Prematurity and intrauterine growth retardation—double jeopardy?

Clin Perinatol 31 (2004) 453 – 473

Prematurity and intrauterine growth retardation—double jeopardy? Rivka H. Regev, MDa,b,*, Brian Reichman, MB, ChBb,c a

Neonatal Unit and Neonatal Follow-Up Clinic, Neonatal Department, Meir Hospital, Sapir Medical Center, Kfar Saba 44281, Israel b Department of Pediatrics, Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel c The Women and Children’s Health Research Unit, Gertner Institute, Sheba Medical Center, Tel Hashomer 52561, Israel

Premature infants born small for gestational age (SGA) are at risk for an adverse outcome resulting from immaturity and deficient intrauterine growth. The continuum of events, which starts in utero because of an unfavorable environment, has been associated with short- and long-term excess morbidity and mortality among such infants [1 –4]. Small for gestational age infants experience various intrauterine cardiovascular, neuroendocrine, and metabolic pathophysiologic processes that may contribute to this adverse postnatal outcome. Uteroplacental dysfunction resulting in a restriction of supply of substrates, including oxygen, glucose, lactate, and amino acids, to the developing fetus is the main determinant of disturbed fetal growth [5,6]. Additionally, these fetuses are frequently chronically hypoxemic and hypoglycemic and have increased blood lactate concentrations without a change in arterial pH [7 –9]. In turn, the fetal hypothalamic-pituitary-adrenal axis is activated by the intrauterine substrate deprivation, leading to excess fetal plasma glucocorticoid levels [10]. The late gestational increase in circulating cortisol concentration is related to the degree of hypoxemia and asphyxial stress [11]. Intrauterine fetal concentrations of the anabolic hormones insulin, insulinlike growth factor (IGF), and thyroid hormone, which are required for normal fetal organ growth, are reduced [7,12,13]. Intrauterine hypoxemia is also associated with oxygen free radical formation and organ damage, suggesting the occurrence of significant oxidative stress in fetuses with intrauterine growth retardation (IUGR) [14,15]. As such, an unfavorable intrauterine environment resulting in growth restriction may cause oxidative fetal stress and damage starting in utero [15] and manifested after birth [16 – 19]. * Corresponding author. Newborn Unit, Department of Neonatology, Meir Hospital, Kfar Saba 44281, Israel. E-mail address: [email protected] (R.H. Regev). 0095-5108/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.clp.2004.04.017

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It is still a common clinical assumption that SGA infants have accelerated maturation owing to the intrauterine stress, and that they are less likely to experience complications of prematurity when compared with appropriate for gestational age (AGA) premature infants [20]. In fact, conflicting evidence has been reported as to the neonatal outcome of SGA preterm or very low birth weight (VLBW) infants. Mortality and major neonatal complications, such as respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), and intracranial pathologies such as severe intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL), have been variously reported as increased, decreased, or unchanged. This seemingly contradictory observation is explained in part by differences in the reference growth charts used [21 – 23] and in the percentile cutoff selected to define IUGR or SGA infants. Because gestational age remains the best measure of maturity and predictor of outcome, data using an adjustment for gestational age are probably better in addressing the outcome of premature or VLBW infants who are SGA [24]. This review evaluates recently reported findings on neonatal morbidity and mortality among premature SGA infants, based largely on data adjusted for gestational age.

Respiratory system maturation Chronic hypoxia adversely affects the structural development of the airways and pulmonary vasculature, particularly in immature lungs [25], and a reduction in alveolar and airway growth has been noted in experimentally induced IUGR [11,26]. Functional developmental abnormalities associated with these abnormally small lungs include an increase in airway resistance or decreased compliance [27] and altered pulmonary defense mechanisms [11]. Chronic placental insufficiency was shown to have a persistent detrimental effect on respiratory function after birth, with a reduction in diffusion capacity and decrease in lung compliance, probably owing to alterations in lung structure together with increased chest wall compliance [28]. Impaired maturation of type II alveolar epithelial cells and reduced surfactant content and surface activity have also been reported in infants with IUGR [11]. Furthermore, intrauterine hypoxia and acidosis may interfere with surfactant synthesis [29]. Conversely, Gagnon et al [30] reported that fetal growth restriction was associated with a significant increase in surfactant-associated proteins, suggesting enhanced lung maturation highly dependent on the degree of increase in fetal plasma cortisol. Nevertheless, the fetal cortisol response to hypoxemia may be variable, and, accordingly, the enhancement of fetal lung maturation in response to chronic intrauterine hypoxemia may vary. Respiratory distress syndrome The previous concept that IUGR is associated with increased pulmonary maturation and a decreased incidence of RDS has not been supported by

