Abstract
Background
Very preterm infants born small for gestational age (SGA) are at risk for short- and long-term excess mortality and morbidity resulting from immaturity and deficient intrauterine growth. However, previous findings are inconclusive, and there is a paucity of contemporary data in Chinese population.
Objectives
To evaluate the excess risks of mortality and morbidity independently associated with SGA birth in very preterm (before 32 weeks of gestation) Chinese infants.
Materials and Methods
The study population included all very preterm infants admitted to the neonatal intensive care units (NICUs) in our hospital and our medical treatment partner hospitals during a 6-year period. The SGA group consisted of 615 SGA infants, and 1230 appropriate-for-gestation-age (AGA) infants were matched with GA and sex as controls at a ratio of 2:1. The associations between SGA birth and outcomes (in-hospital mortality and morbidity) were evaluated by using multivariate logistic regression analysis after adjustment for potential confounders. The CRIBII score was used to indicate admission illness severity, acting as a covariate in the multivariate analysis.
Results
The SGA group was associated with increased risks of mortality [odds ratio (OR) 2.12; 95% CI: 1.27–3.54] and BPD [OR 1.95; 95% CI: 1.58–2.41] compared to the AGA group. No significant incidences of respiratory distress syndrome (RDS), severe retinopathy of prematurity (sROP), severe intraventricular hemorrhage (sIVH), and necrotizing enterocolitis (NEC) were observed in the SGA group. Further GA-stratified subgroup analysis showed SGA status exhibited certain patterns of effects on mortality and morbidity in different GA ranges.
Conclusions
SGA status is associated with excess risks of neonatal mortality and BPD in very preterm infants, but the increased risks of mortality and morbidity are not homogeneous in different GA ranges. The contemporary data can help inform perinatal care decision-making and family counseling, particularly for very preterm SGA neonates.
Introduction
SGA is highly prevalent in low- and middle-income countries, particularly in South Asia [Citation1]. SGA birth, commonly used as a proxy for intrauterine growth restriction, increases the risk of mortality and morbidity in the neonatal period and beyond. It is generally acknowledged that infants born before 32 weeks of gestation suffer “double jeopardy,” as the combined presence of prematurity and SGA confers a higher risk than that of either characteristic alone [Citation2,Citation3].
Although the association between SGA birth and adverse outcomes among very preterm infants has been widely investigated, the strength and direction are not fully established. The divergence has been commonly attributed to the GA range, sample size, and the presence of confounding factors, including illness severity [Citation4].
Admission illness severity has a substantial impact on mortality and morbidity of preterm infants. However, most studies, especially population-based ones, did not use appropriate measurement to adjust for it. The clinical risk index for babies (CRIB) II is a widely used neonatal illness severity scoring system in NICU which provides a recalibrated and simplified measurement within 12h of admission, avoiding the potential problems of early treatment bias [Citation5]. Its applicability has been confirmed by many prediction models [Citation6].
With the improvement of maternal and perinatal care over time, more contemporary data is needed to inform decision-making in NICU, family counseling, and prediction of adverse outcomes associated with SGA birth. Therefore, we conducted the present study to evaluate the excess risk of mortality and morbidity independently associated with SGA status in very preterm Chinese infants.
Patients and methods
Study population
The medical records of all very preterm (before 32 weeks of gestation) infants admitted to the NICUs at the First Affiliated Hospital of Shantou University Medical College and its medical treatment partner hospitals between 1 January 2015 and 31 December 2020 were reviewed. Demographic and clinical data were retrieved from clinical progress notes and discharge summaries in the electronic patient record database. The records were identified using the following ICD-9 codes: preterm (644.21), premature (644.21), and small for gestational age (656.5x). Infants with a GA under 32w were included. An infant was defined as SGA if the birth weight was below the 10th percentile according to the latest sex-specific birth weight for GA standards in Guangdong Province, China [Citation7,Citation8]. Exclusion criteria included congenital anomalies and neonatal death during delivery.
