International Health 2021; 0: 1–7

doi:10.1093/inthealth/ihab012 Advance Access publication 0 2021

A nomogram to predict in-hospital mortality of neonates admitted

ORIGINAL ARTICLE
to the intensive care unit

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Xihua Huang, Zhenyu Liang, Tang Li, Yu Lingna, Wei Zhu∗ and Huiyi Li

Department of Pediatrics, Guangdong Second Provincial General Hospital, No. 466 Middle Xingang Road, Zhuhai District, Guangzhou,
Guangdong 510317, P.R. China
∗ Corresponding author: Tel: +86 020–61322569; E-mail: [email protected]

Received 31 July 2020; revised 30 November 2020; editorial decision 21 February 2021; accepted 1 March 2021

Background: To explore the influencing factors for in-hospital mortality in the neonatal intensive care unit (NICU)
and to establish a predictive nomogram.
Methods: Neonatal data were extracted from the Medical Information Mart for Intensive Care III (MIMIC-III)
database. Both univariate and multivariate logit binomial general linear models were used to analyse the factors
influencing neonatal death. The area under the receiver operating characteristics (ROC) curve was used to assess
the predictive model, which was visualized by a nomogram.
Results: A total of 1258 neonates from the NICU in the MIMIC-III database were eligible for the study, including
1194 surviving patients and 64 deaths. Multivariate analysis showed that red cell distribution width (RDW) (odds
ratio [OR] 0.813, p=0.003) and total bilirubin (TBIL; OR 0.644, p<0.001) had protective effects on neonatal in-
hospital death, while lymphocytes (OR 1.205, p=0.025), arterial partial pressure of carbon dioxide (PaCO2 ; OR
1.294, p=0.016) and sequential organ failure assessment (SOFA) score (OR 1.483, p<0.001) were its independent
risk factors. Based on this, the area under the curve of this predictive model was up to 0.865 (95% confidence
interval 0.813 to 0.917), which was also confirmed by a nomogram.
Conclusions: The nomogram constructed suggests that RDW, TBIL, lymphocytes, PaCO2 and SOFA score are all
significant predictors for in-hospital mortality in the NICU.

Keywords: in-hospital mortality, MIMIC database, neonates, nomogram.

Introduction estimates indicate that increasing the coverage of existing in-

terventions can prevent about 75% of newborn deaths.8,9 Al-
Despite a significant decrease in global childhood mortality, though these solutions are achievable, neonatal mortality is still
neonatal mortality remains relatively high, accounting for ap- a big challenge for LMICs, especially in southern Asia and sub-
proximately 40% of all childhood mortality.1,2 Each year 2.6 mil- Saharan Africa.10 Identifying the risk factors is beneficial to pre-
lion neonates die globally, with 75% of neonatal deaths occurring dict the mortality of neonates, especially where intervention is
in the first week of life and 99% die in low- and middle-income feasible with modest resources.11,12 Houweling et al.12 found
countries (LMICs).1,3 Due to the lack of a surveillance system in that preterm birth, multiple births and poor condition at 5 min
developing countries, neonatal sepsis in LMICs is likely underre- post-partum were associated with a significantly increased risk
ported, indicating the proportion of neonatal mortality may be of neonatal mortality and thus they established prediction mod-
even higher.4 Neonatal mortality is becoming a prominent com- els for neonatal death. However, these prediction models are ap-
ponent of the overall mortality of children <5 y of age.5 Prema- propriate for assessing neonatal mortality in the general popu-
turity, intrapartum-related complications like birth asphyxia and lation of South Asia. The current study explores the influencing
neonatal sepsis are thought to be the three leading causes of factors for neonatal mortality in the neonate intensive care unit
neonatal mortality.6 (NICU) using the Medical Information Mart for Intensive Care III
Currently neonatal deaths can be decreased via extra care for (MIMIC-III) database and to construct a nomogram for predict-
preterm newborns, provision of feeding support, improvement ing neonatal mortality, aimed at providing more evidence for the
of resuscitation skills and infection prevention.7 Recent global prevention and treatment of neonatal mortality in the NICU.

