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Indian Pediatr 2013;50:
1119-1123 |
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Predictors of Mortality and Major Morbidities
in Extremely Low Birth Weight Neonates
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Kanya Mukhopadhyay, Deepak Louis, Rama Mahajan, and Praveen Kumar
From the Neonatal Unit, Department of Pediatrics, Postgraduate
Institute of Medical Education and Research, Chandigarh, India.
Correspondence to: Dr Kanya Mukhopadhyay, Additional Professor
(Neonatology), Department of Pediatrics,
PGIMER, Chandigarh, India.
Email: [email protected]
Received: February 11, 2013;
Initial review: February 12, 2013;
Accepted: July 07, 2013.
Published online: July 5, 2013.
PII: S097475591300140
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Objectives: To determine predictors of mortality and morbidity in
extremely low birth weight neonates (ELBW) from a developing country
Study design: Prospective observational study.
Setting: Level III neonatal unit in Northern
India.
Subjects: Neonates <1000g born and admitted to
intensive care during study period were enrolled. They were analyzed
based on survival and development of major morbidity. Multivariable
logistic regression model was used to determine independent risk
factors.
Outcome: Mortality and major morbidity (one or
more of the following: Bronchopulmonary dysplasia (BPD), Retinopathy of
Prematurity (ROP) requiring laser, grade III or IV intraventricular
hemorrhage (IVH), periventricular leukomalacia (PVL) and necrotizing
enterocolitis (NEC) stage III) during hospital stay.
Results: Of 255 ELBW neonates born, 149 received
optimal care, of which 78 (52%) survived and 57 (39%) developed
morbidities. Mean birth weight and gestational age were 29.1±2.6 weeks
and 843±108g. Major causes of mortality were sepsis (46%), birth
asphyxia (20%) and pulmonary hemorrhage (19%). Birth weight
≤800g
[OR (95% CI)-3.51 (1.39-8.89), P=0.008], mechanical ventilation
[4.10 (1.64-10.28), P=0.003] and hypotensive shock [10.75
(4.00-28.89), P<0.001] predicted mortality while birth weight
≤800g
[3.75 (1.47-9.50), P=0.006], lack of antenatal steroids [2.62
(1.00-6.69), P=0.048), asphyxia [4.11 (1.45-11.69), P=0.008],
ventilation [4.38 (1.29-14.79), P=0.017] and duration of oxygen
therapy [0.004 (1.001-1.006), P=0.002] were the predictors of
major morbidities.
Conclusions: Low birth weight, mechanical
ventilation and hypotensive shock predicted mortality in ELBW neonates
while low birth weight, lack of antenatal steroids, birth asphyxia,
ventilation and duration of oxygen therapy were predictors for major
morbidity.
Keywords: ELBW neonate, India, Mortality, Morbidity, Predictors,
Survival.
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Survival of extremely low birth weight neonates
(ELBW) is on a rising trend. This has been attributed to advances in
perinatal and neonatal care especially with the use of antenatal
steroids, ventilation and surfactant therapy. Fanaroff, et al.
[1] reported outcomes of very low birth weight neonates (VLBW) from
NICHD neonatal network (1997 to 2002) and compared it with two previous
epochs. They found an increasing survival of ELBW neonates during
1997-2002 compared to the previous epochs. Similar trend has been
reported by other groups [2,3].
Studies from developed countries have focused on
identifying risk factors for mortality in preterm population [4-6].
However, there is dearth of similar data from developing countries.
Tagare, et al. [7] recently reported 56% survival among ELBW
neonates from a level III neonatal unit in India. Narayan, et al.
[8] observed a survival of 49% in the ELBW group from Northern India.
They found that lower birth weight and gestational age, asphyxia, air
leak syndrome, sclerema, seizures and acute renal failure were the risk
factors for mortality. But neither of them reported major morbidities or
associated risk factors.
Since neonatal care has changed significantly in the
last decade, it becomes relevant to study ELBW neonates and their
outcomes in the present scenario. Hence we planned this study to look at
the various risk factors affecting mortality and major morbidities among
ELBW neonates.