The SGA group consisted of 615 SGA infants with a GA between 24w2/7∼ 31w6/7, and 1230 appropriate-for-gestation-age (AGA) infants were matched with controls of the same GA and sex at a ratio of 2:1. The GA in weeks and days was determined by the last menstrual period or by prenatal ultrasound if the last menstrual period was uncertain.
The ethical committee of the First Affiliated Hospital of Shantou University Medical College approved the study with a waiver of consent.
Outcome definitions
The study outcomes were death; respiratory distress syndrome (RDS); bronchopulmonary dysplasia (BPD); severe (stage 3–5) retinopathy of prematurity (sROP); severe (grade 3–4) intraventricular hemorrhage (sIVH); and necrotizing enterocolitis (NEC).
Mortality was defined as death before hospital discharge. RDS was defined as: room air partial pressure of oxygen (PaO2) >50mm Hg, or supplemental oxygen to maintain a pulse oximeter saturation over 85%; and a chest radiograph consistent with RDS within the first 24 h of life [Citation9]. BPD was defined as continuous use of supplemental oxygen at 36 weeks’ post-menstrual age or on oxygen at discharge at 34 to 35 weeks if discharged before 36 weeks [Citation10]. Severe ROP was defined as stages 3 to 5 on the basis of a retinal examination before hospital discharge [Citation11]. Severe IVH was defined as grades 3 or 4 by using Papile’s classification within 28 days of birth [Citation12]. NEC was diagnosed based on >1 clinical signs and >1 radiographic findings [Citation13].
Statistical analysis
Comparisons of the independent and outcome variables, in either the entire population or its GA subgroups, were made using Student’s t-test or Wilcoxon rank-sum tests according to the data distribution. Normality test was applied to determine the data distribution. Continuous variables were expressed as the mean ± SD. or median with interquartile range if the data were skewed. A value of p < 0.05 was considered to be statistically significant. Post hoc sample size calculations were performed to ensure statistical power.
The following neonatal and maternal characteristics were included as covariates: sex, gestation age, birth weight, head circumference at birth, length at birth, multiple birth, in-vitro fertilization (IVF), cesarean section, use of antenatal steroids, Apgar scores at 1 min, Apgar scores at 5 min, mechanical ventilation, surfactant administration, the CRIBII score, sepsis, patent ductus arteriosus (PDA), length of hospitalization (LOS), premature rupture of membranes (>18 h) (PROM), and maternal age.
Multivariate logistic regression models were developed and performed following adjustment for the potential confounding variables. The results are presented as odds ratios (OR) plus 95% confidence intervals (CI). The variables to be adjusted included most of the above-mentioned ones, particularly CRIBII as a proxy of admission illness severity. The dependent variable was considered to be significantly associated with the outcome if the odds ratio (OR) differed from 1.0 and p < 0.05.
In regression models predicting specific outcomes, the included independent variables were those factors that might possibly affect the outcome variables, based on clinical experience and previous literature. For example, the model predicting BPD included variables such as use of antenatal steroids, mechanical ventilation, surfactant administration, and prevalence of RDS.
GA-stratified subgroup analysis can explore unique mortality and morbidity characteristics that differ from those of the group as a whole. To investigate the association of SGA with outcome variables in different GA subgroups, the logistic analysis was further performed in three GA strata: 24–27 weeks (from 24w2/7 to 27w6/7 exactly), 28–29 weeks (28w to 29w6/7) and 30–31 weeks (30w to 31w6/7).
Statistical analysis was performed by using Stata version 12 (Stata Corporation, College Station, TX, USA).
Results
A total of 1845 infants with a GA of 24–31 weeks were hospitalized in our NICUs during the 6-year period. Of them, 615 were SGA, and 1230 were AGA. Demographic, perinatal, maternal, baseline clinical data were compared between the SGA and AGA groups, as shown in . The mortality and morbidity rates were compared between the SGA and AGA groups, as presented in .
Table 1. Demographic and perinatal characteristics of the SGA and AGA groups.
Table 2. Mortality and morbidity rates of the SGA and AGA groups.