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more recently published studies [2,3,23,31,32]. McIntire et al reported that the incidence of RDS in premature infants was influenced by fetal growth and fetal age, being higher in all of the birth weight percentiles below the 26th than in the reference group (birth weight of 26th through 75th percentiles for gestational age) (Fig. 1) [3]. The incidence of RDS increased with decreasing birth weight percentile, challenging the concept of accelerated maturation in growth-restricted infants. Using various growth charts for the definition of SGA, Tyson et al found an odds ratio (OR) for RDS among these infants ranging from 1.05 (95% confidence interval [CI], 0.58– 1.90) to 5.48 (95% CI, 3.26 –9.20), again not showing any evidence to support the concept of accelerated lung maturation in SGA infants [23]. Spinillo et al reported a significantly increased risk of RDS with fetal growth retardation in 24 to 31 weeks’ gestation infants, supporting the view that fetal growth restriction increases the risk for RDS [4]. Others have similarly reported an excess risk for RDS among SGA infants ranging from 1.09 to 1.70 after adjustment for gestational age and other confounding variables [2,32,33]. Ley et al reported an increased risk for RDS with an OR of 1.98 (95%CI, 1.12 – 3.52) in SGA infants born at 25 to 28 weeks’ gestation but not in more mature (29 – 32 weeks’ gestation) SGA infants [31]. Conversely, other studies have not confirmed an increase in RDS among SGA infants [20,34 –36]. The possible increased risk for RDS may be caused by a reduced or impaired release of surfactant or a diminished response to endogenous and exogenous

Incidence of Respiratory Distress (%)

100

28–30 wk 31–32 wk 33–34 wk 35–36 wk

80 60 40 20 0

h

0

1

0t

0t

-1 st

11

t

2 h-

h

h

0t

21

-3 st

h 0t

31

-4 st

h

41

h

0t

-5 st

0t

51

-6 st

0t

61

-7 st

h

0t

-8 st

71

h

0t

81

-9 st

h

9t

h

-9 st

91

Birth-Weight Percentile Fig. 1. Incidence of respiratory distress among 12,317 preterm infants according to birth weight percentiles after stratification according to gestational age (28 through 30 weeks, 31 or 32 weeks, 33 or 34 weeks, and 35 or 36 weeks)]. (From McIntire DD, Bloom SL, Casey BM, Leveno KJ. Birth weight in relation to morbidity and mortality among newborn infants. N Engl J Med 1999;340: 1234 – 8; with permission.)

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corticosteroids [11]. Ley et al reported that, in premature SGA infants, antenatal corticosteroid administration did not seem to have an equally beneficial effect on mortality, RDS, and cerebral hemorrhage when this group was compared with AGA infants [31]. Furthermore, maternal corticosteroid administration may have an adverse effect on subsequent lung alveolarization and growth [37], and it is possible that the compromised fetal lungs of an IUGR fetus may not benefit from maternal steroid administration. Bronchopulmonary dysplasia There is an apparent association between BPD and IUGR in premature infants, with a reported positive relationship between IUGR and prolonged neonatal lung disease. Data on the incidence of BPD or chronic lung disease (CLD) in SGA infants refer to the need for oxygen supplementation at the age of 28 days or at 36 weeks’ postmenstrual age (PMA) (Table 1). An increased rate of oxygen supplementation at the age of 28 days has generally been noted among SGA infants. In a large population-based study of VLBW infants born at 24 to 31 weeks’ gestation, a 3.42-fold excess risk for BPD (95% CI, 2.29 –5.13) was found, and IUGR was suggested to cause lasting Table 1 Risk for chronic lung disease in premature SGA infants compared with AGA infants Study Reiss [36] Regev [1] Zaw [21]

GA (weeks) and BW (g)

O2 at age 28 days, OR (95% CI)

O2 at 36 weeks’ PMA, OR (95% CI)

Comments

<32 24 – 31 and
1500 <34

3.80 (2.11 – 6.84) 3.42 (2.29 – 5.13)

— —

Multivariate analysis Multivariate analysis

1.77 (0.93 – 3.36)

—

Neonatal growth standards Fetal growth standards Adjusted for antenatal steroids and gender; similar GA Multivariate analysis Adjusted for GA For each increase in 1 Z-score Multivariate analysis Similar mean GA

2.18 (1.33 – 3.59)

Egreteau [39] Lal [38] Redline [41]

<31 24 – 32 <32 and <1500

2.4 (1.4 – 4.0) 2.23 (1.57 – 3.15) —

4.7 (2.5 – 8.8) 2.84 (2.01 – 4.00) 0.4 (0.3 – 0.6)

Gortner [35]

27 – 32

Bardin [34]

24 – 26

Spinillo [4] Baud [33]

24 – 31 <33

20.2% (AGA) / 37.3% (SGA)** 100% (SGA) / 83% (AGA)* 1.20 (0.80 – 1.81) —

4.2% (AGA) / 13.6% (SGA)** 65% (SGA) / 32% (AGA)** — 0.50 (0.16 – 1.60)

Korhonen [40]

<1500

0.39 (0.18 – 0.85)

—

Unadjusted Multivariate analysis Multivariate analysis; IUGR and/or PET Adjusted for prenatal factors

Abbreviations: BW, birth weight; GA, gestational age; PET, preeclamptic toxemia. * P < .05; ** P < .01.

