*These authors contributed equally to this work.
The outcomes of small for gestational age (SGA) infants especially in extremely low birth weight infants (ELBWIs) are controversial. This study evaluated the mortality and morbidity of ELBWIs, focusing on whether or not they were also SGA.
The medical records of 415 ELBWIs (birth weight <1,000 g), who were inborn and admitted to the Samsung Medical Center neonatal intensive care unit from January 2000 to December 2008, were reviewed retrospectively. Mortality and morbidities were compared by body size groups: very SGA (VSGA), birth weight ≤3rd percentile; SGA, 3rd to 10th percentile; and appropriate for gestational age (AGA) infants, >10th percentile for gestational age. For gestational subgroup analysis, groups were divided into infants with gestational age ≤24+6 weeks (subgroup I), 25+0 to 26+6 weeks (subgroup II), and ≥27+0 weeks (subgroup III).
Gestational age was 29+2±2+6 weeks in the VSGA infants (n=49), 27+5±2+2 weeks in the SGA infants (n=45), and 25+4±1+4 weeks in AGA infants (n=321). Birth weight was 692±186.6 g, 768±132.9 g, and 780±142.5 g in the VSGA, SGA, and AGA groups, respectively. Cesarean section rate and maternal pregnancy-induced hypertension were more common in the VSGA and SGA than in AGA pregnancies. However, chorioamnionitis was more common in the AGA group. The mortalities of the lowest gestational group (subgroup I), and also of the lower gestational group (subgroup I+II) were significantly higher in the VSGA group than the SGA or AGA groups (
Of ELBWIs, extremely SGA in the lower gestational subgroups, had an impact on mortality, which may provide information useful for prenatal counseling.
With social and environmental changes including increased maternal age and advances in in vitro fertilization techniques, the risk of preterm birth has increased. Of all preterm births, the proportion of extremely low birth weight infants (ELBWIs) has been rising; for example, the birth rate of ELBWIs in Korea increased by 360% from 1993 to 2007
In most preterm deliveries, small for gestational age (SGA) infants are generally associated with intrauterine growth restriction, which is caused by an inadequate supply of oxygen and nutrients that is attributable to placental insufficiency
In this study, we evaluated the mortality and morbidity of ELBWIs focusing on whether or not the infants were SGA. We hypothesized that the prognosis for SGA ELBWIs would be different from appropriate for gestational age (AGA) ELBWIs, depending on the gestational subgroups and the severity of SGA.
This study was retrospective, involving 415 infants born with weight below 1,000 g and admitted to Samsung Medical Center NICU between January 2000 and December 2008. Among these infants, we excluded 1 infant with a gestational age of 21 weeks who died soon after birth. There were no cases of congenital anomalies, such as chromosomal abnormality or congenital infection.
For gestational subgroup analysis, infants of gestational age ≤24+6 weeks formed subgroup I, infants between 25+0 and 26+6 weeks formed subgroup II, and infants of gestational age≥27+0 weeks formed subgroup III. The number of infants in each subgroup was as good as equally distributed (subgroup I, n=126; subgroup II, n=151; subgroup III, n=138).
The parents consented to have their infants cared for in the NICU and enrolled in the study using retrospective chart review.
We reviewed maternal medical records for factors including multiple pregnancy,
Gestational age was calculated by last menstrual period, evaluated by early prenatal obstetric ultrasonography, and confirmed by modified Ballard Score examined within 12 hours after birth
Neonatal mortality was defined as death before discharge. RDS was defined as respiratory distress needing oxygen over 40% to maintain PaO2 over 50 mmHg with radiological findings of air-bronchogram, decreased lung volume, and bilateral reticular infiltration. Because RDS can be assessed soon after birth, mortality cases were included in the count of RDS.
PDA was clinically diagnosed by symptoms and signs and confirmed by echocardiography. PDA was treated by indomethacin and/or surgical ligation. Surgery was done in cases of contraindications to indomethacin or failed indomethacin therapy. The definition and severity of BPD was investigated according to the criteria established by Jobe and Bancalari
All analyses were performed using SPSS ver. 12.0 (SPSS Inc., Chicago, IL, USA). Categorical variables were analyzed by χ2 test for a parametric test and Fisher's exact test for non-parametric test, and comparisons of continuous variables were conducted with one-way analysis of variance for a parametric test and Kruskal-Wallis test for a non-parametric test.
