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## Jornal de Pediatria

##
*On-line version* ISSN 1678-4782

### J. Pediatr. (Rio J.) vol.81 no.3 Porto Alegre May/June 2005

#### http://dx.doi.org/10.1590/S0021-75572005000400005

**ORIGINAL ARTICLE**

**An assessment
of the severity, proportionality and risk of mortality of very low birth weight
infants with fetal growth restriction. A multicenter South American analysis**

**Carlos Grandi ^{I}; José L.
Tapia^{II}; Guillermo Marshall^{III}; NEOCOSUR Collaborative
Group^{IV}**

^{I}PhD. Researcher, School of Medicine,
Universidade de Buenos Aires. Perinatal Epidemiology, Maternidade Sardá,
Buenos Aires, Argentina

^{II}Professor, School of Medicine, Pontificia Universidad Católica
de Chile, Santiago, Chile

^{III}Associate professor of Public
Health, School of Medicine. Associate professor, of Statistics, School of Mathmatics,
Pontificia Universidad Católica de Chile, Santiago, Chile

^{IV}Collaborative centers and collaborators:

Argentina – Clínica e Maternidade Suíço-Argentina:
Gabriel Musante, Hospital de Clínicas José de San Martín:
Isabel Kurlat, Hospital Italiano: Gonzalo Mariani, Hospital Juan Fernández:
Liliana Roldán, Hospital Lagomaggiore: Daniel Agost, Maternidade Ramón
Sardá: Carlos Grandi, Sanatorio de la Trinidad: Marcelo Decaro

Chile – Hospital Clínico Universidade Católica: Alberto Estay,
Hospital Clínico Universidade do Chile: Rodrigo Ramírez, Hospital
Guillermo Grant: Aldo Bancalari, Hospital Gustavo Fricke: Jane Standen, Hospital
San José: Agustina Gonzalez, Hospital Sótero del Río: Angélica
Alegría

Paraguay – Hospital de Clínicas de Assunção: José
M. Lacarruba

Peru – Hospital Cayetano Heredia: Jaime Zegarra

Uruguay – Hospital Pereyra Rossel: Rubén Panizza

**ABSTRACT**

**OBJECTIVES:** To evaluate the clinical
severity and proportionality of small for gestational age, very low birth weight
neonates (< 1,500 g) and to estimate the neonatal mortality risk associated
with the condition of being small for gestational age according to the degree
of severity and proportionality.

**METHODS:** Observational design. All of the NEOCOSUR Collaborative Group's
very low birth weight infants (25-36 weeks' gestation) were included (n = 1,518).
Anthropometric indices: birth weight < 3rd and 10th percentile. Severity
(fetal growth ratio = observed weight/mean birth weight for gestational age);
no growth restriction: fetal growth ratio 0.90-1.10, mild: fetal growth ratio
0.80-0.89, moderate: fetal growth ratio 0.75-0.79 and severe: fetal growth ratio
< 0.75. Proportionality: coefficient of bimodality and z score for ponderal
index (PI = g/cm^{3} x 100). Neonatal mortality until discharge.

**RESULTS:** < 3rd percentile: 13.5% (p < 0.001); < 10th percentile:
31% (p < 0.001); fetal growth ratio: 0.90±0.21 (p < 0.001), mild
restriction: 20.8%, moderate restriction: 8.7% and severe restriction: 32.6%.
Coefficient of bimodality: 0.53; PI z score < -1: 8%. Maternal hypertensive
disease was systematically associated with being small for gestational age (aOR
1.20, 95% CI 0.86-1.67), fetal growth ratio __<__ 0.89 (aOR 1.71, 1.24-2.36)
and PI z score < -1 (aOR 1.60, 1.03-2.41). Adjusted odds ratios for neonatal
mortality were: 2.64 (95% CI 1.71-3.92) for being small for gestational age,
2.76 (95% CI 1.85-4.10) for fetal growth ratio __<__ 0.89, and 1.37 (95%
CI 0.80-2.32) for z score PI < -1.