Overall adjusted odds ratios with 95% CI of outcome variables for the SGA group are presented in . The SGA group was significantly associated with increased odds of mortality [OR 2.12; 95% CI: 1.27–3.54] and BPD [OR 1.95; 95% CI: 1.58–2.41] compared with the AGA group. The SGA group did not show statistically significant odds of RDS, sROP, sIVH, or NEC. The GA-stratified subgroup analysis found that increased odds of mortality remained significant in the subgroup with a GA of 28–29 weeks. The significance of increased odds of BPD remained in the subgroups with a GA of 24–27 weeks and 30–31 weeks. Different from the insignificant results in the full GA range, the SGA birth was significantly associated with increased odds of RDS in the lowest GA subgroup.
Table 3. Multivariate-adjusted odds ratio (95% CI) of outcome variables for the SGA group and subgroups stratified with gestational age (the AGA groups and subgroups as reference).
Discussion
The present study found the GA infants who were very preterm had increased mortality and an increased incidence of BPD compared with their AGA peers with a GA of 24–31 weeks after adjusting for potential confounding factors. Recently, a population-based multi-center study discovered increased risks of death, BPD, RDS, sROP, and NEC among SGA very preterm infants, but the risks are not homogeneous across the GA range [Citation14]. Further GA-stratified analysis confirmed similar patterns in mortality and morbidity risks across the GA range.
Substantial studies reveal that premature SGA infants have been shown to be at a greater than 1 to several-fold increased risk for mortality and major neonatal morbidity. It is generally believed that the underlying mechanism is that the continuing effect of suboptimal fetal growth intensifies complications of prematurity.
Mortality
We observed an increased odds of death in the full GA range [OR 2.12; 95% CI: 1.27–3.54] and the middle GA subgroup [OR 2.88; 95% CI: 1.02–8.26].
Increased mortality rates related to SGA birth have been reported in most of previous studies [Citation2,Citation14–23]. Several lines of research suggest that excess mortality and morbidity among SGA compared with AGA preterm infants stems from an additive “double insult” due to fetal growth restriction and postnatal sequelae attributed to prematurity [Citation3,Citation4]. A population-based cohort study proposes that the prevention of neonatal death should focus on combined preterm birth and concomitant severe SGA, which serves as a useful perinatal surveillance indicator [Citation2].
Boghossian et al. reported that SGA infants had 1.02 to 2.87-fold higher risks of mortality compared with AGA peers starting at a GA of 23 weeks, which increased until 29 weeks in a population-based multicenter study [Citation14].
In the analysis stratified by GA, we didn’t observe the significant mortality increase that remained in the lowest GA subgroups. This pattern was similar to the findings of a case-control study from Taiwan [Citation17] and a mortality pattern study from Greece [Citation24]. We speculate that prematurity predominates growth restriction at the early GA (24–27 weeks), which may shadow the adverse effects of SGA birth. However, such a pattern did not exactly match the findings from an early report [Citation21].
The mechanisms for the increased mortality among premature SGA infants are not fully understood. Presumably, unfavorable intrauterine environment exerts a detrimental effect on various organs, which leads to deprivation of nutrients and oxygen, may trigger off a cascade of adverse respiratory, neurological, and metabolic events. Various adverse morbidities, including RDS, BPD, sROP, NEC, etc., may be interpreted as a constellation of physiologically linked sequelae contributing to the higher risk of mortality observed.
BPD
The need for oxygen supplementation at the age of 28 days or at 36 weeks’ postmenstrual age has generally been acknowledged among SGA infants, which reflects a continuum of adverse events, including a systemic inflammatory response secondary to intrauterine hypoxia and acidosis, and more severe early neonatal lung diseases.
Multivariate logistic analysis showed the association between SGA status and BPD was significant [OR 1.95; 95% CI: 1.58–2.41] after adjusting for the confounding factors. The result was in concordance with the findings of most previous studies [Citation14,Citation17,Citation21,Citation25–27]. In GA stratified analysis, the increased risks for BPD remained significant in the SGA infants with a GA of 24–27 weeks [OR 2.45; 95% CI: 1.15–5.21].