Methods
This prospective study was conducted in a level III
neonatal unit of a teaching hospital in Northern India between January
2009 and March 2011. All intramural neonates >23 weeks and between
400-999g birth weight were consecutively enrolled after obtaining
informed consent from parents. Exclusion criteria included presence of
life threatening malformations. All antenatal and natal details were
recorded in a predesigned, structured proforma. Gestational age was
based on maternal last menstrual period, urine pregnancy test and early
ultrasound and when dates were not reliable, ultrasound based assessment
was used and confirmed postnatally by New Ballard Score [9]. Small for
gestational age (SGA) was defined when birth weight was <10 th
centile in Lubchenco’s intrauterine growth charts [10]. These neonates
were followed till death or discharge. The study was approved by the
Institute Ethics Committee.
After initial stabilization, these neonates were
shifted to intensive care unit depending on the availability of beds and
parental consent. Those who were not shifted were provided compassionate
care in delivery room. Neonates with respiratory distress syndrome
received early rescue surfactant and nasal continuous positive airway
pressure (CPAP). Those failing CPAP were given a trial of nasal
intermittent positive pressure ventilation (NIMV) before initiating
mechanical ventilation. Prophylactic surfactant was not used. Trophic
feeding was initiated at the earliest and transitioned to full feeds
depending on tolerance. Vitamin A was not used as a standard therapy in
our unit. Blood culture by BACTEC
method was used for bacterial isolation in neonates with
suspected sepsis and antibiotics were initiated in them.
Echocardiography was performed for identification of hemodynamically
significant patent ductus arteriosus (PDA) in symptomatic babies and in
all ventilated babies within first 24 hours, if they remained
asymptomatic [11]. Persistent pulmonary hypertension of newborn (PPHN)
was defined on the basis of labile oxygen saturation, pre and post-ductal
oxygen saturation difference of >10% or pre- and post-ductal partial
pressure of arterial oxygen (PaO2)
difference of >20mmHg in the presence of echocardiographic evidence of
PPHN [12]. Hypotensive shock was defined as per Zubrow’s charts when
systolic and/or diastolic blood pressure (BP) was <5th
centile for the particular gestational age, weight and postnatal age
[13]. Packed red blood cell transfusion was given when PCV <35% in sick
neonates and <21% in asymptomatic neonates [14].
Risk factors for mortality as well as major
morbidities were pre-defined. Cause of mortality was assigned by two
independent experienced physicians in the unit, not involved in the
active management of the neonate.
Major morbidity was defined as the composite of one
or more of the following: Bronchopulmonary dysplasia (BPD), Retinopathy
of Prematurity (ROP) requiring laser therapy, grade III or IV
intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL)
and NEC stage III. BPD was defined based on the NICHD criteria of
receiving treatment with oxygen >21% for at least 28 days [15]. IVH was
graded using Volpe’s classification [16]. NEC was defined as per
modified Bell’s staging [17].
Statistical analysis: To determine the
association between each risk factor and outcome, chi-square test was
used for categorical variables and independent t test was used for
normally distributed continuous data and Mann- Whitney U test for skewed
data. Those risk factors that were significant on univariate analysis (P<0.05)
were entered in to a forward stepwise multivariable logistic regression
model and independent risk factors were determined. To adjudge the model
with the best fit, Hosmer-Lemeshow goodness-of-fit test was used and a
P value >0.05 was considered as good fit. Any association between
the risk factors was tested using correlation. Survival at discharge was
estimated by the method of Kaplan and Meier. Risk of death was compared
across the groups defined by the each of the independent predictors
using the log-rank test. P value <0.05 was considered
significant.
Results
Of the 255 ELBW infants born during the study period,
149 were admitted to the intensive care. The remaining could not be
transferred either due to non-availability of beds or lack of consent
from parents due to financial constraints. 78 (52%) of them were
discharged alive. 3 neonates discontinued therapy during the ICU stay,
but were included for analysis. The baseline characteristics of the
cohort are shown in Table I.