**CONCLUSIONS:** Small for gestational age, mostly symmetric and severe restriction
is a frequent condition in < 1,500 g neonates and is associated with higher
mortality rates.

**Key words:** Very low birth weight, small
for gestational age, multicenter networks.

**Introduction**

Intrauterine growth restriction (IGR) is defined as insufficient expression of genetic fetal growth potential. In general, any newborn infant (NI) whose birth weight is below the 10th percentile for the weight that corresponds to their gestational age is included. Such NI are classified as small for gestational age (SGA).

The importance of IGR is that those affected
exhibited greater perinatal morbidity and mortality,^{1-3} reduced postnatal
growth and an increased risk of compromised intellectual development^{4,5} and stillbirth during the next pregnancy.^{6} Furthermore, IGR
has recently been linked to an increased probability of developing chronic diseases
during adulthood, such as arterial hypertension, cardiovascular diseases and
diabetes.^{7}

A recent study of 11 neonatal intensive care
units in four South American countries,^{8} found that 33% of the 38
NI included whose birth weights were below 1,500 g were SGA.

In addition, SGA infants born live are also heterogeneous in terms of severity, i.e. the degree of growth restriction, and little is known about the impact on prognosis.

Considerable interest has recently been generated
in subdividing SGA infants into asymmetrical (wasted: normal length and head
circumference for gestational age, but with low weight for length) and symmetrical
(stunted: symmetrical reductions in weight, length and head circumference).
The main reason for this classification is that there is some evidence that
these two subtypes of growth restriction represent different etiologies, operate
in different stages during pregnancy and have different prognostic significance.^{9,10}

In consequence, it is relevant to take account of the condition of SGA when analyzing the prognosis of NI with birth weights below 1,500 g in our region. All of these facts lead us to undertake wider-ranging studies with dependent variables being the condition of SGA, its severity and proportionality according to varying degrees of prematurity, which could be of use for establishing recommendations or interventions to better care for these NI.

The objectives of the present study were: 1) to evaluate the prevalence, severity and proportionality of NI weighing less than 1,500 g and SGA at varying degrees of prematurity and, 2) to estimate the risk of mortality according to SGA, degree of severity and proportionality.

**Methods**

*Population*

Between October 1997 and May 2003 all infants
were prospectively enrolled if they were born weighing from 500 to 1,500 g at
one of 16 neonatal units in South America (Argentina, Chile, Peru, Paraguay
and Uruguay) that cooperate in a neonatal network (NEOCOSUR Collaborative Group).
Data for the study was compiled at one of the centers which acts as a central
database (Neonatology Department, *Universidad Católica*, Chile).
Data is updated online via the Internet. Records include demographic characteristics,
morbidity, mortality and interventions, permanently controlling the degree of
data consistency. Cases involving transfers, the presence of lethal congenital
malformations and chromosomal diseases were excluded.

This is an observational and analytical study
of a historical cohort. Infants were defined as small for gestational age if
birth weight was below the 10th percentile on a weight for postnatal gestational
age curve from Argentina.^{11} Gestational age was estimated (in completed
weeks) from the first day of the last menstrual period and usually confirmed
with ultrasound at the start of the second trimester. Prematurity, based on
gestational age, was classed as extreme (24-28 weeks), moderate (29-32 weeks)
and mild (33-36 weeks).

*Pre-established outcome measurements*

- Birth weight below the 3rd percentile.

- Birth weight below the 10th percentile (SGA).

- Severity: using the fetal growth ratio (FGR), defined as the ratio between the observed birth weight and the mean birth weight for each gestational age adapted from previously published standards.