Boghossian et al. reported the risks of BPD were 1.84- to 3.56-fold among SGA infants with a GA of 22–29 weeks [Citation14]. Nobile et al. discovered that being SGA is significantly associated with BPD [OR 2.69] [Citation25]. Tsai et al. found the SGA group is associated with increased risks of BPD [OR 2.08] compared to the AGA group [Citation17]. Qiu et al. observed that SGA infants have a higher odds of BPD [OR 1.78] [Citation26]. Regav et al. reported that SGA infants have a 3.42-fold risk of BPD [Citation21]. Sharma et al. observed that SGA infants had a significantly higher risk for developing BPD as compared to AGA infants [OR 2.2] [Citation27]. Other studies also found that SGA infants have an increased risk of developing BPD but did not report relative risk data [Citation15,Citation16,Citation20,Citation23,Citation24,Citation28].
The higher risk of BPD associated with SGA can be partially explained by the following two reasons. First, SGA infants are more vulnerable to the traumatic effects of mechanical ventilation. Second, SGA infants have less chronologic time ex utero to recover from oxygen dependence.
RDS
In this study, we did not find that SGA birth is associated with RDS in the full GA range but an increased odds of RDS in the lowest GA subgroup [OR 2.89; 95% CI: 1.26–6.84].
The association between RDS and SGA status remains inconclusive and mixed. The previous concept that increased pulmonary maturation in response to “stress” from IUGR leads to a decreased incidence of RDS has been challenged by more recently published studies. Giapros et al. and Turitz et al. showed that SGA is not associated with RDS or other adverse respiratory conditions [Citation24,Citation29]. Nobile et al. revealed that being SGA was not related to increased risk of RDS, but significantly associated with BPD due to multiple pathophysiologic mechanisms [Citation25]. RDS may be a predisposing factor for BPD, but it is widely acknowledged that BPD can develop in the absence of RDS. Sharma et al. found no change in RDS risk in SGA infants at GA ≤ 32 weeks [Citation27].
Several studies have shown an increased incidence of RDS in SGA children [Citation22,Citation30,Citation31]. Recently, Boghossian et al. showed 1.15- to 1.43-fold excess risks of RDS among SGA infants in a large population-based study [Citation14]. Ley et al. reported 1.98-fold excess risk for RDS in SGA infants at GA 25–28 weeks, but not at GA 29–32 weeks, which is consistent with our findings [Citation32].
It is noteworthy that the odds ratios of SGA birth are quite low even in the studies reporting positive results, which implies a weak relationship between SGA status and RDS. RDS is universal in extremely and very preterm neonates, attributed to reduced or impaired surfactant production. Antenatal glucocorticoid treatment and postnatal surfactant therapy may alleviate the adverse effects of low GA, but their effects on SGA infants developing RDS are still not clear.
Conversely, several other studies have confirmed a decrease in RDS among SGA infants. Bartels et al. found a lower incidence of RDS in SGA preterm infants in a large population-based study [Citation33].
Other major morbidity
In our study, we did not find any significant differences in other major morbidities, including sROP, sIVH, and NEC, between the SGA and AGA groups in the full GA range.
Strength and limitation
The strengths of this contemporary 6-year single-center study are the application of the latest birthweight reference and the CRIBII score.
First, using the latest birthweight standard can minimize misclassification, which is critical for assessing the impact of SGA birth on neonatal mortality and morbidity [Citation34]. At present, the Chinese 1988 reference curve of newborn birthweight is still widely used. Obviously, a latest standard is very necessary for evaluation. Second, admission illness severity (CRIBII score) was considered a confounding covariate in the analysis, which was usually ignored in previous studies. Although GA and BW are still decisive factors in evaluating the impact of SGA birth, the effect of illness severity should not be ignored.
Despite the above points, several limitations of the study should be acknowledged. First, it is a retrospective, case-control study which is subject to potential selection biases, so the generalizability of our findings may be limited to similar settings. Second, the study did not apply propensity score matching, which is widely regarded as an effective way to mitigate the differences between experimental and control groups. Third, the relatively small sample size in relation to certain event rates may affect power in subgroup analysis. Fourth, a lack of detailed maternal and fetal growth data limited the effectiveness of conclusions. Therefore, the findings should be interpreted with caution.