© The Author(s) 2021. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. This is an Open Access
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nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For
commercial re-use, please contact [email protected]

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Table 1. Comparison of the baseline characteristics of neonates with different outcomes

Variables Survival group (n=1194) Death group (n=64) Total (N=1258) Statistic p-Value

Gestational age (weeks) 27.89±1.95 27.78±1.70 27.89±1.94 t=0.44 0.660

Gender, n (%) χ 2 =0.03 0.854

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Male 695 (58.21) 38 (59.38) 733 (58.27)
Female 499 (41.79) 26 (40.62) 525 (41.73)
Birthweight (kg) 1.60 (1.13–2.40) 0.92 (0.68–1.50) 1.58 (1.11–2.36) Z=−6.061 <0.001
Heart rate (bpm) 156 (144–166) 154 (144–165) 156 (144–166) Z=0.783 0.434
Laboratory parameters
Bicarbonate (mmol/L) 21.00 (19.00–23.00) 20.70 (19.00–22.00) 21.00 (19.0–23.00) Z=−1.943 0.052
Haematocrit (%) 46.60 (41.70–50.90) 43.22 (40.05–47.05) 46.25 (41.60–50.80) Z=−3.201 0.001
Haemoglobin (g/dl) 15.50 (13.90–17.00) 14.66 (13.50–15.60) 15.50 (13.80–17.00) Z=−3.096 0.002
WBC count (×109 /L) 10.20 (6.90–14.50) 8.80 (5.00–11.55) 10.20 (6.90–14.50) Z=−2.171 0.030
RBC count (×106 /μl) 4.16 (3.74–4.61) 3.83 (3.47–4.22) 4.14 (3.73–4.59) Z=−4.319 <0.001
PLT count (×109 /L) 251.00 (198.00–311.75) 214.50 (174.00–240.75) 248.00 (197.00–309.00) Z=−3.705 <0.001
RDW (%) 17.00 (16.30–17.80) 16.80 (15.75–17.26) 17.00 (16.30–17.70) Z=2.892 0.004
Neutrophils (%) 29.00 (18.00–44.00) 23.50 (17.75–35.00) 29.00 (18.00–44.00) Z=2.178 0.029
Lymphocytes (%) 57.00 (40.00–70.00) 62.00 (49.75–72.50) 57.00 (41.00–70.00) Z=−2.220 0.026
Sodium (mEq/L) 139.00 (136.00–141.00) 139.68 (138.00–144.50) 139.00 (136.00–141.00) Z=2.649 0.008
TBIL (mg/dL) 5.10 (4.00–6.20) 2.60 (2.25–3.10) 5.10 (3.90–6.20) Z=−7.782 <0.001
FiO2 30.00 (23.25–50.00) 40.00 (30.00–70.00) 30.00 (24.00–50.00) Z=3.805 <0.001
PaCO2 (mmHg) 47.00 (40.00–54.00) 47.00 (39.00–60.75) 47.00 (40.00–54.00) Z=1.309 0.191
PaO2 (mmHg) 50.00 (41.00–71.00) 58.00 (44.75–73.50) 50.00 (41.00–71.00) Z=1.816 0.069
Scoring systems
SOFA score 6.00 (4.00–7.00) 8.00 (6.00–9.00) 6.00 (4.00–7.00) Z=5.593 <0.001
SAPS II 34 (30–39) 37 (33–41) 34 (30–39) Z=2.376 0.018

Values are presented as median (IQR; quartile 1–quartile 3) unless stated otherwise.

Methods red blood cell [RBC] count, platelet [PLT] count, red cell distribu-
tion width [RDW], neutrophils, lymphocytes, sodium, total biliru-
Patients bin [TBIL], fraction of inspired oxygen [FiO2 ], arterial partial pres-
The MIMIC-III database was used to extract data. The MIMIC-III sure of carbon dioxide [PaCO2 ], arterial partial pressure of oxygen
is a large, free database that contains de-identified health data [PaO2 ]), sequential organ failure assessment (SOFA) score and the
for >40 000 ICU patients from the Beth Israel Deaconess Med- Simplified Acute Physiology Score II (SAPS II). These data could be
ical Center (Boston, MA, USA) between 2001 and 2012.13 It not downloaded from several sources, including archives from crit-
only contains demographics, vital signs, medications and labo- ical care information systems, hospital electronic health record
ratory tests, but also includes observations and notes charted databases and Social Security Administration Death Master File.14
by care providers, procedures and diagnostic codes, fluid bal- Neonatal deaths in this study were defined as death occur-
ance, imaging reports, length of stay and survival data. According ring within 30 d following admission to the NICU. The SOFA score
to the MIMIC-III, 7874 neonates were admitted to the NICU.14 was developed to assess the acute morbidity of critical illness
Neonates with a gestational age of 23–31 weeks were included at the patient level based on six criteria—cardiovascular, respira-
in our study, while those with missing data, including birthweight, tory, nervous, hepatic, renal and haematological systems—each
vital signs and laboratory measurements, were excluded. scored on a scale of 0–4. The higher the SOFA score, the worse the
Since the data used in this study were accessed from MIMIC- organ dysfunction.15 The SAPS II provides an estimate of the risk
III, an openly available dataset, the study did not get approval of death without specifying a primary diagnosis. It contains 17
from the Institutional Review Board of Guangdong Second Provin- variables: age, type of admission, 12 physiology variables and 3
cial General Hospital. underlying disease variables.16 PaO2 and FiO2 are commonly used
for diagnosis of lung injury and TBIL reflects liver metabolism.17,18