^{12}Infants were classed as having no growth restriction if FGR was between 0.90 and 1.10. Growth restriction was classed as mild: FGR 0.80-0.89; moderate: FGR 0.75-0.79 (below percentile 4.3) and severe, FGR < 0.75 (percentile below 1.7).^{13}The cutoff point for the group without restricted growth (which includes 10% of the mean – FGR 1.00), represents a similar relative weight to that commonly utilized for identifying the optimal nutritional status level in older children and adults. The cutoff point for the group with restricted growth (<0.89) is approximately comparable with the conventional definition (< 10th percentile). We used this approach because it provides important clinical information (weight percentage below the mean).^{14}- Proportionality: estimated by the z score for ponderal index (PI = g/cm

^{3}x 100) and the coefficient of bimodality. Ponderal index z-scores were computed as follows: the observed PI (x) for each NI is subtracted from the mean (X) and divided by the corresponding standard deviation (SD) of each gestational age from the curve adopted._{i}^{11}Therefore the z-score indicates the number of standard deviations by which the PI diverges from the mean. If the z-score was below -1 (PI 1 SD below the average) this was defined as asymmetrical growth restriction.^{12}

Due to the increasing variation in z-score, which theoretically could be caused by deviation (lack of symmetry), platykurtosis (flattened distribution curve) or bi or multimodality of frequency distribution, a coefficient of bimodality was calculated for PI for each gestational age using the ratio: 1 + deviation ^2/kurtosis + 3. Values < 0.55 indicate unimodal distribution – equivalent to symmetrical growth restriction – and values>0.55 indicate bimodality – equivalent to asymmetrical growth restriction.^{12-15}- Neonatal mortality up to discharge: adjusted for gestational age. Potential confounding variables: gestational age, adolescence (mother younger than 18), control of pregnancy, multiple birth, hypertension induced by pregnancy (gestational hypertension and preeclampsia), diabetes and prenatal diagnosis of restricted growth (by two ultrasound fetal anthropometric indicators: rate of fetal abdominal circumference growth and ratio abdominal circumference/length of femur below the 10th percentile).

Any significant interaction between pregnancy-induced hypertension and intrauterine growth restriction would suggest that the effect of restriction on the results is modified by maternal hypertension.

*Statistical analysis*

Measures of central tendencies (mean, median
or proportions, as applicable) and measures of distribution (standard deviation,
first and third quartiles, 95% confidence interval). In order to compare means,
the Student *t* tests and one way analysis of variance were used and to
compare medians the Mann-Whitney test was employed.

The c^{2}
test was utilized to compare proportions. Bivariate risk was calculated from
the unadjusted odds ratio (OR) with 95% confidence interval. Finally, the population
attributable risk(PAR) was calculated together with its 95% confidence interval.

The risks for a variety of adverse events, adjusted for potential confounding variables, was estimated using multiple logistic regression models (adjusted OR with 95% confidence intervals). The result of including birth weight in the models was colinearity.

Statistical significance was defined as p < 0.05 (two tailed). Sample sizes for certain variables may produce small differences due to lack of data.

For all statistic analyses, Statistica (Version
5.1, Statsoft, Tulsa, OK) and Epidat 2.0 (PAHO/WHO and *Xunta de Galicia*)
were used.

**Results**

One hundred and twenty-nine (6.9%) of the 1,895 live births with weights below 1,500 g that had originally been included in the database were excluded because of lethal congenital anomalies or chromosomal syndromes, 77 (4.1%) were excluded because their gestational ages were less than 24 weeks, three (0.16%) because data on gestational age was missing and 132 (7.1%) because length at birth was unknown. Thus, 1,518 (81.6%) records made up the final sample and were included in the analysis.

The population's characteristics appear in Table 1. Two thirds of mothers had undergone prenatal control (64% received antenatal corticoids), with the elevated prevalence of arterial hypertension and IGR among mothers giving birth to SGA infants meriting special mention (p < 0.001). These infants were born more mature and lighter than those with appropriate weights (p < 0.001).

Two hundred and fourteen newborns (13.5%; 95%
CI 11.8-15.3) presented birth weight below the 3rd percentile, while for birth
weight below the 10th percentile this figure rose to 455 (30.7%; 95% CI 27.8-32.2),
both positively correlated with increasing gestational age (c^{2}
for linear trend, p < 0.001).

The mean FGR was 0.90 (SD = 0.21) and there
was a significant (p < 0.001) tendency for FGR to reduce as gestational age
increased (Figure 1). Fetal growth ratio values were below
0.76 in 32.6% (95% CI 30-35.3, n = 387) of cases while 63% (95% CI 60-66.4,
n = 734) exhibited FGR __<__ 0.89 which correlated positively with increasing
gestational age (p < 0.001; Figure 2).

