Differential effects of growth restriction and immaturity on predicted psychomotor development at 4 years of age in preterm infants

BACKGROUND Fetal growth restriction and immaturity are associated with poor neurocognitive development and child psychopathology affecting educational success at school and beyond. However, the differential effects of either obstetrical risk factor on predicted psychomotor development have not yet been deciphered. OBJECTIVE This study aimed to separately study the impact of growth restriction and that of immaturity on predicted psychomotor development at the preschool age of 4.3 (standard deviation, 0.8) years using birthweight percentiles in a prospective cohort of preterm infants born at ≤37+6/7 weeks of gestation. Differences between small for gestational age newborns with intrauterine growth restriction and those without were described. We examined predicted total psychomotor development score, predicted developmental disability index, calculated morphometric vitality index, and predicted intelligence quotient, Porteus Maze test score, and neurologic examination optimality score in 854 preterm infants from a large prospective screening cohort (cranial ultrasound screening, n=5,301). STUDY DESIGN This was a prospective cranial ultrasound screening study with a single-center cohort observational design (data collection done from 1984–1988, analysis done in 2022). The study included 5,301 live-born infants, of whom 854 (16.1%) were preterm infants (≤37+6/7 weeks’ gestation), and was conducted on the day of discharge of the mother at 5 to 8 days postpartum from a level 3 perinatal center. Predicted psychomotor development, as assessed by the predicted total psychomotor development score, predicted developmental disability index, calculated morphometric vitality index, predicted intelligence quotient, Porteus Maze test score, and neurologic examination optimality score were calculated. We related psychomotor development indices and measures to gestational age in 3 groups of birthweight percentiles (ie, 10%, 50%, and 90% for small, appropriate, and large for gestational age newborns, respectively) using linear regression analysis, analysis of variance, multivariate analysis of variance, and t test procedures. RESULTS The key result of our study is the observation that in preterm infants born at ≤37+6/7 weeks of gestation, growth restriction as compared with immaturity is the prime risk factor for impairment of overall predicted psychomotor development, intelligence quotient, Porteus Maze test results, and neurologic examination optimality score at the preschool age of 4.3 (standard deviation, 0.8) years (P<.001). This is particularly true for intrauterine growth restriction. These detrimental effects of growth restriction become more prominent with decreasing gestational age (P<.001). As expected, growth restriction in preterm infants born at ≤37+6/7 weeks of gestation was associated with a number of obstetrical risk factors, including hypertension in pregnancy (P<.001), multiple pregnancy (P<.001), pathologic cardiotocography (P=.001), and low pH (P=.007), increased pCO2 (P=.009), and poor pO2 (P<.001) in umbilical arterial blood. Of note, there were no differences in cerebral hemorrhage or white matter damage among small, appropriate, and large for gestational age birthweight percentile groups, suggesting an independent mechanism of brain injury caused by preterm growth restriction resulting in poor psychomotor development. CONCLUSION Compared with immaturity, growth restriction in preterm infants has more intense detrimental effects on psychomotor development, necessitating improved risk stratification. This finding has implications for clinical management, parental consultation, and early intervention strategies to improve school performance, educational success, and mental health in children. The mechanisms of brain injury specific to growth restriction in preterm infants require further elucidation.


AJOG Global Reports at a Glance
Why was this study conducted?We explored the differential effects of growth restriction and immaturity on predicted psychomotor development to improve risk stratification, clinical management, early intervention strategies, preschool support, and mental health in children.

Key findings
Compared with immaturity, the detrimental effects of growth restriction on predicted psychomotor development at 4 years of age in preterm infants born at ≤37 +6/7 weeks of gestation are much more intense and increase with decreasing gestational age.

What does this add to what is known?
Apparently independently of cerebral hemorrhage and/or white matter damage, growth-restricted preterm infants fare far worse in predicted psychomotor development than solely immature infants at the same gestational age.This suggests specific brain damage occurring during chronic hypoxemia and malnutrition, circulatory centralization, and brain-sparing requiring timely risk stratification to improve management in clinical obstetrics, parental consultation, and early intervention strategies to prevent harm.