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changes in lung structure and function [1]. Reiss et al examined premature infants aged less than 32 weeks’ gestation and showed that being born SGA increased the risk for BPD fourfold [36]. They suggested that IUGR was one of the most important risk factors for prolonged oxygen requirement. The use of fetal growth standards identified preterm SGA infants as being at greater risk for respiratory morbidity when compared with neonatal growth standards [21]. This increased risk was similarly reported by others [34,38,39]; however, Spinillo et al could not show a higher risk for BPD despite the increased risk of RDS [4]. Conversely, others have reported a decreased need for oxygen therapy at 28 days in premature SGA infants [35,40]. Although Korhonen et al showed a lower risk of BPD at 28 days of age among SGA infants, a tendency for later recovery from BPD was noted [40]. A threefold to fourfold increase in oxygen dependency at 36 weeks’ PMA has been reported in SGA infants when compared with AGA infants [38,39]. Redline et al [41] concluded that severe fetal growth restriction as defined by a Z-score more than 2.0 standard deviations (SD) below the mean for gestational age was a highly significant risk factor for CLD, but only after adjustment for gestational age. For each increase in the Z-score of 1, the OR for CLD was 0.4 (95% CI, 0.3 –0.6). Gortner et al reported that supplemental oxygen therapy at 28 days of age and at 36 weeks’ PMA was significantly increased in SGA infants [35]. Conversely, in a cohort of preterm infants born at less than 33 weeks’ gestation, Baud et al found that, among infants born after intrauterine growth restriction or pre-eclampsia, the risk for CLD was not increased despite the increased risk of RDS [33]. The increased risk for BPD may reflect a continuum of events starting in utero and persisting after birth. Harding et al conducted a series of studies of growthrestricted ovine fetuses, concluding that intrauterine compromise had the potential to induce lasting changes in lung structure and function associated with the later development of BPD [11]. Joyce et al reported that alterations in the lung and chest wall in lambs with IUGR resulted in persistent impairment of respiratory function, causing impaired gas exchange, reduced lung compliance, and increased chest wall compliance present at 8 weeks after birth [28]. These changes were still evident 2 years after birth, indicating that fetal growth retardation may result in permanent changes in the lung [42]. Several underlying mechanisms have been suggested to explain the apparent excess risk of BPD among SGA infants, including delayed metabolic adaptation [43], a systemic inflammatory response secondary to intrauterine hypoxia, acidosis and postnatal reperfusion injury [35,44], and more severe early neonatal lung disease [7,25,43]. Malnutrition-induced events have been implicated in adverse pulmonary effects during the perinatal period [45]. Oxygen free radicals have been implicated in the pathogenesis of BPD and other neonatal morbidities. In animal studies, generation of oxygen free radicals has been documented in the presence of in utero hypoxia [46] and in IUGR [15]. Reduced antioxidant defense mechanisms associated with prematurity may result in major neonatal morbidity [19], and chronic malnutrition may further aggravate this deficiency

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in antioxidants, already present in low concentrations in premature infants [34]. The excess risk for BPD among SGA premature infants may result in part from oxygen free radical generation starting in utero and continuing after birth [16,47].

Central nervous system disorders The association between central nervous system lesions and IUGR is controversial. Few studies have addressed IUGR among the perinatal risk factors for IVH or PVL, and most early studies of obstetric and neonatal risk factors did not evaluate the effect of size for gestational age. Intrauterine growth-restricted fetuses have centralization of fetal circulation, resulting in preferential shunting of blood to the fetal brain and adaptive sparing of fetal head growth [48]. IUGR fetuses maintain normal brain weight despite decreased body weight [49]. The increased blood flow to the brain or ‘‘brainsparing effect’’ present in IUGR fetuses is probably a protective mechanism against fetal brain hypoxia [50 – 53]. Cerebral blood flow autoregulation is set by various mechanisms, including neuroendocrine factors, prostaglandins, and nitric oxide. The limited ability of preterm infants to maintain a steady cerebral blood flow may be caused by an imbalance of these mechanisms [54]. The sympathoadrenal system in the IUGR fetus responds to the adverse intrauterine environment by diminishing fetal adrenaline and enhancing noradrenaline responses [43]. Cerebral blood flow and brain growth may be maintained through redistribution of blood flow owing to a precise relationship between the degree of hypoxemia and noradrenaline concentration [43]. The high cerebral blood flow in the cerebral arteries of IUGR fetuses was shown not to be associated with detectable neurosonographic abnormalities [50 – 52]. Accelerated neurophysiologic maturation owing to intrauterine stress has been demonstrated clinically [55,56], as well as in neurophysiologic observations of advanced maturation of auditory [57] and visual [53,58] evoked potentials. Precocious activation of the fetal hypothalamic-pituitary-adrenal axis in the presence of an adverse intrauterine environment causes increased levels of fetal cortisol. The glucocorticoids and catecholamines, which are elevated in these pregnancies, have an important role in the process of intrauterine adaptation by the fetus to inadequate oxygen and metabolic availability [59], as well as ensuring synchronous maturation of fetal organ enzyme systems, including those in the brain [60]. Significant histopathologic findings have been documented in the central nervous system of IUGR fetuses, including delayed or abnormal cerebral cortical neuronal migration [49,61], a reduction in neuronal numbers in various parts of the brain despite normal brain weight [62], migration disorders in the cerebral cortex, and a reduction in dendritic growth and arborization [63]. The significance of these findings is not completely understood, but they are thought to have an effect on later development and behavior [49,62].

