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- Patients and Methods
Preterm birth is a health problem associated with a high risk of cognitive1, sensory2, and behavioral3 disabilities, that can lead to academic underachievement and social and emotional difficulties4. Early interventions in preterm infants improve brain development5 as well as cognitive6 and behavioral7, 8 outcomes. Thus, identification of premature infants at higher risk of neurobehavioral problems forms the basis of targeted preventive interventions.
A substantial proportion of premature newborns are subject to intrauterine growth restriction (IUGR)9, which is associated with exposure to chronic hypoxia and undernutrition during fetal life due to placental insufficiency10. Evaluation of placental function by umbilical artery (UA) Doppler examination is the standard diagnostic procedure used to distinguish between IUGR and constitutional smallness11–13. Long-term outcome studies of such infants have revealed a specific profile of neurocognitive difficulties with poor executive functioning, cognitive inflexibility with poor creativity, and language problems14, 15. Studies of preterm IUGR babies have linked these difficulties during childhood with behavioral impairment already present during the neonatal period16–18.
During growth restriction due to placental insufficiency, hemodynamic adaptation occurs with blood flow redistribution preferentially to the brain, i.e. the brain-sparing effect. Controversy remains as to whether this phenomenon indicates a higher risk of brain injury or is a protective mechanism2, 19–23. In early stages, brain-sparing is expressed as a reduction in the Doppler cerebroplacental ratio, which is present in almost all early-growth restricted fetuses with placental insufficiency24. However, as placental insufficiency and hypoxia progress, a further decrease in resistance to blood flow in the middle cerebral artery (MCA) is observed24. Abnormal MCA Doppler findings indicate an advanced stage of brain-sparing, since it is correlated with established hypoxemia25, 26 and with a relative decrease in blood flow in the frontal areas in favor of the basal ganglia27. No information exists on the neurobehavioral consequences of advanced brain-sparing, as defined by abnormal MCA Doppler parameters, in preterm IUGR infants during the neonatal period, a time when environmental influences are still negligible.
This study aimed to evaluate the neurobehavioral outcomes of preterm infants with IUGR, with normal and abnormal prenatal MCA Doppler parameters.
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- Patients and Methods
A total of 140 preterm newborns were initially included (70 controls and 70 with IUGR). Subsequently, one infant in the control group was excluded because of histological signs of chorioamnionitis. Another control and two IUGR infants died before 40 weeks of corrected age. Two controls (each with Grade III intraventricular hemorrhage) and three IUGR infants (two with Grade III intraventricular hemorrhage and one with periventricular leukomalacia) were excluded because of neurological complications as defined in the exclusion criteria. Finally, the parents of two controls and three IUGR infants declined to participate after initial acceptance, leaving a final population of 126 preterm infants (64 controls and 62 with IUGR). A neurobehavioral assessment was scheduled for each of them at 40 ( ± 1) weeks of corrected age. The habituation category could not be assessed in 30 newborns (15 controls and 15 IUGR) due to the absence of a sleeping period during the evaluation.
Table 1 depicts the maternal characteristics of the population. None of the mothers used drugs other than tobacco and alcohol during pregnancy. Table 2 shows the perinatal outcomes of the groups. As expected, IUGR newborns had a lower birth weight and a smaller head circumference than controls. Pre-eclampsia and delivery by Cesarean section were more common among the mothers in both IUGR subgroups (with normal and abnormal MCA Doppler findings) than among the control mothers. Neonates in both IUGR subgroups had a higher frequency of adverse perinatal outcomes than controls as well as more severe neonatal illness, as reflected by the significantly higher SNAP-II values.