Statistical analysis
Results are presented as means and SD.The a priori level of significance for rejecting the null hypothesis was set at a 2-tailed alpha level of <0.05.We evaluated growth restriction and immaturity at birth in relation to z-score transformed (z) predicted psychomotor development indices and measures using parametric and nonparametric statistical procedures, analysis of variance, multivariate analysis of variance, and analysis of covariance, as appropriate.To account for multiple comparisons, the Games−Howell test was used.All procedures were performed using the IBM SPSS Statistics, Version 28.0 (IBM Corp, Armonk, NY) statistical software.Deviations from the total number of participants are due to missing values.

Results
A total of 854 (16.1%) preterm infants born at ≤37 +6/7 weeks (51.8% male) underwent cranial ultrasound screening (including twins).No sex-related differences were found in the overall rate of cerebral hemorrhage, white matter damage, Apgar scores at 1, 5, and 10 minutes, or umbilical artery pH.
There was a close relation between gestational age (weeks) and predicted TPMDS in each of the SGA, AGA, and LGA birthweight percentile groups (10%, 50%, and 90%).Namely, lower gestational age was associated with poorer yields in the composite TPMDS (Figure 1), predicted IQ (Figure 2), predicted PMT results (Figure 3), and predicted NOS (Figure 4).Furthermore, the predicted DDI was negatively correlated with gestational weeks (Figure 5).These results underscore the    Jensen.Newborn growth restriction and psychomotor development.Am J Obstet Gynecol Glob Rep 2024.
The differential effects on psychomotor development in SGA newborns with IUGR (n=67) and those without (n=146) are shown in Table 5. Gestational age, acid−base balance, blood gases, and Apgar scores were not different between the groups.However, in the group with IUGR, there were significantly poorer results in psychomotor development indices (zpTPMDS, MVI, pDDI) and measures (zpIQ, pzNOS) and higher rates of peri-and intraventricular hemorrhage (P<.05) and white matter damage (P<.05), reduced morphometric measures, and lower percentiles for birthweight, length, and head circumference, clearly indicating IUGR as the most important threat to predicted psychomotor development.
Jensen.Newborn growth restriction and psychomotor development.Am J Obstet Gynecol Glob Rep 2024.

Principal findings
This study demonstrates that in 854 preterm infants born at ≤37 +6/7 weeks of gestation from a large prospective cohort (n=5,301), growth restriction compared with immaturity had significantly more harmful effects on predicted psychomotor development at preschool age.−14 In previous accounts, we have established that simple birth variables and obstetrical risk factors allow for predicting neurocognitive development at the preschool age of 4 years. 1−3 However, the differential effects of growth restriction compared with those of immaturity could not be deciphered. 3s evidenced by the significantly different slopes and constants of the regressions between the AGA (50%) and SGA (10%) birthweight percentile groups, the harmful effects of growth restriction increase with decreasing gestational age (Figures 1, 2, 4, and 5).Although the specific mechanisms are elusive, structural changes in brain development including reduced gray matter volume in various brain regions may be involved, [15][16][17][18][19]28 making the poor neurocognitive development in growth-restricted infants comprehensible relative to infants presenting with immaturity only.Importantly, the detrimental and potentially microstructural effects of growth restriction on the fetal brain and hence on preschool The correlations between predicted Maze test results (z-score units) at 4.3 years (SD, 0.8) of age and Gestational age (weeks) in three groups of birth weight percentiles SGA, AGA, and LGA The correlations between predicted PMT results (z-score units) at 4.3 (SD, 0.8) years of age and gestational age (weeks) in 3 groups of birthweight percentiles (small [10%], appropriate [50%], and large [90%] for gestational age) in 302 preterm newborns born at ≤37 +6/7 weeks of gestation are depicted (zpPMT_10=À12.580+0.300£ gestational week; r=0.904;SE estimate=0.341;n=210; P<.001; zpPMT_50=À12.788+0.340£ gestational week; r=0.991;SE estimate=0.138;n=60; P<.001; zpPMT_90=À13.052+0.378£ gestational week; r=0.935;SE estimate=0.448;n=28; P<.001). 1,3,22The slope (P<.003) and intercept of the regression line of growth-restricted preterm newborns (10% percentile group) are significantly different from those of immature newborns without growth restriction (50%) (P<.007).The slope (P<.023) and intercept of the regression line of the large for gestational age preterm infants (90%) are significantly different from those of immature newborns without growth restriction (50%) (P<.024).Reduced predicted PMT results in growth-restricted preterm infants are clinically relevant because PMT domains are considered largely independent of standard intelligence quotient testing because of its untimed, configural, and problem-solving task.Furthermore, the PMT is a uniquely sensitive measure of executive function ability, comprising the domains of fine motor ability, dexterity, planning capacity, stability, and learning ability. 1,3,22T, Porteus Maze test; SD, standard deviation; SE, standard error.
Jensen.Newborn growth restriction and psychomotor development.Am J Obstet Gynecol Glob Rep 2024.