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Intraventricular hemorrhage The risk of IVH in SGA premature infants has variously been reported to be lower, higher, or similar. These studies have included differences in the gestational age and birth weight of the infants, in the definition of SGA, and in the type of growth standards used, and some of the studies included mature infants with growth restriction. Amato et al [64] found a reduced incidence of IVH in SGA infants when they were compared with AGA infants; however, inclusion in the study was determined by birth weight and not gestational age, and the SGA infants in this study were 3 weeks more mature. A decreased incidence of IVH was also reported in SGA infants with a birth weight less than 1000 g [65] and in SGA infants at 28 weeks’ gestation [66]. Gilbert and Danielsen found no difference between SGA and AGA infants at 30 to 32 weeks’ gestation; however, higher rates of IVH were found in infants with IUGR at 34 to 40 weeks’ gestation, suggesting that IUGR is a risk factor in late gestation [66]. Several investigators have reported similar rates of IVH in AGA and SGA premature infants [20,31]. After adjustment for gestational age, IUGR was not associated with a significant risk for IVH in SGA infants [67,68]. Bernstein et al reported a trend toward the association of IUGR with an increased risk of IVH [2] (Table 2). Other researchers have shown an increased risk of IVH in SGA infants. Berger et al [69] found a significantly increased incidence of IVH in growthretarded infants when the arterial blood cord pH was 7.29 or less, and noted that the combination of fetal growth retardation and acidemia caused an increased risk of brain hemorrhage. Spinillo et al found IUGR to be a significant risk factor for IVH after correction for potential confounders [4]. Using neonatal growth standards, Zaw et al suggested that the risk for IVH was the same in SGA and Table 2 Risk of intraventricuar hemorrhage in premature SGA infants compared with AGA infants Study

GA (weeks) and BW (g)

Results, OR (95% CI)

Zaw [21]

<34

1.08 (0.64 – 1.82) 1.67 (1.13 – 2.45)

Bernstein [2]

25 – 30 and <1500

1.13 (0.99 – 1.29) 1.25 (0.98 – 1.59)

Simchen [20] Baud [33]

27 – 35 27 – 32 <33

1.23 (0.39 – 3.91) 2.03 (0.52 – 7.89) 0.61 (0.17 – 2.25)

Gleissner [67] Spinillo [4]

23 – 36 24 – 31

1.28 (0.74 – 2.20) 1.61 (1.15 – 2.24) 2.77 (1.5 – 5.11)

Comments Neonatal growth standards Fetal growth standards Adjusted for antenatal steroids and gender; similar mean GA All grades of IVH Severe IVH Multivariate analysis Multivariate analysis Multivariate analysis; IUGR and/or PET Adjusted for GA All grades of IVH Severe IVH Multivariate analysis

Abbreviations: BW, birth weight; GA, gestational age; PET, preeclamptic toxemia.