The mean z-score was 0.007 (±1.01) and was lower for SGA (-0.188±0.88 versus 0.099±1.05; p < 0.0010). One hundred and twenty (8%, 95% CI 6.6-9.3) of the NI with weights below 1,500g presented PI z-scores below -1 (asymmetrical growth restriction), with this proportion being greater among SGA infants (63/467, 13.5%) when compared with children whose weights were appropriate (57/1,051; 5.42%) (p < 0.001). No differences in the rates of z-score < -1 were observed according to degree of prematurity (p = 0.178). Furthermore, those preterms suffering from asymmetrical restriction exhibited more severe restriction (FGR < 0.75) than did those with symmetrical restriction (OR 3.16, 95% CI 2.1-4.7).

The coefficient of bimodality oscillated between -0.27 and 0.78 (mean 0.53) with no relation to gestational age, while mean PI was 2.26 (SD = 0.39). When compared with appropriate for gestational age children, SGA infants exhibited lower PI (2.30±0.33 and 2.18±0.57, respectively, p < 0.001).

In Table 2 it will be observed that the coefficient of bimodality reduced in line with severity of restriction, while the proportion of asymmetry increases with severity of growth restriction (p < 0.001).

Prenatal diagnosis of restricted growth and
maternal arterial hypertension were the only conditions linked to an increased
risk of being small for gestational age and having FGR __<__ 0.89, with
elevated PAR values meriting attention (Tables 3 and 4),
while the condition of adolescence revealed a mild protective effect, although
not a statistically significant one. The slight increase in risk in the absence
of prenatal control, while statistically significant, did not correlate with
a transcendent impact at the population level.

Once more, maternal hypertension (aOR 1.60, 95% CI 1.03-2.04) and intrauterine growth restriction (aOR 1.80, 95% CI 1.16-2.82) were the only variables that remained statistically associated with the condition of asymmetrical growth restriction with a discrete repercussion at the population level (PAR = 17% [95% CI 4-30] and 24% [95% CI 9-39], respectively).

Small for gestational age or severely growth restricted infants born at weights below 1,500 g exhibited a risk of death more than double that of those who did not present these conditions (p < 0.05). No prenatal characteristic or pathology was associated with a biological risk and/or statistically altered risk of mortality, with the exception of the absence of prenatal, control, which exhibited a significantly elevated risk with similar magnitude for each of the three outcomes (p < 0.05), suggesting delayed detection and treatment of medical and/or obstetric complications during pregnancy (Table 5). As would be expected, for every extra week that pregnancy lasts the risk of death reduces by 30 to 40% (p < 0.05).

When FGR was processed in a continuous manner, the risk of neonatal mortality increased by 0.027 times for every 0.10 units that FGR reduced (95% CI 0.009-0.07, p < 0.001).

**Discussion**

The present study, based on a hospital sample from 16 neonatal units at 16 Latin American university hospital maternity units, demonstrates that the prevalence of the condition of being small for gestational is elevated among preterms born with weights below 1,500 g and that the condition is severe in a third of such infants. The condition is inversely related to gestational age and is linked with an elevated risk of mortality. The characteristic of asymmetry conferred little additional risk to that already generated by the degree of restriction severity.

Among the differentiating features of our study,
it is worth mentioning that this is the first exploration of this problem in
our region, describing FGR and PI in preterms and employing standardized data
collection and accruing a large sample size. In contrast with other studies,^{16}
the sample was not limited by gestational age.

A number of limitations can be listed. Several
different authors^{17} have proposed that postnatal weight curves based
on an estimate of gestational age calculated from the date of the last menstrual
period overestimate gestational age and thus underestimate the prevalence and
severity of compromised growth in preterms. Ott,^{18} suggests that
standards for birth weight based on fetal growth gauged by ultrasound and adjusted
for maternal variables^{19} offer better predictive value for abnormal
outcomes. Until a local standard is developed by ultrasound we consider that
the findings are sufficiently representative of the study population.