Conclusions
In conclusion, SGA status is associated with excess risks of neonatal mortality and BPD in very preterm infants, but the increased risks of mortality and morbidity are not homogeneous in different GA ranges. The contemporary data can help inform perinatal care decision-making and family counseling, particularly for very preterm SGA neonates.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
The data that support the findings of this study are available from the corresponding author, C. Liu, upon reasonable request.
Additional information
Funding
References
- Lee AC, Kozuki N, Cousens S, et al. Estimates of burden and consequences of infants born small for gestational age in low and Middle income countries with INTERGROWTH-21st standard: analysis of CHERG datasets. BMJ. 2017;358:j3677. doi:10.1136/bmj.j3677.
- Ray JG, Park AL, Fell DB. Mortality in infants affected by preterm birth and severe small-for-gestational age birth weight. Pediatrics. 2017;140(6):e20171881. doi:10.1542/peds.2017-1881.
- Katz J, Lee AC, Kozuki N, et al. Mortality risk in preterm and small-for-gestational-age infants in low-income and Middle-income countries: a pooled country analysis. Lancet. 2013;382(9890):417–425. doi:10.1016/S0140-6736(13)60993-9.
- Regev RH, Reichman B. Prematurity and intrauterine growth retardation – Double jeopardy? Clin Perinatol. 2004;31(3):453–473. doi:10.1016/j.clp.2004.04.017.
- Parry G, Tucker J, Tarnow-Mordi W. CRIB II: an update of the clinical risk index for babies score. Lancet. 2003;361(9371):1789–1791. doi:10.1016/S0140-6736(03)13397-1.
- Park JH, Chang YS, Ahn SY, et al. Predicting mortality in extremely low birth weight infants: comparison between gestational age, birth weight, Apgar score, CRIB II score, initial and lowest serum albumin levels. PLoS One. 2018;13(2):e0192232. doi:10.1371/journal.pone.0192232.
- Fei Y, Miao H, Zhu X, et al. Study on singleton birth weight percentiles curve for gestational age in Guangdong. Matern Child Health Care China. 2018;33(07):1448–1452.
- Fei Y, Miao H, Zhu X, et al. Birth weight percentiles curve by gestational age for twins born in Guangdong Province. China J Reproductive Health. 2018;29(02):126–133.
- Vermont Oxford Network. Manuals and forms; [cited 2022 Oct 12]. Available from: https://public.vtoxford.org/manuals-forms/.
- Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001;163(7):1723–1729. doi:10.1164/ajrccm.163.7.2011060.
- The international classification of retinopathy of prematurity revisited. Arch Ophthalmol. 2005;123(7):991–999.
- Papile LA, Munsick-Bruno G, Schaefer A. Relationship of cerebral intraventricular hemorrhage and early childhood neurologic handicaps. J Pediatr. 1983;103(2):273–277.
- Bell MJ, Ternberg JL, Feigin RD, et al. Neonatal necrotizing enterocolitis. Ann Surg. 1978;187(1):1–7.
- Boghossian NS, Geraci M, Edwards EM, et al. Morbidity and mortality in small for gestational age infants at 22 to 29 weeks gestation. Pediatrics. 2018;141(2):e20172533.
- Jensen EA, Foglia EE, Dysart KC, et al. Adverse effects of small for gestational age differ by gestational week among very preterm infants. Arch Dis Child Fetal Neonatal Ed. 2019;104(2):F192–F198.
- Sasi A, Abraham V, Davies-Tuck M, et al. Impact of intrauterine growth restriction on preterm lung disease. Acta Paediatr. 2015;104(12):e552–6–e556. doi:10.1111/apa.13220.
- Tsai L-Y, Chen Y-L, Tsou K-I, et al. The impact of small-for-gestational-age on neonatal outcome among very-low-birth-weight infants. Pediatr Neonatol. 2015;56(2):101–107. doi:10.1016/j.pedneo.2014.07.007.