Table 1. Maternal characteristics of the study population
| || ||IUGR|| |
|Characteristic||Controls (n = 64)||Normal MCA (n = 29)||Abnormal MCA (n = 33)||P*|
|Primiparous||28 (43.8)||18 (62.1)||15 (45.5)||0.24|
|Non-Caucasian ethnicity||11 (17.2)||6 (20.7)||11 (33.3)||0.19|
|Maternal age (years)||31.5 ± 5.2||31.8 ± 5.7||31.9 ± 3.7||0.92|
|Body mass index (kg/m2) at admission||23.7 ± 3||23.5 ± 2.4||22.5 ± 1.7||0.12|
|Low socioeconomic level†||23 (35.9)||15 (51.7)||18 (54.5)||0.15|
|Smoking status|| || || ||0.85|
| Non-smoking||53 (82.8)||23 (79.3)||28 (84.8)|| |
| 1–9 cigarette(s)/day||7 (10.9)||5 (17.2)||4 (12.1)|| |
| 11–19 cigarettes/day||4 (6.3)||0||1 (3)|| |
| ≥ 20 cigarettes/day||0||1 (3.4)||0|| |
|Alcohol consumption > 170 g/week||2 (3.1)||2 (6.9)||1 (3)||0.65|
Table 2. Perinatal outcome of the study population
| || ||IUGR|| || |
|Characteristic||Controls (n = 64)||Normal MCA (n = 29)||Abnormal MCA (n = 33)||P*||P†|
|Gestational age at delivery (weeks)||31.2 ± 2.4||30.9 ± 2.2||31.3 ± 2.6||1||1|
|Birth weight (g)||1674 ± 460||1032.9 ± 404||1075 ± 462||< 0.001||< 0.001|
|Birth-weight centile||44.3 ± 21.6||4.9 ± 3.5||4.4 ± 3.4||< 0.001||< 0.001|
|Head circumference (mm)||289 ± 2.7||263 ± 2.6||261 ± 2.7||< 0.001||< 0.001|
|Antenatal steroids||49 (76.6)||21 (72.4)||26 (78.8)||0.67||0.8|
|Pre-eclampsia||3 (4.7)||19 (65.5)||16 (39.4)||< 0.001||< 0.001|
|Cesarean section||29 (45.3)||28 (96.6)||27 (81.8)||< 0.001||0.001|
|Apgar score < 7 at 5 min||1 (1.6)||4 (13.8)||4 (12.1)||0.032‡||0.044‡|
|Umbilical artery pH < 7.15 at delivery||1 (1.6)||5 (17.2)||5 (15.2)||0.011‡||0.016‡|
|Neonatal unit stay (days)||8.3 ± 12.1||13.4 ± 20.2||13.3 ± 17.6||0.5||0.43|
|Severe respiratory distress syndrome||5 (7.8)||3 (10.3)||3 (9.1)||0.69||0.82|
|SNAP-II||11.9 ± 8.8||20.1 ± 16.4||21.2 ± 13.7||0.01||0.002|
Between both IUGR groups there were no significant differences in the mean z-scores of the UA (2.21 vs. 2.58; P = 0.17) or ductus venosus PI (1.46 vs. 1.54; P = 0.82).
Table 3 and Figure 1 detail the neurobehavioral outcomes by NBAS categories. The neurobehavioral scores of infants in the IUGR subgroup with normal MCA Doppler parameters did not differ significantly from those in the control group, but were significantly lower for infants in the IUGR subgroup with abnormal MCA Doppler, specifically in the areas of habituation, motor system, social-interactive (for auditory and visual stimuli) and attention. Similarly, the proportion of infants with abnormal neurobehavioral scores did not differ significantly between the control group and the IUGR subgroup with normal parameters, but was significantly higher in the IUGR subgroup with abnormal MCA Doppler, specifically in the areas of habituation, social-interactive, motor system and attention. Figure 2 shows the adjusted odds ratios for abnormal scores in each NBAS area in IUGR infants with abnormal MCA Doppler in relation to the control group.
Figure 2. Adjusted odds ratios (and their 95% CIs) for abnormal Neonatal Behavioral Assessment Scale in intrauterine growth restricted infants with abnormal middle cerebral artery Doppler values in relation to the control group.
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Table 3. Neonatal Behavioral Assessment Scale scores according to study group
| || ||IUGR|| |
|Assessment category||Controls (n = 64)||Normal MCA (n = 29)||Abnormal MCA (n = 33)||P*||P†|
|Habituation‡||6.52 ± 1.29||6.22 ± 1.25||5.59 ± 1.53||0.27||0.007|
|Motor system||5.39 ± 0.69||5.40 ± 0.5||4.88 ± 0.82||0.93||0.003|
|Social-interactive||5.86 ± 1.48||5.55 ± 1.62||4.79 ± 1.76||0.94||0.012|
| Visual||5.61 ± 1.66||5.23 ± 1.82||4.34 ± 1.87||0.61||0.004|
| Auditory||6.25 ± 1.45||6.00 ± 1.7||5.13 ± 1.74||0.86||0.006|
|State organization||3.87 ± 0.83||3.97 ± 0.64||3.80 ± 0.83||0.44||0.99|
|State regulation||4.45 ± 1.14||4.09 ± 1.42||4.33 ± 1.45||0.4||0.57|
|Autonomic system||5.52 ± 0.91||5.52 ± 0.94||5.50 ± 1.25||0.94||0.27|
|Attention||5.78 ± 1.48||5.68 ± 1.51||5.11 ± 1.86||0.5||0.013|
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- Patients and Methods
Premature infants with IUGR and abnormal UA Doppler parameters, a surrogate marker of placental insufficiency, are known to be at high risk of developing neurobehavioral and neurocognitive deficits44–46. Our study shows that, in this group of neonates, prenatal abnormal MCA Doppler parameters are associated with this higher risk, which suggests that this reflects an advanced stage of brain-sparing where disrupted neurological maturation secondary to hypoxia is already present.