Multivariate logistic regression analyses were done to evaluate outcomes after adjusting for confounding factors. Factors significant in the univariate analysis were included in the initial model. The demographic variables of gestational age, maternal PIH, pathologic CAM, and mode of delivery were considered confounding factors. Each variable was assessed by each outcome. Interactions between variables were considered, and a stepwise selection was used for modeling. For the final models, goodness-of-fit test was done according to the Hosmer and Lemeshow method of multivariate analysis.
The average gestational age was 26+2±2+2 weeks (range, 23+0 to 34+4 weeks) and birth weight was 768±149 g (range, 350 to 999 g) in 415 ELBWIs. The number of VSGA, SGA, and AGA infants was 49 (11.8%), 45 (10.8%), and 321 (77.3%), respectively.
The proportion of VSGA or SGA infants did not significantly increase during the time period; however, the ratio of infants with lower gestational age did increase (
There were 126 patients in subgroup I (≤24+6 weeks), which was composed of 4 (3.2%) VSGA, 7 (5.6%) SGA, and 115 (91.3%) AGA infants. There were 151 patients in subgroup II (25+0 to 26+6 weeks) with 8 (5.3%) VSGA, 3 (2.0%) SGA, and 140 (92.7%) AGA infants. There were 138 patients in subgroup III (≥27+0 weeks) with 37 (26.8%) VSGA, 36 (26.1%) SGA, and 65 (47.1%) AGA infants.
The etiologies of being small were investigated, and PIH was identified as a dominant factor in both the SGA (25/45, 55.6%) and VSGA (30/49, 61.2%) groups. In the SGA group, discordant twin, gestational diabetes in the mother, and advanced maternal age contributed to 22.2% (10/45). Other risk factors for being small included donors of twin-to-twin transfusion cases, 6.7% (3/45) and preterm labor with oligohydramnios (because of membrane rupture), 15.6% (7/45). In the VSGA group, factors leading to being small were discordant twin, placental anomaly, cord blood flow abnormality, maternal vascular disease, 26.5% (13/49), oligohydramnios with or without membrane rupture, 10% (5/49), and donor of twin to twin transfusion case, 2% (1/49).
The total mortality rate in ELBWIs was 24.1% (100/415). The mortality rate in each of the VSGA, SGA, and AGA groups is described in
When analyzed by gestational subgroups, the mortality rate of subgroup I was 100% (4/4) in the VSGA group, resulting in a significant difference compared to AGA infants (
The mortality in subgroup II was higher in the VSGA than in SGA or AGA group, however, there was no statistical significance. Subgroup II had only 3 mortality cases in the VSGA group. Causes of death were severe asphyxia, air leak, and bowel perforation with NEC, and all death were within 28 days of birth. The main causes of death in subgroup II AGA infants were not different from subgroup I.
Because the number of VSGA and SGA cases in subgroup II was small, the statistics of infants in subgroup I and II were assessed together. VSGA infants with gestational age <27 weeks (subgroup I+II) showed significantly increased mortality compared to AGA infants with gestational age <27 weeks (
The mortality rate in subgroup III was not different in the VSGA, SGA, and AGA groups after adjusting a confounding factor, gestational ages.
The VSGA group showed a significantly lower incidence of RDS, symptomatic PDA, ductal ligation, BPD (≥moderate), and IVH (≥grade 3) than the non-SGA group. However, by gestational subgroup analysis, the difference was not significant especially in subgroup I and II. In subgroup III, VSGA infants had lower RDS frequency than SGA or AGA infants (
This study examined the effect of small for gestational age on mortality and morbidity in ELBWIs. The prognosis of preterm SGA infants, especially ELBWIs, is controversial because there are few studies of preterm SGA infants, and most of the outcomes have been confounded by varying gestational age and different populations. This retrospective study covering nine years was done in a single center, which is one of the largest NICUs in Korea. The ratio of ELBW SGA infants and the outcomes according to gestational age were not significantly different during the period, although the proportion of infants with lower gestational age has increased.