TABLE I Baseline Characteristics of the Study Subjects (n = 149)
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Characteristics
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No. (%)
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Gestational age (wks)* |
29.1 (2.6) (Range 23-36) |
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Birth weight (g) |
843 (108) (Range 446-997) |
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Males |
78 (52) |
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Multiple gestation |
29 (19) |
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SGA |
77 (52) |
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Received antenatal steroids
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111 (74) |
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PROM |
40 (27) |
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Delivered by LSCS |
48 (32) |
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Umbilical artery AEDF/REDF |
37 (25) |
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Medical illness in mother |
33 (22) |
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Obstetric problems in mother |
127 (85) |
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Apgar at 1 min# |
6 [3, 7] |
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Apgar at 5 min# |
8 [6, 9] |
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Age at intensive care# (hrs) |
10 [2.5, 27]
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* mean (SD) #median [IQR]. SGA – small for
gestational age, PROM-premature rupture of membranes, LSCS –
lower segment cesarean section, AEDF/REDF-absent/reversed end
diastolic flow.
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Of the 68 neonates that died, 9 (13%) died in the
first 24 hours, 35 (51%) died between 2 to 7 days, 18 (26%) between 8
and 28 days and 6 (9%) beyond 28 days. The predominant causes of
mortality were sepsis (46%), perinatal asphyxia (20%) and pulmonary
hemorrhage (19%). Others included extreme prematurity (6%), pulmonary
artery hypertension (4%), apnea (3%), aspiration pneumonia (1%) and NEC
(1%).
For the purpose of analysis, those neonates who
discontinued care (n=3) were grouped under those who died.
Univariate analysis for mortality is depicted in
Web Table I.
The final model with the best fit is given in Table II.
There was no significant correlation between any of the variables in the
regression model (all correlation coefficients were <0.8). This model
had an internal prediction accuracy of 83% and model fitted the data
well (Hosmer-Lemeshow goodness-of-fit, P=0.52). The C statistic
of the model was 0.82 (95% CI 0.75-0.89, P<0.001).
TABLE II Multivariable Logistic Regression Model for Prediction of Mortality
Risk factor
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Adjusted odds
ratio (95% CI) |
P
value |
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Birth weight £800g |
3.51 (1.39-8.89) |
<0.01 |
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Requiring invasive ventilation |
4.10 (1.64-10.28) |
<0.01 |
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Shock |
10.75 (4.00-28.89) |
<0.01 |
Kaplan Meier survival curves till discharge were made
for each independent predictor (Fig. 1). Survival of
neonates in the birth weight category >800g versus
£800g [60% (95%
CI-50-68%) vs. 44% (95% CI-33-56%), P=0.028], those
without and with shock [75% (95% CI-66-85%) vs. 24% (95%
CI-16-33%), P<0.001], those not mechanically ventilated versus
ventilated [73% (95% CI-64-83%) vs. 31% (95% CI-21-40%), P<0.001]
were statistically different.
Fifty seven neonates (39%) developed major
morbidities. These were BPD in 19 neonates (33%), Grade III or IV IVH in
39 neonates (68%), PVL in 8 neonates (14%), NEC stage III in 4 neonates
(7%) and ROP requiring laser therapy in 2 neonates (3%). The final model
with the best fit is given in Table III. Further, there
was no significant correlation between any of the variables in the
regression model (all correlation coefficients were <0.8). This model
had an internal prediction accuracy of 77% and model fitted the data
well (Hosmer-Lemeshow goodness-of-fit, P=0.31). The statistic of
the model was 0.74 (95% CI 0.65-0.83, P<0.001).
TABLE III Multivariable Logistic Regression Model for Prediction of Major Morbidity
Risk factor
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Adjusted odds ratio
(95% CI) |
P
value |
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Birth weight £800g |
3.75 (1.47-9.50) |
<0.01 |
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Not received antenatal steroids |
2.62 (1.00-6.79) |
<0.05 |
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Asphyxia
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4.11 (1.45-11.69) |
<0.01 |
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Ventilated |
4.38 (1.29-14.79) |
<0.05 |
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Duration of oxygen (h) |
1.004 (1.001-1.006) |
0.002 |
Discussion
We found that birth weight, hypotensive shock and
mechanical ventilation independently predicted mortality in ELBW
neonates while birth weight, lack of antenatal steroids, birth asphyxia,
ventilation and duration of oxygen therapy predicted major morbidities
in them.