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AGA infants; however, when fetal growth standards were used, a significant increased risk of IVH was found in the SGA group, with an OR of 1.67 (95% CI, 1.13 – 2.45) [21]. Hesser et al evaluated the association of perinatal risk factors with cranial ultrasound pathology and found that SGA was significantly associated with IVH grades I to III ( P < .01) [70]. Viscardi and Sun [71] similarly found an almost twofold higher incidence of IVH in IUGR infants, and suggested that the chronically adverse intrauterine environment increased the susceptibility of the IUGR fetus to IVH. Larroque et al [72] reported a twofold risk for parenchymal hemorrhagic infarction in IUGR infants aged less than 32 weeks’ gestation. The pathophysiologic mechanisms of IVH involve acute fluctuations together with impaired autoregulation of cerebral blood flow. An increase in cerebral blood flow predisposes to IVH, whereas a reduction in blood flow and perfusion causes ischemic necrosis and PVL in the susceptible developing periventricular white matter [48,73]. No apparent connection between the altered cerebral blood flow in IUGR fetuses and increased neonatal IVH has been shown [51,74]. A possible explanation is the enhanced cerebral maturation and perhaps vasomotor stability following intrauterine stress [50]. Cytokine-mediated injury has also been implicated in the pathogenesis of IVH and PVL [48,75 – 78], and cytokine release has been associated with subsequent endothelial damage to the germinal matrix and white matter [75,79,80]. Increased umbilical interleukin-6 (IL-6) levels were strongly associated with IVH and PVL in premature infants [79,81]. Decreased IL-6 in was reported in growth restriction related to preeclampsia [82]. Prostanoids and nitric oxide are reported to influence cerebral blood flow autoregulation in response to hypoxia and asphyxia [48,83 – 85]. Their synthesis is generally lower in SGA infants, possibly as protection against further fetoplacental vasoconstriction [86,87]. This mechanism may explain the possible lower incidence of IVH in SGA infants. Endogenous nitric oxide production in growth-restricted fetuses is controversial and has been reported to be both higher and lower compared with that in appropriately growing fetuses [87,88]. Vasodilatatory nitric oxide induces impairment of cerebral autoregulation and probably has a role in the occurrence of IVH [89,90], and the low levels of nitric oxide found in IUGR infants may have a protective effect. Periventricular leukomalacia The reported incidence of the spectrum of white matter damage diagnosed by brain ultrasonography is difficult to interpret because of variable definitions of this condition. Most reports refer to increased echodensities or echolucent lesions in the periventricular region. When examining the obstetric risk factors for PVL, Spinillo et al [91] could not show that being born SGA was a significant risk factor for overall leukomalacia (OR, 1.10; 95% CI, 0.19– 4.36) or cystic PVL (OR, 1.07; 95% CI, 0.29– 3.25). Other investigators also have not found SGA to be a risk factor for PVL [31,64,68,70– 72,76]. Using fetal and neonatal growth standards to define SGA, Zaw et al did not show an association between PVL and SGA [21]. Conversely, in an adjusted model, Baud et al examined a group of in-

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Table 3 Periventricular leukomalacia in premature SGA infants compared with AGA infants Study

GA (weeks) and BW (g)

Results, OR (95% CI)

Comments

Baud [33]

<33

0.08 (0.02 – 0.41)

Zaw [21]

<34

0.95 (0.28 – 3.27) 0.93 (0.36 – 2.40)

Spinillo [91]

25 – 33

Larroque [72]

22 – 32

1.07 (0.29 – 3.25) 0.94 (0.46 – 1.84) 1.9 (1.1 – 3.1)

Gortner [35]

27 – 32

4.3% (AGA) / 10.2% (SGA)*

Cystic PVL Multivariate analysis; IUGR and/or PET Neonatal growth standards Fetal growth standards Adjusted for antenatal steroids and gender; similar mean GA Cystic PVL Overall leukomalacia In survivors, in the presence of GLH/IVH Same mean GA

Abbreviations: BW, birth weight; GA, gestational age; GLH, germinal layer hemorrhage; PET, preeclamptic toxemia. * Nonsignificant.

fants with IUGR or maternal preeclampsia and stated that these two perinatal factors were associated with a low incidence of PVL (OR, 0.08; 95% CI, 0.02 – 0.41 (Table 3) [33]. The pathogenesis of cerebral white matter injury has been related to three major interacting factors: an immature vascular supply to the white matter, maturation-dependent impairment of cerebral blood flow autoregulation, and maturational-dependent vulnerability of oligodendroglial precursor cells. In the presence of an ischemia –reperfusion event, free radicals formed cause oligodendroglial precursor cell apoptosis. Early differentiating oligodendroglial cells are vulnerable to free radical attack, whereas mature cells are resistant [92]. The lack of an association between IUGR and PVL could be explained by preferential protective cerebral blood flow, as well as accelerated brain maturity. Cerebral blood flow in premature SGA neonates has been reported to be significantly increased in the first 36 hours of life with normalization afterward, suggesting that prolonged intrauterine stress with chronic hypoxia leads to an increase in cerebral blood flow. As stress is relieved at birth, the circulation readapts to normal [93]. It is possible that SGA infants whose brain is spared by an increase in cerebral blood flow are less likely to experience white matter insult, because the periventricular border zone is sufficiently supplied. Accelerated maturation, which has been shown in visual [58] and auditory pathways [56], may be the result of accelerated myelination. The more mature oligodendroglial cells may be less vulnerable to insults causing PVL. Ischemia with reperfusion may lead to brain injury through oxygen free radical generation [48,94,95]. Cytokines, mainly in the presence of maternal intrauterine infection or inflammation, are involved in the pathogenesis of a proportion of cases of PVL [92,95]. These products are reported to be elevated [96] or similar

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in SGA pregnancies when compared with AGA pregnancies [97]. Increased umbilical IL-6 levels were strongly associated with IVH and PVL in premature infants [78,81]; however, in growth restriction related to preeclampsia, decreased IL-6 levels were reported [82]. It is possible that the combination of increased cerebral blood flow, accelerated cerebral maturation, and decreased IL-6 have a protective effect on the brain of premature SGA infants, despite the adverse intrauterine environment they experience.

