Extremely low birth weight (ELBW) infants (birth weight <1000 g) have high rates of mortality and morbidity.1 2 The survival of ELBW infants has improved significantly with the widespread use of exogenous surfactant agents, maternal steroids, mechanical ventilation, and advancements in neonatal technologies.1 3 4 5 6 7 The minimum age of viability is currently regarded as 21 to 22 weeks’ gestation; accordingly, there have been scattered reports of survivors born at 21 to 22 weeks’ estimated gestation.2 8 9 10 11 Periviable birth is defined as delivery occurring from 20 weeks to 25 weeks 6 days of gestation.12 Notably, the rate of survival at 3 years for infants born at 22 weeks’ gestation has been reported as approximately 36% in some centres.13 This study aimed to review mortality and morbidity of ELBW infants at a tertiary neonatal unit in Hong Kong.

Demographic and clinical data were analysed for consecutive neonates admitted to the neonatal unit of a university-affiliated teaching hospital (Prince of Wales Hospital) in Hong Kong between 1 January 2010 and 30 June 2017. During the study period, the Prince of Wales Hospital provided regional neonatal intensive care service for the Eastern New Territories of Hong Kong, with a catchment population of over 1.1 million (approximately 25% were children aged <12 years). A standard data form was used for data abstraction by the investigators. All Clinical Management System records, in-patient records, and computerised laboratory data were examined. Numerical data were expressed as median (interquartile range) and compared by using the Mann-Whitney U test; categorical data were compared by using the Chi squared test, or Fisher’s exact test for data fields that contained >20% cells with an expected count <5. Backward binary logistic regression was conducted on mortality; backward linear regressions were conducted on lengths of neonatal intensive care unit (NICU) stay and hospital stay for survivors. Corresponding Kaplan-Meier survival curves were constructed with survival distribution comparisons by log-rank test using SPSS (Windows version 20.0; IBM Corp, Armonk [NY], US). Two-tailed P values <0.05 were considered statistically significant.

A total of 78 ELBW neonates were admitted to the NICU between 1 January 2010 and 30 June 2017; 16 of these neonates died (mortality 21%) [Table 1]. For non-survivors and survivors, the median gestational ages were 24.1 and 26.2 weeks, respectively, and birth weights were 650 and 780 g, respectively (P<0.001). The median (interquartile range) of NICU stay before death was 2.5 (2.0-11.5) days. The median durations of NICU stay and total hospital stay among survivors before discharge were 93.5 days and 4.1 months, respectively. Backward binary logistic regression analysis showed that non-survival was associated with lower gestational age (adjusted odds ratio [aOR]=6.71 for every 1-week decrease; 95% confidence interval [95% CI]=1.73-26.00; P=0.006) and grade 3 or 4 intraventricular haemorrhage [IVH] (aOR=29.23; 95% CI=1.39-613.84; P=0.030); non-survival was negatively associated with the presence of bronchopulmonary dysplasia (BPD) [aOR=0.01; 95% CI=<0.001-0.23; P=0.005), after adjustment for multiple births, caesarean section, birth weight, Apgar score at 1 minute, antenatal steroid administration, infant apnoea, necrotising enterocolitis (NEC), retinopathy of prematurity (ROP), and anaemia of prematurity in the first step of the regression analysis (Table 2). Backward linear regression revealed that the length of NICU stay for survivors was positively associated with the presence of NEC (B-coefficient=89.60; 95% CI=43.86-135.34; P<0.001), after including gestational age, caesarean section, birth weight, Apgar score at 1 minute, and blood stream infection in the first step of the regression analysis (Table 3). The length of hospital stay was positively associated with presence of NEC (B-coefficient=2.08; 95% CI=0.43-3.73; P=0.015), but negatively associated with Apgar score at 1 minute (B-coefficient= –0.63; 95% CI= –1.04 to –0.22; P=0.003), after including gestational age, birth weight, Apgar score at 1 minute, and Apgar score at 5 minute in the first step of the regression analysis (Table 3).

Survival curves were constructed for gestational age (Fig 1) and birth weight (Fig 2). Median Kaplan-Meier survival estimates for gestational ages <24, 24, and 26 weeks were 43%, 52%, and 92%, respectively (no death records were available for other groups), during the period of postnatal NICU stay before discharge; importantly, their survival distributions were significantly different (χ²=31.1; P<0.001). Median Kaplan-Meier survival estimates for birth weights <600 g, 600 to 699 g, and 700 to 799 g were 55%, 63%, and 81%, respectively (no death records were available for other groups); their survival distributions were significantly different (χ²=13.9; P=0.008) [Fig 2].

Extremely low birth weight infants, especially those born at periviable gestations of 22 to 23 weeks, exhibit significantly higher mortality. In this cohort of ELBW infants, we confirmed two independent factors associated with ELBW non-survival: gestation age below 24 weeks and the presence of grade 3 or 4 IVH. Although not specifically analysed in this series, congenital anomalies did not appear to be a pertinent risk factor influencing survival among ELBW infants. Among infants in the non-survival group, the median time until death was 2.5 days after birth; in our series, no survival was observed for ELBW infants whose birth occurred prior to 23.6 weeks or who exhibited birth weight of <550 g. These local data are expected to be useful in counselling pregnant women who are at risk for the delivery of ELBW infants. Non-survival was associated with an increased aOR of 6.7 for every 1-week decrease in gestation.