ELBW SGA infants seem to have a similar pathogenesis of being small, which is distinct from term or near term SGA infants who may have other etiologies of growth restriction. ELBW SGA infants were more likely to be born from PIH mothers. The pathogeneses of being small, maternal vascular disease, cord blood flow abnormality, placental anomaly, smaller placenta of discordant twins are all similar to PIH because they can cause 'placental insufficiency'. In this study, the etiologies causing 'placental insufficiency' were present in 78% of SGA and 88% of VSGA groups. In contrast, ELBW AGA infants were more likely to be born from mothers with CAM mainly after preterm premature rupture of membranes. Thus, SGA and AGA preterm infants may experience different
In this study population, SGA infants were analyzed by SGA severity. The study showed that overall survival of VSGA, SGA, and AGA infants was similar. However, in subgroup I, the VSGA infants showed significantly higher mortality compared to AGA infants. Asphyxia was the main cause of death in the subgroup I VSGA infants, consistent with significantly lower Apgar scores in this group. It follows that the smaller the baby, the more their birth condition is an immediate extension of the
The most serious morbidities that led to mortality were pulmonary hypertension (r2=0.606,
Our result regarding NEC are inconsistent with some studies
RDS was decreased in the subgroup III VSGA group. Other studies report that the incidence of RDS is decreased in SGA infants due to accelerated lung maturation related to the stressful intrauterine environment
This study showed that the rate of BPD (≥moderate) was not significantly different depending on body size, after adjusting for gestational age. The prevalence of BPD in SGA infants is important in terms of long-term neurological outcome. There are some data suggesting that there are higher BPD rates in preterm SGA infants with longer ventilator duration and hospital stay than in AGA infants, which implies poorer neurologic outcomes in preterm SGA infants
The rate of symptomatic PDA and ductal ligation was not significantly different according to body size according to a multivariate analysis. The effect of being small on PDA is also controversial. Several studies have suggested that maternal PIH may reduce the risk of symptomatic PDA because mothers with PIH are likely to deliver before labor and thus, have a low possibility of prostaglandin exposure which is known to be important for ductal patency
The incidence of IVH in SGA infants is also controversial. Some studies have reported that the incidence of IVH is decreased in SGA infants from PIH mothers, suggesting that pre-exposure to hypoxia may induce adaptive mechanisms, with fetal cerebral blood flow modulated by prostanoids
This study has a few limitations due to some missing infants whose birth weight might be over 1,000 g while gestational age at birth could be in the range of subgroup III. Thus, no significant difference in mortality and morbidity according to body size in subgroup III is inconclusive. However, the mortality difference according to body size with a summation of subgroup I and II, can be a useful information in the perinatal medicine. Getting information of micropremies below 27 weeks of age at birth, is now available due to advanced neonatal intensive care medicine. The number of SGA infants below 27 weeks of gestation is usually not enough for the investigation, though. Thus, survived SGA infants of lower gestational age should be more investigated for the understanding of morbidity outcomes.
Demographic Findings in Extremely Low Birth Weight Infants According to Body Size
Values are presented as mean±SD or number (%).
VSGA, very small for gestational age (birth weight ≤3rd percentile for gestational age); SGA, small for gestational age (birth weight between 3rd to 10th percentile for gestational age); AGA, appropriate for gestational age (birth weight 10th to 90th percentile for gestational age); IVF, in vitro fertilization, PIH, pregnancy-induced hypertension; CAM, chorioamnionitis.
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Mortalities in Extremely Low Birth Weight Infants According to Gestational Subgroups and Body Size
Values are presented as number (%) or mean±SD.
VSGA, very small for gestational age (birth weight ≤3rd percentile for gestational age); SGA, small for gestational age (birth weight between 3rd to 10th percentile for gestational age); AGA, appropriate for gestational age (birth weight 10th to 90th percentile for gestational age).
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Morbidities in Extremely Low Birth Weight Infants According to the Body Size
Values are presented as number (%) or mean±SD.
VSGA, very small for gestational age (birth weight ≤3rd percentile for gestational age); SGA, small for gestational age (birth weight between 3rd to 10th percentile for gestational age); AGA, appropriate for gestational age (birth weight 10th to 90th percentile for gestational age); RDS, respiratory distress syndrome; PDA, patent ductus arteriosus; BPD, bronchopulmonary dysplasia; IVH, intraventricular hemorrhage; PVL, periventricular leukomalacia; NEC, necrotizing enterocolitis; TPN, total parenteral neutrition; NA, not applicable.
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