Necrotizing enterocolitis The risk of NEC in premature SGA infants has generally been reported to be increased compared with that in AGA infants (Table 4) [2,21,98]. A significantly higher risk for NEC was reported by Zaw et al when neonatal growth standards were used, and a trend toward such an increase was seen when fetal growth standards were used [21]. Bernstein et al analyzed data from the Vermont-Oxford database of VLBW infants born at 25 and 30 weeks’ gestation and reported that the OR for NEC was 1.27 (95% CI, 1.03– 1.26) [2]. Hallstrom et al [98] assessed the risk factors for NEC in premature infants less than 33 weeks’ gestation. In their multivariate analysis of severe NEC, IUGR was a significant factor with a risk of 4.55 (95% CI, 1.00 –19.5). In a population-based study, Gilbert et al reported the incidence of NEC by gestational week for infants aged 26 to 41 weeks of gestation [66]. NEC was not different in SGA and AGA infants until 34 weeks’ gestation, after which infants with IUGR had an increased risk for NEC. Although Simchen el al found that NEC was more frequent among SGA preterm infants (unadjusted OR, 5.73; 95% CI, 1.34– 24.48) in a multivariate model adjusted for perinatal and neonatal risk factors, this difference did not reach statistical significance (P = .053) [20]. Three major factors have been implicated in the pathogenesis of NEC: mucosal injury from hypoxia and ischemia, formula feeding, and the presence of bacteria [99]. Perinatal insults are believed to induce a ‘‘diving reflex’’ shunting blood away from nonvital organs such as the intestines in favor of vital organs, compromising vascular supply to the gastrointestinal tract. IUGR Table 4 Necrotizing enterocolitis in premature SGA infants compared with AGA infants Study

GA (weeks) and BW (g)

Results, OR (95% CI)

Zaw [21]

<34

2.47 (1.21 – 5.07) 1.78 (0.93 – 3.38)

Bernstein [2] Hallstrom [98]

25 – 30 and <1500 <33

1.27 (1.05 – 1.53) 4.55 (1.00 – 19.5)

Abbreviations: BW, birth weight; GA, gestational age.

Comments Neonatal growth standards Fetal growth standards Adjusted for antenatal steroids, gender; similar mean GA Multivariate analysis Severe NEC Multivariate analysis

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results in redistribution of cardiac output away from various organs, including the gut [43]. Doppler studies on the first day of life show reduced blood flow velocity in the superior mesenteric artery and the celiac axis in SGA infants, especially following absent end-diastolic flow in the fetal aorta. These changes in gastrointestinal blood flow continue into the first week of life and are thought to be caused by persistently increased intestinal vascular resistance ‘‘programmed’’ during fetal life [100]. Necrotizing enterocolitis has been associated with low levels of epidermal growth factor, which affects epithelial cell proliferation, differentiation, and migration in the gastrointestinal tract [101]. Epidermal growth factor levels are significantly reduced in IUGR infants [102,103], and oral treatment with this factor has been shown to reduce the development and incidence of NEC in a neonatal rat model [104]. IGF-I, which is a potent stimulator of cell division and differentiation, is also found in very low levels in the serum of IUGR fetuses [105,106]. Among premature infants in whom several postnatal morbidities develop, including NEC, serum IGF-I deficiency persists after birth, never reaching comparable age-matched fetal in utero levels [98]. The increased risk for NEC in IUGR infants may be due to hypoxemic-ischemic damage occurring in utero, or may occur as a consequence of increased vascular resistance persisting after delivery [43] and decreased growth factors associated with fetal compromise.

Retinopathy of prematurity Retinopathy of prematurity is a vasoproliferative disorder of the eye affecting premature infants that has important implications in terms of future sight. This disorder is a two-phase disease initiated by delayed retinal vascular growth, leading to retinal ischemia, with subsequent release of stimulating growth factors that may lead to new and abnormal retinal blood vessel growth [107]. An increased risk for ROP in SGA infants has recently been reported (Table 5). Regev et al determined an OR of 2.06 (95% CI, 1.15 – 3.66) for severe ROP, and demonstrated that SGA, decreasing gestational age, and RDS were independent risk factors for severe ROP [1]. Using fetal and neonatal growth standards to define SGA, Zaw et al showed that the excess risk for ROP in SGA infants was 5.38 (95% CI, 1.21– 5.07) and 3.88 (95% CI, 2.33 –6.48), respectively [21]. Bardin et al found a significantly higher incidence of all stages of ROP, as well as of stages III to IV separately [34]. Although a higher overall incidence of ROP in SGA infants was reported by Gortner et al, the incidence of severe stages of ROP was similar in SGA and AGA infants [35]. Intrauterine growth retardation may be implicated in the pathogenesis of ROP by a combination of factors, including intrauterine hypoxia, altered levels of various growth factors, and deficient antioxidant capacity [34]. Low serum levels of IGF-I were found in fetuses and infants with IUGR [105,106], and these low postnatal levels were reported to be associated with ROP [106]. Lack of IGF-I in animal studies was shown to prevent normal levels of retinal vascular growth