During the second half of gestation, profound changes in brain organization occur, involving critical neural connections and myelination of important neural tracts47. It is not known how the susceptibility of the brain changes as such maturation progresses, but it is plausible that even mild degrees of hypoxia induce permanent changes resulting from the adaptation of the developing brain to a hypoxic and undernourished environment. IUGR fetuses with chronic hypoxemia exhibit a delay in development and behavioral milestones48–50. Our findings provide neonatal correlates for these previous observations.
The data provided by our study add to the body of evidence suggesting that increased brain perfusion is not an entirely protective mechanism. In keeping with this contention, we have demonstrated previously that full-term, small-for-gestational age (SGA) infants with Doppler signs of brain-sparing have reduced neurobehavioral competencies as newborns42, 51 and at 2 years of age52 than do their counterparts without Doppler signs of brain-sparing. Similarly, a large cohort study19 carried out in The Netherlands showed that brain-sparing during the third trimester of pregnancy was associated with a 23% higher than normal prevalence of behavioral problems at 18 months. Evidence of the effects of brain-sparing on neurobehavior in preterm infants with early-onset IUGR is scarce. A series including 31 preterm infants with signs of brain-sparing (18 born SGA) and 58 preterm infants without signs of brain-sparing revealed no differences between the groups in neurobehavior at 11 years23. Another study that included 16 preterm babies (13 born SGA) revealed differences between those with and without signs of brain-sparing according to the Mental Developmental Index at 2 years, which includes the assessment of habituation and social competencies53. However, these differences were not significant after adjustment for brain volume. Both studies included in the brain-sparing group a mixture of infants who were appropriately sized and small for gestational age. In addition, brain-sparing was defined as an abnormal cerebroplacental ratio, which is known to become abnormal earlier as placental insufficiency progresses24. Previous research from our group27, 51, 54 suggests that brain-sparing is a continuum, where increased brain perfusion is first detected by power-Doppler techniques followed by a reduction in the cerebroplacental ratio. At the other end of the spectrum, abnormal findings reflect a more advanced stage of brain hypoxia, which coincides with a relative decrease in blood supply to frontal areas in favor of the basal ganglia27. The results of the current study, where the effects of abnormal MCA blood flow on neurobehavior were more marked than in previous series that defined brain-sparing as an abnormal cerebroplacental ratio, are consistent with this concept. It is also noteworthy that IUGR groups with normal and abnormal MCA Doppler parameters did not differ in head circumference at birth, suggesting an independent effect of abnormal MCA blood flow on behavioral maturation. This may seem inconsistent with the long-recognized association between lagging head growth and neurodevelopment in the overall population of SGA babies55, but this association seems more pronounced in term neonates than in preterm neonates56. In fact, studies comparing symmetrical and asymmetrical growth restriction have failed to demonstrate differences in fetal acid–base status at the time of cordocentesis57 and other indices of perinatal outcome58, 59.
From a clinical perspective, the findings of this study are relevant to prenatal and neonatal management of early-onset IUGR. The evolution of medical technology and therapy has led to a substantial decrease in mortality among premature infants60. However, concern is growing with respect to the persistence of high rates of adverse neurobehavioral outcomes, which represent an educational4 and social61 burden. Identifying at-risk infants is essential to understanding the association between fetal wellbeing and later neurodevelopmental problems and forms the basis for possible preventive interventions. During fetal life, MCA Doppler parameters in preterm growth-restricted fetuses could help define management strategies and timely delivery. In the neonatal period, interventions aimed at reducing stress in the premature infant have been shown to improve frontal region cerebral white matter development5. In low-risk premature infants, it has been reported that individualized developmental interventions prevent short-term neurobehavioral dysfunction8. Furthermore, as these infants are at risk of impaired neurodevelopmental outcome they might benefit from early educational intervention, which has been found beneficial in selected cases6, 7.
This study had certain limitations. First, although NBAS is a reference standard for evaluating a newborn's capacity to respond to the environment and therefore reflects brain maturation, it assesses only neurobehavior and not cognitive function62. However, several studies have demonstrated the correlation between neonatal neurobehavior and later neurocognitive development in infants born preterm16, 18, 63 and at full term64, 65. Furthermore, mothers in the two study groups were not matched on some perinatal conditions. Especially relevant is the higher prevalence of pre-eclampsia in the IUGR subgroup with normal MCA Doppler parameters. Our finding of a better neurobehavioral outcome in this subgroup compared to the IUGR subgroup with abnormal MCA Doppler parameters could be explained by a protective effect of pre-eclampsia (prompting delivery because of maternal indications before fetal deterioration occurs), or secondary to the drugs commonly administered in such cases, e.g. magnesium sulphate. Although we adjusted for some of these potential confounders, we cannot rule out some residual confounding effects. Finally, because of the sample size, our study could be underpowered for detection of some associations and for stratification of the sample according to the presence of pre-eclampsia.
In summary, this study shows that abnormal MCA Doppler, as a sign of advanced brain-sparing, is a major contributor to neurobehavioral impairment among preterm infants with IUGR.