In view of the elevated prevalence of absent prenatal control and in the face of the possibility of selection bias, all of the logistic models were re-analyzed with cases where there was no prenatal control excluded with no changes in the OR resulting, and superimposed confidence intervals being observed (data not shown).

The absence of bimodality (coefficient <
0.55 and low prevalence of z-score < -1) is strong evidence against the existence
of two different IGR subtypes (symmetrical *vs* asymmetrical), even in
the most severe subsets.

Several different studies have linked fetal
growth restriction with neonatal morbidity and mortality of preterms born weighing
less than 1,500 g^{1-5,13,20-22} although without contemplating, as
does the present study, severity and proportionality. Both the diagnosis and
severity of growth restriction were associated (as expected) with a high risk
of neonatal death, with absence of prenatal control being the only preceding
factor that was potentially controllable to be systematically associated with
death for the three outcomes investigated (SGA, FGR < 0.89 and z-score <
-1).

Maternal arterial hypertension and prenatal restricted growth diagnosis were the only maternal variables systematically and statistically associated with an increased risk for the three outcomes. It is important to point out the absence of interactions between these two variables, suggesting that each has an independent effect on the outcomes established. The magnitude of the PAR values associated with arterial hypertension and growth restriction are probably a reflection of the elevated prevalence of the two nosological entities among the study population (30.7 and 36.8%, respectively).

The etiology of premature delivery is plurifactorial,
but the many different maternal diseases and pregnancy-related conditions that
limit fetal growth and contribute to the chance of adverse events among more
mature fetuses may also have an effect on the growth and birth weights of very
premature infants.^{20}

The pathophysiology of restricted growth in
fetuses destined to be born preterm is explained by a reduction in uterine flow
and placental perfusion. This would promote a reduction in hormones that induce
fetal growth, increasing cortisol and stimulating the myometrium, with the consequent
triggering of labor and premature delivery. The activation of compensatory mechanisms
can lead two one of two outcomes: 1) if they fail then stillbirth occurs and
2) if they are successful, growth is restricted and adaptation takes place.
If this is sufficient the result will be a small for gestational age fullterm
infant and, if insufficient, the mechanisms of labor will be activated and the
preterm may survive.^{23}

Only one study^{16} agrees with ours
about the fact that SGA prevalence, and also severity, increase with advancing
gestational age, in contrast with other authors. In a study that included 4,700
preterms, Zeitlin et al. concluded that the relationship between restricted
growth and premature delivery was strongest before 34 weeks' gestation.^{24}
Another population study,^{25} found that the prevalence of restriction
increased up to the thirtieth week (12.3%) and then quickly decreased. Finally,
in one study that enrolled 8,663 singleton infants, the proportion of SGA infants
(< 2 SD from the mean) reduced from 21% between 26 and 30 weeks to 11.1%
from 31 to 37 weeks.^{26} These discrepancies may be the result of sample
size, policies on inducing labor, gestational age estimation, SGA definition,
cutoff points for weight or gestational age among those under 1,500 g and termination
of pregnancy. Owen et al., in a contrastive article comparing spontaneous and
induced premature deliveries did not find any significant difference in neonatal
outcomes.^{27}

Our values for PI agree with data published
by other authors.^{13,28} Employing this indicator, the most common
type of growth restriction was symmetrical. In common with the majority of developing
countries, this can be attributed to its association with greater severity and
increased prevalence of certain risk factors (for example a very small mother).^{29}

We conclude that the prevalence of the condition of small for gestational is elevated among preterm infants born with birth weights below 1,500 g and that when this is very severe, irrespective of the cause, there is a high risk of mortality. Asymmetric growth restriction confers very little additional risk to that already conferred by the degree of restriction severity. We suggest an early test for restricted growth during prenatal control.

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**Correspondence to**

Carlos Grandi

Cabello 3150 (1425), 7° B

Buenos Aires, Argentina

Tel.: +54 (11) 4803.7622

Fax: +54 (11) 4943.7779

E-mail: cgrandi@intramed.net

Manuscript received Sep 13 2004, accepted for publication Fev 23 2005