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Table 5 Risk of retinopathy of prematurity in premature SGA infants compared with AGA infants Study

GA (weeks) and BW (g)

Results, OR (95% CI)

Comments

2.06 (1.15 – 3.66)

Zaw [21]

24 – 31 and
1500 <34

Bardin [34]

24 – 26

90% (SGA) / 58% (AGA)* 65% (SGA) / 12% (AGA)*

Gortner [35]

27 – 32

15.5% (AGA) / 37.3% (SGA)** 1.6% (AGA) / 1.7% (SGA)***

ROP stages III – IV Multivariate analysis Neonatal growth standards Fetal growth standards All stages of ROP Adjusted for antenatal steroids and gender; similar mean GA All stages of ROP ROP stages III – IV Unadjusted All stages of ROP ROP stage III Same mean GA

Regev [1]

5.38 (2.87 – 10.90) 3.88 (2.33 – 2.45)

Abbreviations: BW, birth weight; GA, gestational age. * P < .05; ** P < .001; *** not significant.

despite the presence of vascular endothelial growth factor, a hypoxia-stimulated growth factor that is critical for vessel development. The greater duration of low IGF-I levels, starting in utero and proceeding after birth in SGA infants, may contribute to the more severe stages of ROP [106].

Mortality The risk of mortality in premature SGA infants has been reported to be decreased [108] (especially when birth weight –defined cohorts rather than gestational age groups are used for comparison), similar [33,34], or increased compared with that in AGA infants [1 –4,20,21,23,31,32,35,36,38,109 – 113]. Studies evaluating the risk of mortality among premature SGA infants compared with AGA infants differ in the growth charts selected to define SGA, the gestational age groups, and the confounding variables selected (Table 6). In a population-based study of VLBW infants, Regev et al reported that one third of SGA infants and 20% of AGA infants died. The percentage mortality of SGA and AGA infants by gestational age at birth is shown in Fig. 2. In each gestational week, the mortality rate is higher in SGA infants, and the difference reaches statistical significance in each week from 25 to 29 weeks (P < .01) [1]. Piper et al also found that SGA infants born at 24 to 36 weeks’ gestation had significantly higher neonatal death rates in each gestational age category, concluding that growth-retarded preterm infants had no survival advantage over appropriately grown infants of the same gestational age [32]. Lal et al studied a geographically defined population and determined that mortality to 28 days post delivery was significantly higher in the SGA group, with an OR of 2.01 (95% CI,

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Table 6 Neonatal mortality in premature SGA infants Study

Ga (weeks) and BW (g)

Neonatal mortality Lal [38] 24 – 32 Piper [32] 34 – 36 Spinillo [4] 24 – 32

Reiss [36] Kok [111] Gortner [35]

<32 <32 and <1500 27 – 32

Mortality to discharge Regev [1] 24 – 31 and <1500 Bernstein [2] 25 – 30 and <1500 Zaw [21] <34

Baud [33]

<33

Results, OR (95% CI) 2.01 1.31 3.71 1.68

(1.49 – 2.72) (1.02 – 1.67)a (1.42 – 9.6) (1.18 – 2.4)

4.54 (2.56 – 8.04) 2.56 (1.26 – 5.26) 0.8% (AGA) / 10.2% (SGA)* 4.52 2.77 3.64 1.62

(3.24 – 6.33) (2.31 – 3.33) (1.64 – 8.09) (0.77 – 3.41)

1.53 (0.64 – 3.64)

Comment Unadjusted, balanced population Multivariate analysis SDS score <1 Each decrease in 1 SDS score Multivariate analysis Multivariate analysis Multivariate analysis Same mean GA

Multivariate analysis Multivariate analysis Neonatal growth standards Fetal growth standards Adjusted for antenatal steroids and gender; similar mean GA Multivariate analysis; IUGR and/or PET

Abbreviations: BW, birth weight; GA, gestational age; PET, preeclamptic toxemia. a J. Piper, personal communication, 2004. * P < .0001.