Data collection
Data from the MIMIC-III used for analysis in this study included Statistical analysis
gender, birthweight, heart rate, laboratory parameters (bicarbon- Categorical data were presented as number and percentage,
ate, haematocrit, haemoglobin, white blood cell [WBC] count, while the χ 2 test or Fisher’s exact test was used for compar-

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Table 2. Factors associated with in-hospital death among neonates

Univariate analysis Multivariate analysis

Variables OR (95% CI) p-Value OR (95% CI) p-Value

Gestational age (weeks) 0.971 (0.853 to 1.104) 0.649 0.968 (0.888 to 1.056) 0.464

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Gender (female) 1.049 (0.629 to 1.751) 0.854
Birthweight (kg) 0.335 (0.216 to 0.518) <0.001
Heart rate (bpm) 0.986 (0.972 to 1.001) 0.059
Laboratory parameters
WBC count (×109 /L) 0.957 (0.914 to 1.001) 0.057
RBC count (×106 /μL) 0.495 (0.352 to 0.696) <0.001
PLT count (×109 /L) 0.995 (0.993 to 0.998) 0.001
Haematocrit (%) 0.957 (0.928 to 0.987) 0.006
Haemoglobin (g/dL) 0.880 (0.801 to 0.966) 0.007
RDW (%) 0.845 (0.723 to 0.990) 0.037 0.813 (0.710 to 0.932) 0.003
Neutrophils (%) 0.982 (0.967 to 0.998) 0.023
Lymphocytes (%) 1.180 (1.022 to 1.361) 0.024 1.205 (1.024 to 1.417) 0.025
TBIL (mg/dL) 0.524 (0.439 to 0.624) <0.001 0.644 (0.529 to 0.785) <0.001
FiO2 1.011 (1.004 to 1.020) 0.004
PaCO2 (mmHg) 1.262 (1.012 to 1.574) 0.039 1.294 (1.049 to 1.596) 0.016
PaO2 (mmHg) 1.000 (0.994 to 1.006) 0.907
Sodium (mEq/L) 1.089 (1.035 to 1.145) <0.001
Bicarbonate (mEq/L) 0.892 (0.827 to 0.963) 0.003
SOFA score 1.533 (1.400 to 1.678) <0.001 1.483 (1.334 to 1.649) <0.001

ison. Continuous variables were expressed as medians and 1345 patients, laboratory parameters 3992 patients and scor-
interquartile ranges (IQRs). Differences in baseline information ing systems 584 patients), 1258 neonates (733 males [58.27%]
of included neonates and clinical characteristics, as well as lab- and 525 females [41.73%]) were eligible for the study. In-hospital
oratory parameters between groups, were compared according death occurred in 64 patients. All included subjects were included
to in-hospital survival outcomes for neonates in the NICU. With in the death group (n=64) and 1194 were included in the survival
neonatal in-hospital death or survival as the dependent variable group. The baseline characteristics of the two groups are com-
and demographic characteristics and laboratory indicators as pared in Table 1. It can be observed that except for gender, heart
independent variables, a univariate logit binomial general linear rate, PaCO2 , PaO2 and bicarbonate, the differences were all pro-
model (GLM) was performed. Independent variables with sig- nounced between the death group and the survival group regard-
nificant difference in the univariate analysis were included in a ing other variables, including birthweight (p<0.001), WBC count
multivariate logit binomial GLM. In view of the multicollinearity (p=0.030), RBC count (p<0.001), PLT count (p<0.001), haema-
among independent variables, a stepwise regression analysis tocrit (p=0.001), haemoglobin (p=0.002), RDW (p=0.004), neu-
was conducted to identify the risk factors and establish a pre- trophils (p=0.029), lymphocytes (p=0.026), TBIL (p<0.001), FiO2
dictive model. The receiver operating characteristics (ROC) curve (p<0.001), sodium (p=0.008), SOFA score (p<0.001) and SAPS II
and the area under the curve (AUC) were used to assess the (p<0.018).
predictive model, which was visualized by a nomogram. The
nomogram is one method used to visualize the predictive model
with graphic scoring.19 All statistical tests were two-sided and
p-values ≤0.05 were considered to be statistically significant. All Univariate and multivariate analysis of in-hospital
statistical analyses were carried out using R statistical software death in neonates
(R Foundation for Statistical Computing, Vienna, Austria).
Univariate and multivariate analysis of in-hospital death in
neonates is presented in Table 2. As it shows, birthweight (odds
ratio [OR] 0.335, p<0.001), RBC count (OR 0.459, p<0.001), PLT
Results count (OR 0.995, p=0.001), haematocrit (OR 0.957, p=0.006),
haemoglobin (OR 0.880, p=0.007), RDW (OR 0.845, p=0.037),
Baseline characteristics of included neonates neutrophils (OR 0.982, p=0.023), TBIL (OR 0.524, p<0.001) and
Of 7874 neonates admitted to the NICU, there were 7800 with bicarbonate (OR 0.892, p=0.003) were all associated with a re-
a gestational age of 23–31 weeks. After excluding 6542 patients duced risk of in-hospital death in neonates, whereas lymphocytes
with missing data (birthweight 621 patients, survival outcomes (OR 1.180, p=0.024), FiO2 (OR 1.011, p=0.004), PaCO2 (OR 1.262,