Original Research
−21 This has to be accounted for in clinical obstetrics.

Clinical implications
1][2][3][4][5]10 The present results indicating that growth-restricted infants fare far worse in development than solely immature infants at the same gestational age shed light on the urgency to manage growth restriction in clinical obstetrics appropriately in a timely manner. 22 his holds particularly true for IUGR (Table 5).29−31 Thus, brain-sparing does not ensure age-appropriate neurocognition, and it is clear from magnetic resonance imaging that growth-restricted infants represent a high-risk subgroup of infants with a complex and distinct set of microstructural brain abnormalities not observed in appropriately grown preterm infants.21 Recent imaging advances even demonstrate more complex changes including altered fiber organization and impaired connectivity networks such as the cortico-basal ganglia-thalamo-cortical loop.21 Thus, management in clinical obstetrics has to make the decision when to deliver intrauterine growth −restricted fetuses to ensure oxygen and nutrient supply in the extrauterine environment.22 This is not an easy task and may require longitudinal ultrasound measurements on a weekly basis, including biparietal diameter, head circumference, abdominal circumference, abdominal transverse diameter, femur length, estimated fetal weight, and head circumference−abdominal circumference ratio plotted in nomograms to detect stunted fetal growth as early as possible.However, the decision to FIGURE 4   The correlations between predicted Neurologic examination optimality score at 4.3 years (SD, 0.8) of age (z-score units) and Gestational age (weeks) in three groups of birth weight percentiles SGA, AGA, and LGA  1,3,22 The slope (P<.003) and intercept of the regression line of growth-restricted preterm newborns (10% percentile group) are significantly different from those of immature newborns without growth restriction (50%) (P<.0001).This is clinically important because growth restriction at lower gestational age particularly affects motor performance in childhood, necessitating early intervention by neurorehabilitation. 1,3,22 NOS, neurologic examination optimality score; SE, standard error.
Jensen.Newborn growth restriction and psychomotor development.Am J Obstet Gynecol Glob Rep 2024.

ajog.org
−33 Conversely, if growth restriction and brain-sparing can be excluded (eg, in constitutionally small infants of small mothers, as in 146/213 [68.5%] cases in our sample [Table 5]), pregnancy should be optimally prolonged by all means to allow for further maturation of the brain and improved development during intrauterine growth.
As expected, EPH (edema, proteinuria, and hypertension) syndrome, hypertension during pregnancy, and multiple pregnancy causing placental insufficiency and pathologic heart rate patterns were associated with poor pO2, increased pCO2, and low pH in umbilical arterial blood in growth-restricted newborns (Tables 1 and 2).This evidence of chronic and/or acute hypoxemia reminds us to apply prospective risk management in clinical obstetrics and early intervention to prevent or ameliorate harm to growth-restricted infants (eg, by timely detection of pathologic cardiotocography patterns that are significantly more frequent in infants with IUGR than in SGA infants without growth restriction [62% vs 38%; P=.002]). 3,22