1.49 –2.72), when compared with the reference group of infants with a birth weight between the 25th to 75th percentiles [38]. McIntire et al reported that mortality rates were proportional to fetal weight across the entire spectrum of birth weight percentiles, suggesting that the risk of an adverse outcome increased continuously with decreasing birth weight percentiles [3] (Fig. 3). Spinillo et al found a 3.7-fold risk for mortality for infants with a birth weight standard deviation score (SDS) less than 1 when compared with infants with an SDS greater than 0. Furthermore, they showed that, for each unit of decrement of birth weight SDS score, the adjusted OR for mortality was 1.65 (95% CI, 1.18 –2.4) [4]. Multivariate analyses adjusting for gestational age and perinatal variables have shown an increased risk for neonatal mortality of 1.2- to 4.5-fold compared with that for AGA premature infants [4,32,36,38,111]. Similarly, mortality until discharge home has, in most reports, been found to be significantly higher in SGA premature infants, with a threefold to fourfold increased risk compared with that in premature AGA infants [1,2,33]. A 3.6-fold increase in mortality was reported by Zaw et al when neonatal growth charts were used to define SGA; however, when fetal growth charts were used, the excess risk of mortality was not significant [21]. This finding may reflect a higher birth weight cutoff for the definition of SGA infants when using neonatal standards, leading to the lower risk of mortality observed.

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100 90

85.7

80

SGA AGA

75.8 72.1

% Mortality

70 60 53.0

55.0 49.0

50 40

35.9 32.1

31.7

30 17.3

20

13.5 9.4

10

8.7

5.2

5.4

2.6

0 24

25

26

27

28

29

30

31

Gestational Age (weeks) Fig. 2. Percent mortality of SGA infants by gestational age at birth. Mortality rate for SGA infants was significantly higher than for AGA infants in the 25th week (P = .015) and from 26 to 29 weeks’ gestation (P < .01). (From Regev RH, Dolfin LA, Litmanovitz I, Arnon S, Reichman B, Israel Neonatal Network. Excess mortality and morbidity among small-for-gestational-age premature infants: a population based study. J Pediatr 2003;143:186 – 91; with permission.)

Two reports have found similar rates of mortality in premature SGA and AGA infants. Bardin et al retrospectively examined the outcome in premature SGA infants aged 24 to 26 weeks’ gestation and found nonsignificant differences in mortality rates as well as in causes for mortality in SGA and AGA infants [34]. The same observation was made by Baud et al who showed that the risk for mortality in infants with growth retardation or preeclampsia was 1.53 (95% CI, 0.64 – 3.64) [33]. Decreased mortality in premature SGA infants was reported by Horbar et al. SGA was associated with an OR of 0.61 (95% CI, 0.45 –0.83) for mortality. This analysis was adjusted for birth weight, and in the model, SGA infants were more mature than AGA infants at any given birth weight [108]. A more recent study from the Vermont-Oxford database shows the opposite finding, with a relative risk for mortality of 2.77 (95% CI, 2.31 –3.33) in SGA infants after adjusting for gestational age and other confounding variables [2]. The reasons for the excess mortality among premature SGA infants have not been clearly defined. Asphyxia-related events and deprivation of nutrients and oxygen may set off a cascade of adverse respiratory, metabolic, and other events. The adverse intrauterine environment has been shown to have a detrimental effect on various organs such as the lungs and gut, putting them at risk for increased extrauterine severe morbidities, including severe RDS and BPD and NEC [11,43,109,114]. The numerous adverse outcomes noted in premature SGA infants should be interpreted as a constellation of effects that are linked

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25

Incidence (%)

20 150

Respiratory distress

10 5

Neonatal death

0 h h h h h h h h h h 0t 0t 0t 0t 0t 0t 0t 0t 0t 9t -1 h-2 t-3 t-4 t-5 t-6 t-7 t-8 t-9 t-9 t 1s 11t 21s 31s 41s 51s 61s 71s 81s 91s

Birth-Weight Percentile Fig. 3. Incidence of respiratory distress and neonatal death among 12,317 preterm infants (born at 24 to 36 weeks of gestation) according to birth weight percentiles. (From McIntire DD, Bloom SL, Casey BM, Leveno KJ. Birth weight in relation to morbidity and mortality among newborn infants. N Engl J Med 1999;340:1234 – 8; with permission.)

physiologically and not as isolated separate sequelae [109], and probably explain the higher risk for mortality observed [112].

Summary Premature infants born with IUGR are at a several-fold increased risk for mortality and major neonatal morbidities, including RDS, BPD, ROP, and NEC. These severe complications of prematurity are intensified by the effect of suboptimal fetal growth. The possible pathophysiologic processes initiated in utero and continuing after birth have been discussed. Recently reported data suggest that IUGR is a risk factor in programming for the later development of cardiovascular diseases [115 –117], hypertension [118], and diabetes mellitus [119] in adult life. Experimental research related to the pathophysiology and etiology of these conditions may enable appropriate intervention directed at reducing the excess risk associated with the short- and long-term mortality and morbidity among premature SGA infants.

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