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Figure 1. The nomogram for predicting 30-d in-hospital mortality in the NICU.

p=0.039), sodium (OR 1.089, p<0.001) and SOFA score (OR 1.533,
p<0.001) related to an increased risk.
Through multivariate analysis, RDW (OR 0.813, p=0.003) and
TBIL (OR 0.644, p<0.001) were found to have protective ef-
fects on neonatal in-hospital death, while the risk of in-hospital
mortality was increased 1.205-fold and 1.294-fold for each in-
crease in lymphocytes (OR 1.205, p=0.025) and PaCO2 (OR 1.294,
p=0.016), respectively. In addition, the SOFA score (OR 1.483,
p<0.001) was also identified as an independent risk factor for
neonatal in-hospital mortality.

Nomogram for predicting in-hospital mortality in the

NICU
A nomogram was constructed using the determinants identi-
fied in multivariate analysis of in-hospital mortality (Figure 1).
The score for each parameter was obtained through upward
projection of each variable to the value of the small ruler
(points). Adding the points assigned to the corresponding fac- Figure 2. The ROC curve for the predictive model.
tors determined the total points. The higher the total score,
the higher the risk of mortality. For each patient, the risk of in-
hospital mortality could be individually predicted by the nomo- tional age of the baby was 28 weeks, the total score would
gram. The predictive accuracy of this model was then assessed be 383 by adding the variables (PaCO2 7 mmHg, RDW 17.19%,
and the AUC of the nomogram was 0.865 (95% CI 0.813 lymphocytes 47%, SOFA score 9, TBIL 3.1 mg/dL), with a risk of
to 0.917) (Figure 2). The data from one patient in the train- death of 0.517. This case was alive, highlighting the predictive ac-
ing set were randomly extracted for validation. If the gesta- curacy (Figure 3).

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Figure 3. The validation for the predictive model.