In addition to perinatal mortality, long-term survival was also low. A previous report stated that first-year survival was 15.5% for infants whose birth weight was <500 g.14 Infants with ELBW are more susceptible to all complications of prematurity, both during the immediate neonatal period and after discharge from the nursery. A study by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network,15 undertaken to relate other known risk factors with the likelihood of survival and impairment, reported that 83% of infants born at 22 to 25 weeks’ gestation received intensive care involving mechanical ventilation. Of the infants whose outcomes were known at 18 to 22 months, 49% died, 61% died or had profound impairment, and 73% died or had impairment.

Additional reports have suggested that other factors should be considered, in combination with gestational age, when determining the likelihood of favourable outcomes with intensive care.15 16 17 18 19 According to the data from a 2011 cohort study, infants born at 23 to 25 weeks’ gestation who received antenatal exposure to corticosteroids exhibited a lower rate of mortality and complications, compared with infants who did not have such exposure.16 Recently, chorioamnionitis was linked to preterm birth and neonatal infection. In a longitudinal observational study that included 2390 extremely preterm infants (gestational age <27 weeks), Pappas et al20 reported that antenatal exposure to chorioamnionitis appeared to increase the odds of cognitive impairment, as well as death/neurodevelopmental impairment.

Survival occurred in 79% of ELBW infants at our centre. Extremely low birth weight survivors exhibited significant morbidity. Our series showed that BPD, severe IVH, NEC, and ROP were present in 81%, 20%, 26%, and 34% of survivors, respectively. Notably, the survivors experienced long stays in the NICU and hospital prior to discharge. Necrotising enterocolitis is particularly associated with long stays in the NICU and hospital. The sequelae of low birth weight have been well-studied, but less information is available regarding sequelae of ELBW.21 Low birth weight is generally closely associated with fetal and perinatal mortality and morbidity, inhibited growth and cognitive development, and a risk of chronic diseases later in life. At the population level, the proportion of infants with low birth weight is an indicator of a multifaceted public health problem that includes long-term maternal malnutrition, poor health, hard work, and poor health care during pregnancy. On an individual basis, low birth weight is an important predictor of newborn health and survival, and is associated with a higher risk of infant and childhood mortality.21 In this regard, ELBW represents the most severe subset of low birth weight outcomes.

Bronchopulmonary dysplasia, grade 3 or 4 IVH, and ROP occurred in a significant proportion of the survivors. Our morbidity data are comparable to those reported in multiple large studies.8 22 23 In recent years, ELBW infants have constituted more than 97% of cases of BPD.24 Importantly, NEC is the most common intestinal emergency in preterm infants.25 26 The routine use of antenatal steroids and surfactant therapy has resulted in increased survival of infants with ELBW, thereby increasing the survival rate in the group at the greatest risk.27

The incidence and severity of IVH are inversely related to gestational age. Infants with ELBW are at particular risk for IVH; however, the use of antenatal steroids decreases the incidence of IVH. Prognosis is correlated with the grade of IVH28; up to 40% of infants with grade 3 IVH exhibit significant cognitive impairment, and up to 90% of infants with grade 4 IVH exhibit major neurologic sequelae, requiring lifetime care. Notably, a study of 1064 infants born at ≤28 weeks’ gestation found that, unless it was accompanied or followed by a white matter lesion, low-grade IVH was associated with a modest to nonexistent risk of adverse developmental outcomes during infancy.29

The outcomes of ELBW infants are evolving as therapy and supportive care continue to change.1 Clinical focus should be placed on the prevention of premature births, as well as equipping NICU staff and facilities with the necessary skills and resources, respectively, to implement evidence-based interventions that improve the survival of ELBW infants. Efforts to minimise injury, preserve growth, and identify interventions focused on antioxidant and anti-inflammatory pathways are currently being evaluated. Thus, treatment and prevention of long-term deficits must be developed in the context of an evolving target. Ensuring health in cases of extreme prematurity (≤23 weeks’ gestation) is extremely difficult.2 Most centres do not have minimum birth weight criteria for resuscitation; often, a “trial of life” may be discussed with the parents before the birth of the infant so that the infant can be resuscitated and evaluated for viability after birth. Viability is the term frequently used to indicate the potential for a fetus to be liveborn and capable of surviving to a specified endpoint (eg, a designated time, attainment of a certain age or landmark event, admission to the NICU, or discharge from the hospital). Many institutions have generated centre-specific data regarding the probability of survival to aid in discussions with families prior to delivery. Discussions regarding the withdrawal of treatment or support are often necessary when the family and medical team agree that the continuation of medical treatment is not in the infant’s best interests. Naturally, these circumstances involve numerous ethical, moral, and legal issues; they may generate more questions than answers. Therefore, each centre caring for ELBW infants must carefully follow and analyse their particular survival statistics, in order to better inform and guide parents concerning the outcomes and prognoses of these periviable infants.

Concept or design: KL Hon, S Liu, JCY Chow.
Acquisition of data: KL Hon, S Liu, JCY Chow.
Analysis and interpretation of data: KL Hon, KYC Tsang.
Drafting of the article: KL Hon, Y Cheng, AKC Leung.
Critical revision for important intellectual content: All authors.

As an editor of the journal, KL Hon was not involved in the peer review of the article. All authors have disclosed no conflicts of interest. All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethics approval for this study was obtained from the Clinical Research Ethics Committee of The Chinese University of Hong Kong.

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