- Soudée S, Vuillemin L, Alberti C, et al. Fetal growth restriction is worse than extreme prematurity for the developing lung. Neonatology. 2014;106(4):304–310. doi:10.1159/000360842.
- Wold SHW, Sommerfelt K, Reigstad H, et al. Neonatal mortality and morbidity in extremely preterm small for gestational age infants: a population based study. Arch Dis Childhood – Fetal Neonatal Edition. 2009;94(5):F363–F367. doi:10.1136/adc.2009.157800.
- Garite TJ, Clark R, Thorp JA. Intrauterine growth restriction increases morbidity and mortality among premature neonates. Am J Obstet Gynecol. 2004;191(2):481–487.
- Regev RH, Lusky A, Dolfin T, et al. Excess mortality and morbidity among small-for-gestational-age premature infants: a population-based study. J Pediatr. 2003;143(2):186–191. doi:10.1067/S0022-3476(03)00181-1.
- Bernstein IM, Horbar JD, Badger GJ, et al. Morbidity and mortality among very-low-birth-weight neonates with intrauterine growth restriction. Am J Obstet Gynecol. 2000;182(1):198–206. doi:10.1016/S0002-9378(00)70513-8.
- Bardin C, Zelkowitz P, Papageorgiou A. Outcome of small-for-gestational age and appropriate-for-gestational age infants born before 27 weeks of gestation. Pediatrics. 1997;100(2):E4–e4. doi:10.1542/peds.100.2.e4.
- Giapros V, Drougia A, Krallis N, et al. Morbidity and mortality patterns in small-for-gestational age infants born preterm. J Matern-Fetal Neonatal Med. 2012;25(2):153–157. doi:10.3109/14767058.2011.565837.
- Nobile S, Marchionni P, Carnielli VP. Neonatal outcome of small for gestational age preterm infants. Eur J Pediatr. 2017;176(8):1083–1088. doi:10.1007/s00431-017-2957-1.
- Qiu X, Lodha A, Shah P, et al. Neonatal outcomes of small for gestational age preterm infants in Canada. Amer J Perinatol. 2012;29(02):87–94.
- Sharma P, McKay K, Rosenkrantz TS, et al. Comparisons of mortality and pre-discharge respiratory outcomes in small-for-gestational-age and appropriate-for-gestational-age premature infants. BMC Pediatr. 2004;4(1):9.
- Gortner L, Wauer RR, Stock GJ, et al. Neonatal outcome in small for gestational age infants. J Perinat Med. 1999;6:484–489.
- Turitz A, Gyamfi-Bannerman C. Comparison of respiratory outcomes between preterm small-for-gestational-age and appropriate-for-gestational-age infants. Amer J Perinatol. 2016;34(03):283–288.
- Tyson JE, Kennedy K, Broyles S, et al. The small for gestational age infant: accelerated or delayed pulmonary maturation? Increased or decreased survival? Pediatrics. 1995;95(4):534–538. doi:10.1542/peds.95.4.534.
- Spinillo A, Capuzzo E, Piazzi G, et al. Significance of low birthweight for gestational age among very preterm infants. Int J Obstet Gynec. 1997;104(6):668–673. doi:10.1111/j.1471-0528.1997.tb11976.x.
- Ley D, Wide-Swensson D, Lindroth M, et al. Respiratory distress syndrome in infants with impaired intrauterine growth. Acta Paediatr. 1997;86(10):1090–1096.
- Bartels DB, Kreienbrock L, Dammann O, et al. Population based study on the outcome of small for gestational age newborns. Arch Dis Child-Fetal Neonatal Ed. 2005;90(1):F53–F59. doi:10.1136/adc.2004.053892.
- Yao F, Miao H, Li B, et al. New birthweight percentiles by sex and gestational age in Southern China and its comparison with the intergrowth-21st standard. Sci Rep. 2018;8(1):7567–7567. doi:10.1038/s41598-018-25744-7.