The association between low birth weight and poor
outcomes has been well established in western literature. Fanaroff,
et al. [1] reporting NICHD network data showed that every 100g
reduction in birth weight was associated with increasing mortality. The
fact that we had more growth restricted babies in our study might be the
reason for gestational age not emerging significant in our analysis.
Other authors have also found higher mortality in their neonates <750g
and <28 weeks gestation [7,8].
We found hypotensive shock as the risk factor with
highest odds for mortality. Hypotension is common among ELBW neonates
and is strongly associated with mortality [18-20]. A retrospective study
showed that septic shock had a 28-day mortality of 40% and 71% mortality
among ELBW neonates [19]. The neonatal mortality in our ELBW neonates
with shock was 75%. The probable reason is that sepsis was the major
cause of mortality in our cohort and might have contributed to the
etiology of shock. Similar high rates of sepsis have also been reported
previously [7,8]. They found that sepsis accounted for 20-41% of
mortality among ELBW neonates, while it was 46% in our study.
Ventilation increased the odds of both dying and
major morbidity in our ELBW population. The possible mechanism is
through ventilator associated pneumonia (VAP). VAP is more common in
babies who are intubated compared to those on non-invasive ventilation
[21]. Ventilation per se can lead to IVH in preterms with RDS by
causing fluctuation in cerebral blood flow velocity (CBFV). A study on
neonates <1500g showed that 91% of them with fluctuating CBFV pattern
developed IVH compared to only 26% with stable CBFV pattern [22]. In
addition, mechanical ventilation can impede central venous return and
can cause raised intracranial pressure. It can further lower the cardiac
output [23]. All these factors can lead to hypoperfusion of the
periventricular white matter in the premature brain. ELBW neonates
getting ventilated longer have been shown to have a higher incidence of
cerebral palsy [24,25].
We also found that neonates with birth asphyxia had
three times the odds for developing major morbidity. Perinatal asphyxia
can predispose to brain injury by various mechanisms: increased cerebral
blood flow due to impaired vascular autoregulation, increase in central
venous pressure, decrease in cerebral blood flow due to hypotension and
due to the possible role of endogenous vasodilators [26]. Further,
ischemia affects the vulnerable periventricular white matter.
Duration of oxygen therapy was another predictor of
major morbidities. Hyperoxia inhibits lung and vascular growth resulting
in low volume lungs and causes interstitial edema by increasing
capillary permeability. This forms the basis why some authors consider
oxygen toxicity as the principal cause of BPD [27]. Oxygen mediated free
radical injury also plays a role in causing BPD, IVH and PVL. Its role
in causing ROP has remained controversial even though recent studies
show that targeting lower oxygen saturations may reduce its incidence in
preterm infants [28].
Ours is the first prospective study with adequate
sample size in a developing country setting looking at predictors of
mortality and morbidities in ELBW neonates. All neonates who were
enrolled were followed till death or discharge without loss to follow
up. The regression models showed good internal prediction accuracies. We
also provided separate survival curves for neonates with each of these
independent risk factors that will help treating physicians in
prognostication of these neonates. However, our drawback was that we did
not use a clinical score at baseline for assessing the severity of
illness in these neonates. Being a referral centre along with very high
patient turn over, a significant proportion of neonates were not shifted
or shifted late to the intensive care area. Our results may not be
generalizable to those who did not get admitted to the NICU.
Contributors/i>: KM: conceptualized the study,
supervised data collection and reviewed the manuscript; DL: Analyzed
data and prepared the manuscript; RM: Collected data; PK: Critically
reviewed the manuscript.
Funding : PGI Research scheme; Competing
interests:: None stated.
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What This Study Adds?
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Sepsis, asphyxia and pulmonary
hemorrhage were the major causes of mortality in ELBW neonates.
•
Low birth weight, mechanical ventilation and hypotensive
shock were independent predictors of mortality among them.
• LLow birth weight, lack of antenatal steroids, asphyxia, any
ventilation and duration of oxygen therapy were predictors of
major morbidity among ELBW neonates.
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