Strengths and limitations
This study demonstrates the differential effects of both growth restriction and immaturity on predicted psychomotor development at the preschool age of 4.3 (SD, 0.8) years in a prospective cohort of 854 preterm infants born at ≤37 +6/7 weeks from a large ultrasound screening trial (n=5,301).This made possible the important observation that the specific detrimental effects of growth restriction on the fetal brain as compared with immaturity appear unrelated to cerebral hemorrhage and/or white matter damage.Hence, these results predicting psychomotor development at preschool age in risk groups are significant for clinical management of growth restriction and immaturity and parental consultation as well as for developing early intervention strategies to improve preschool support and reduce psychopathology in children.A general limitation of this study is that the preterm infants were The correlations between predicted Developmental disability index determined at 4.3 years (SD, 0.8) (z-score units) and Gestational age (weeks) in three groups of birth weight percentiles SGA, AGA, and LGA The correlations between predicted DDI determined at 4.3 (SD, 0.8) years of age (z-score units) and gestational age (weeks) in 3 groups of birthweight percentiles (small [10%], appropriate [50%], and large [90%] for gestational age) in 302 preterm newborns born at ≤37 +6/7 weeks of gestation are depicted (pDDI_10=8.969À0.222£ gestational week; r=0.690;SE estimate=0.559;n=207; P<.001; pDDI_50=5.932À0.155£ gestational week; r=0.707;SE estimate=0.451;n=58; P<.001; pDDI_90=5.882À0.163£ gestational week; r=0.719;SE estimate=0.469;n=27; P<.001). 1,3,22The slope (P<.009) and intercept of the regression line of growth-restricted preterm newborns (10% percentile group) are significantly different (P<.0008) from those of immature newborns without growth restriction (50%).These results underscore the significance of detecting growth restriction in preterm infants for predicting developmental trajectories and the degree of predicted disability at 4 years of age, whereby the probability of future disability increases with decreasing gestational age. 1,3,22I, developmental disability index; SD, standard deviation; SE, standard error.
Jensen.Newborn growth restriction and psychomotor development.Am J Obstet Gynecol Glob Rep 2024.

Original Research
ajog.org part of a prospective cranial ultrasound screening performed from 1984 to 1988.Although this holds true for growth-restricted infants and for immature infants, this database is a valid source for the prediction of psychomotor trajectories among preschool-aged children within the boundaries of the data collection period.Furthermore, unlike information on IUGR, precise information on genetically or metabolically small infants in the SGA group is not provided in the screening database, and no cerebral Doppler studies are available.

TABLE 4
Relation between psychomotor development indices and measures and gestational week at birth defined by date of last menstrual period and birthweight percentile allowing for full range prediction (n=854)

TABLE 5
Obstetrical and birth-related risk factors and psychomotor development indices and measures in small for gestational age preterm infants (birthweight percentile group 10%; 24−37 weeks' gestation; n=213) without (n=146) and with (n=67) intrauterine growth restriction derived from a prospective cranial ultrasound screening database (n=5,301) Jensen.Newborn growth restriction and psychomotor development.Am J Obstet Gynecol Glob Rep 2024.(continued)

TABLE 5
Obstetrical and birth-related risk factors and psychomotor development indices and measures in small for gestational age preterm infants (birthweight percentile group 10%; 24−37 weeks' gestation; n=213) without (n=146) and with (n=67) intrauterine growth restriction derived from a prospective cranial ultrasound screening database (n=5,301)(continued) Jensen.Newborn growth restriction and psychomotor development.Am J Obstet Gynecol Glob Rep 2024.February 2024 AJOG Global Reports 15

TABLE 5
Obstetrical and birth-related risk factors and psychomotor development indices and measures in small for gestational age preterm infants (birthweight percentile group 10%; 24−37 weeks' gestation; n=213) without (n=146) and with (n=67) intrauterine growth restriction derived from a prospective cranial ultrasound screening database (n=5,301)(continued)Jensen.Newborn growth restriction and psychomotor development.Am J Obstet Gynecol Glob Rep 2024.