Discussion increased awareness of the association between RDW and the

risk of neonatal mortality.
Considering the high neonatal mortality rates, neonatal health is
TBIL is a crucial diagnostic marker.24 Our results showed the
still a matter of great concern around the world. In this study, we
protective role of TBIL in NICU neonates, as the risk of death
used data from 1258 NICU neonates in the MIMIC-III database,
in neonates increase 0.644-fold at each 1 mg/dL addition. A
including 1194 surviving patients and 64 deaths. Our results indi-
study presented by Dani et al.25 found a lower TBIL level in in-
cated that RDW and TBIL had protective effects on neonatal in-
fants with moderate to severe hypoxic–ischaemic encephalopa-
hospital death, while lymphocytes, PaCO2 and SOFA score were
thy (HIE) than in those without HIE. They speculated that the
independent risk factors for neonatal in-hospital mortality. Using
increased TBIL was not a neuroprotective mechanism in infants
our findings, we constructed a nomogram that was easy to use
with HIE. The correlation between TBIL levels and oxidative stress
in the prediction of in-hospital mortality in the NICU. The model,
among newborns has been investigated and it was found that
with its high accuracy, is helpful for the optimization of clinical
low physiologic TBIL levels are relevant to antioxidant effects,
management.
whereas high pathologic TBIL levels are correlated with pro-
RDW, a standard parameter of the complete blood count, rep-
oxidant effects.26 In contrast, Song et al.27 showed that low TBIL
resents variability in RBC size. Its increase reflects greater variabil-
levels appear to reduce resistance to oxidative stress and con-
ity in RBC size, usually suggesting dysfunctional erythropoiesis,
tribute to the disruption of lipid metabolism in neonates with
premature release of reticulocytes or shortened RBC lifespan.
nephrotic syndrome. However, the effect of TBIL on the prognosis
RDW can not only help diagnose iron deficiency anaemia, but can
of infants cannot be judged from data in the literature.
also predict outcomes of various comorbidities in children and
The SOFA score is a well-known scoring system in the ICU set-
adults. Studies on the association of RDW with neonatal sepsis
ting. It was designed for severity assessments of clinical status
have shown that RDW is an independent outcome predictor for
and the response examination to a given treatment.28 Our study
mortality related to neonatal sepsis, highlighting the prognos-
shows that the SOFA score was a significant risk factor for in-
tic value of RDW in neonatal sepsis, the third leading cause of
hospital mortality in the NICU, with 1.483-fold risk of mortality
neonatal deaths.20–22 In our study, RDW was also identified as a
for each 1 point addition. This was in line with the findings of
significant protective factor for in-hospital mortality in the NICU,
Ha et al.29 that the sequential assessment of SOFA score within
which was supported by the study of Said et al.23 This finding
a few days following NICU admission was a good prognostic

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predictor in oncology children mechanically ventilated >3 d, and a systematic analysis for the Global Burden of Disease Study 2013.
it was strongly associated with mortality. Lancet. 2014;384(9947):957–79.
As a prognostic device, the nomogram has been extensively 2 Orsido TT, Asseffa NA, Berheto TM. Predictors of neonatal mortality in
used in oncology and medicine to predict the probability of clini- neonatal intensive care unit at referral hospital in southern Ethiopia:
cal events. It can help clinicians make quick and sound decisions a retrospective cohort study. BMC Pregnancy Childbirth. 2019;19(1):
due to the characteristics of better accuracy, straightforward 83.
digital interfaces and readily comprehensible prognosis.30,31 To 3 Liu L, Johnson HL, Cousens S, et al. Global, regional, and na-

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the best of our knowledge, this is the first study to construct a tional causes of child mortality: an updated systematic analysis for
nomogram for predicting the risk of in-hospital mortality in the 2010 with time trends since 2000. Lancet. 2012;379(9832):2151–
NICU, which simply and easily depicted the associations of each 61.
predictor with in-hospital mortality risk. Moreover, the AUC of the 4 Zea-Vera A, Ochoa TJ. Challenges in the diagnosis and management
present nomogram in predicting neonatal in-hospital mortality of neonatal sepsis. J Trop Pediatr. 2015;61(1):1–13.
was 0.865, showing good predictive accuracy. However, there 5 Andegiorgish AK, Andemariam M, Temesghen, S, et al. Neonatal mor-
are still some limitations that needed to be addressed. First, tality and associated factors in the specialized neonatal care unit As-
although the sample size retrieved from MIMIC-III database mara, Eritrea. BMC Public Health. 2020;20:10.
was large enough, the number of neonates in the death group 6 Mekonnen Y, Tensou B, Telake DS, et al. Neonatal mortality in Ethiopia:
was small, which may affect the statistical power of the current trends and determinants. BMC Public Health. 2013;13:483.
study. Second, MIMIC-III data were from a single medical centre. 7 Lawn JE, Davidge R, Paul VK, et al. Born too soon: care for the preterm
Additionally, some information, such as maternal height, mater- baby. Reprod Health. 2013;10(Suppl 1):S5.
nal age, BMI, preterm birth, intrapartum-related complications, 8 Akseer N, Lawn JE, Keenan W, et al. Ending preventable new-
education and wealth, was missing in the MIMIC-III database, born deaths in a generation. Int J Gynaecol Obstet. 2015;131(Suppl
which may affect the applicability of our predictive model. In 1):S43–8.
the future, more large-scale, multicentre studies on neonatal 9 Bhutta ZA, Das JK, Bahl R, et al. Can available interventions end pre-
mortality should be conducted to further verify our results. ventable deaths in mothers, newborn babies, and stillbirths, and at
what cost? Lancet. 2014;384(9940):347–70.
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