and > 10 mg/dL HB in group 2 was selected? This needs to be scientifically substantiated. At what time this level was measured?
How TSB was measured? Were the lab values confirmed by internal calibration? This must be clarified.
Fig 1 shows that the time course of HB is different in the 2 groups being the bilirubin peak reached 24 h later in group 2. This difference accounts for the different TcB cutoff values. This needs to be considered and addressed in the discussion.
How was the correlation between TcB and TSB at 72h? This information is important to assess the reliability of the two techniques (see also point #3).
The abstract is inaccurate as data reported are different from those indicated in the text (see for example the lack of 48H values).

Is the work clearly and accurately presented and does it cite the current literature?

No
Is the study design appropriate and is the work technically sound?

No
Are sufficient details of methods and analysis provided to allow replication by others?

No
If applicable, is the statistical analysis and its interpretation appropriate?

Partly
Are all the source data underlying the results available to ensure full reproducibility?

No
Are the conclusions drawn adequately supported by the results?

Partly

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Bilirubin, Jaundice

Respond to this report

Responses (1)

Author Response

07 Sep 2020

Mahendra Tri Arif Sampurna, Department of Pediatrics, Dr. Soetomo Academic Teaching Hospital, Faculty of Medicine Universitas Airlangga, Surabaya, Indonesia

1). Reviewer's Comment: The indication when TSB was measured is unclear and confusing. In the abstract it is stated that TSB was assessed before 72 h if TcB showed “abnormal results”. What does this mean? Detailed numerical values must be provided to allow to understand why TSB was performed.

Author's response:
Dear Reviewer,
Thank you for your comments.

We added in our method à variables section as follows:
The bilirubin level of each neonate was measured on the sternum by TcB (Dräger® Jaundice Meter 105) at 12 hours, 24 hours, and 72 hours with ±3 hours tolerance (the TcB measurement could be taken within three hours before/after the exact time). The TSB measurement was taken for each neonate at the age of three days or if the TcB bilirubin level was ≥5.76 (7-1.24) mg/dL for Group I and TcB ≥8.76 (10-1.24) mg/dL for Group II and it had to be taken within six hours before or after the TcB measurement (assumption of TcB standard deviation being ±1.24 mg/dL). The TSB measurement also had to be taken if the TcB measurement showed abnormal results. Hyperbilirubinemia was defined as TSB ≥7 mg/dL for preterm neonates with birth weights of 1000–1500 g and TSB >10 mg/dL for preterm neonates with birth weights of 1501–2000 g as suggested by the Kaplan et al., in Martin’s Neonatal-Perinatal Medicine (2011).

2). Reviewer's Comment: On what basis the TSB value of ≥ 7 mg/dL in group 1 and > 10 mg/dL HB in group 2 was selected? This needs to be scientifically substantiated. At what time this level was measured?

Author's response:
Dear Reviewer,
Thank you for your comments.

The cut off 7 and 10 mg/dl are based on the recommendation of Martin Fanaroff (Reference source: Kaplan M, Wong R, Sibley E, et al.: Neonatal Jaundice and Liver Disease. In: Martin’s Neonatal-Perinatal Medicine. 2011; 1443–90.) In this recommendation they use birth weight category regardless postnatal age in hours.

3). Reviewer's comment: How TSB was measured? Were the lab values confirmed by internal calibration? This must be clarified.

Author's response:
Dear Reviewer,

Thank you for your comments.
TSB measurements were performed by retrieving peripheral blood samples of each subject.
Added in methods à variables section :
Total serum bilirubin was measured in the central laboratory using SIEMENS Dimension® with a modified Doumas 22 reference method, which is a modification of the diazo method described by Jendrassik and Grof in 1938 23. Internal calibration was completed daily, with a quality control printout. The Indonesian External Quality Assurance Service performed external quality control.

4). Reviewer's comment: Fig 1 shows that the time course of HB is different in the 2 groups being the bilirubin peak reached 24 h later in group 2. This difference accounts for the different TcB cut-off values. This needs to be considered and addressed in the discussion.

Author's comment:
Dear Reviewer,
Thank you for the comment.

We added in the discussion:

It shows that that higher birth weight has opportunity to be hyperbilirubinemia later than the lower birthweight. The lower birthweight has lower threshold bilirubin, because they have higher chance to become encephalopathy in lower bilirubin level (high risk infants). The younger gestational age and lower birth weight, lead to a higher prevalence of infants developing hyperbilirubinemia. It is a result of excessive neonatal red cell hepatic and immaturity of the gastrointestinal system. Prematurely delivered infants have a likelihood of slower maturation of hepatic bilirubin uptake and conjugation.

5). Reviewer's comment: How was the correlation between TcB and TSB at 72h? This information is important to assess the reliability of the two techniques (see also point #3)

Author's response:
Dear Reviewer,
Thank you for your comments.
We actually did not assess the correlation between TcB and TSB at 72 hours of age. We would like to mention our reasons why we did not perform the assessment as the followings:

We were not specifically aiming at performing diagnostic test;
We only discovered fewer observed subjects who had reached observation at 72 hours of age thus the sample size at that age was not abundant in number. Most of the infants underwent phototherapy before 72 hours (group 1). Those infants were excluded from the study for further analysis.

6) Reviewer's Comment: The abstract is inaccurate as data reported are different from those indicated in the text (see for example the lack of 48H values).

Author's response:
Dear Reviewer,

Thank you for noticing. We adapted our abstract accordingly

We also found that there was an unsuitable data between those mentioned in the study abstract and the ones in figures. However, we would like to inform that the proportional data provided in the study abstract is correct already meanwhile the ones in figures were attained by integrating the data percentages. Therefore, we are going to amend and adjust the data provided in abstract.

View more View less

Competing Interests

we declare that no competing interests.

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

[1] 1. Han S, Yu Z, Liu L, et al.: A Model for Predicting Significant Hyperbilirubinemia in Neonates From China. Pediatrics. 2015; 136(4): e896–905. PubMed Abstract | Publisher Full Text

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Transcutaneous bilirubin level to predict hyperbilirubinemia in preterm neonates

Abstract

Keywords

Introduction

Methods

Study background and ethical approval

Participant eligibility

Variables

Statistical analysis

Results

Table 1. Maternal and neonatal characteristics of subjects.

Figure 1. Incidence of hyperbilirubinemia in preterm neonates.

TcB bilirubin level to predict hyperbilirubinemia at the age of 48 hours in group I preterm neonates

Figure 2. Transcutaneous bilirubinometer (TcB) level to predict hyperbilirubinemia at the age of 48 hours.

Table 2. Transcutaneous bilirubinometer (TcB) bilirubin level cut-off point to predict hyperbilirubinemia at the age of 48 hours for group I.

TcB bilirubin level to predict hyperbilirubinemia at the age of 48 hours in group II preterm neonates

Table 3. TcB Bilirubin Level Cut-off Point to Predict Hyperbilirubinemia at the age of 48 hours for Group II.

TcB bilirubin level to predict hyperbilirubinemia at the age of 72 hours in Group I preterm neonates

TcB bilirubin level to predict hyperbilirubinemia at the age of 72 hours in Group II preterm neonates

Figure 3. Transcutaneous bilirubinometer (TcB) level to predict hyperbilirubinemia at the age of 72 hours.

Table 4. TcB Bilirubin Level Cut off Point to Predict Hyperbilirubinemia at the age of 72 hours for Group II.

Discussion

Conclusion

Data availability

Underlying data

Extended data

Reporting guidelines

Acknowledgements

References

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