Physical growth and intelligence development of discordant dizygotic twins from birth to preschool age: a prospective cohort study

Twin growth discordance is a common finding in multiple gestations. The term describes a significant weight difference between the two fetuses of a twin pregnancy. The definition of significant discordance considered at least a 20% difference in birth weight between the twins [1], although it varies from 15–25% with different cutoffs in clinical practice and research [2, 3]. Twins with ≥ 20% birth weight discordance are associated with adverse pregnancy outcomes, including a high rate of preterm birth, malformation, mortality, neonatal asphyxia, respiratory distress, and admission to the Neonatal Intensive Care Unit (NICU) [4‐6]. Nevertheless, data regarding other growth parameters among discordant twins following hospital discharge are lacking. Recent studies have shown that the smaller of the discordant twins after birth attempt to catch up with their siblings in physical growth, thereby significantly reducing the gaps between them during the first year of life [7].

Typically, the prenatal period is the duration of rapid brain development, which includes marked changes in cortical folding [8], myelination [9], and gray-matter distribution [10]. These findings raise the hypothesis that infants who suffer growth restriction during the prenatal period are likely to be deprived of an optimal supply of nutritional substrates and are at risk of impaired neural and cognitive development. Low birth weight is a crucial determinant of psychological development; this the earlier the birth in terms of gestation weeks and the lower the birth weight, the greater the delay in psychological development, especially in the first few years of life [11, 12].

Among healthy twins, growth discordance may be due to the inability of the uterine environment to meet the demands of multiple fetuses, leading to intrauterine growth restriction (IUGR). Twin growth discordance is a complication of both monochorionic and dichorionic twin pregnancies. The etiologies for intrauterine dysplasia in dizygotic twins emerge from maternal and fetal factors, while in monozygotic twins, non-intrauterine nutrition factors, such as twin transfusion syndrome (TTTS) and selective IUGR (sIUGR), underlie poor prognosis. Chorionicity represents a putative confounder in the prevalence of neurologic morbidity among twin survivors. The current studies on postnatal physical and mental development in discordant twins have not distinguished the chorion, which could skew the results. Therefore, the present study discusses the physical growth and intelligence development of discordant dizygotic twins. Can the smaller of the discordant twins catch up with their sibling in physical and mental development after birth?

Several studies have shown a strong association of low birth weight to adult growth and health [11, 12]. Birth weight can be seen as an index of fetal nutrition, influenced by maternal factors and fetal genetics [13, 14], the latter acting through the intrauterine environment. A twin study model is an insightful means to control maternal factors; however, the data describing the growth patterns among discordant twins are limited and whether the smaller twins present a worse outcome than their larger counterparts in adult life is debatable. Mazkereth R et al. [15] showed that the gaps in growth parameters between the smaller the discordant twins and their larger siblings are significantly decreased during the first year of life. Ross GS et al. [16] suggested that the smaller the discordant twins exhibited an appropriate catch-up, resulting in no differences in any growth parameters at the age of 3; nonetheless, only 16 pairs of discordant twins were assessed, and the mean gestational age was 31 ± 2.4 weeks. The current study indicated that the difference in birth weight of dizygotic twins had a lasting effect on the physical growth in infancy, and the smaller had no obvious catch-up growth from birth to 6 years. Next, we measured the growth rates of discordant dizygotic twins at different time points and found that the smaller of the discordant twins, except for the one that gained weight quickly in the first 6 months after birth, did not catch up with the larger twins. Regarding height, there were no rules in the growth rate pattern. We suggested the follow-up physical examination should be required for discordant twins in the future, especially for the smaller one, to guard against short statures, malnutrition and growth retardation in adult. Some studies demonstrated that the twins attained normal final physical development compared to children from the general population until late adolescence [17, 18]. Thus, monitoring these discordant dizygotic twins is recommended to observe whether they have narrowed the gap in physical parameters during adolescence.

Low birth weight and prenatal malnutrition are associated with neurodevelopmental disorders [19, 20]; however, the exact mechanism is yet to be clarified. A previous study speculated that the adverse intrauterine environment leads to the hypothalamus-pituitary-adrenal axis resetting, and long-term stimulation of glucocorticoids damages the microvascular endothelial cells, resulting in nerve injury in infants with IUGR [21]. The scarcity of uterine resources restricts intrauterine growth, which has a detrimental effect on cognitive development in childhood. The intelligence development level of the same twin pairs was measured at ages 1 and 6. The smaller twins performed significantly worse in psychomotor skills but not cognition at the age of 1, and their psychomotor retardation rates were 17.6% compared to the larger twins (2.9%). Birth weight growth discordance of ≥20% confers an independent adverse effect on the long-term neurodevelopment of the smaller twin. According to the results of multiple linear regression analysis on psychomotor development, we proposed that delayed psychomotor development was associated with small body size during infancy, as described previously by Silventoinen K et al. [22] In addition, Halling C et al. [23] considered birth weight growth as an independent adverse effect on the long-term neurodevelopment and demonstrated a negative impact of growth discordance on the smaller twin at the age of 2.5 years across all three domains of development: motor, language, and cognition. We suggested discordant twins should be tested with BSID routinely at one year old, so as to give access to early clinical intervention for the smaller infants with psychomotor retardation.

The gap in intelligence development in discordant dizygotic twins at the age of 6 appears to be bridged because no significant difference was detected in VCI, PRI, WMI, PSI, and the full-scale IQ in our study. However, smaller twins had a PRI score 4 points lower than the larger twin (Twin-L 99.61 ± 15.25 vs. Twin-H 103.58 ± 11.87). Thus, we suspected that the wide PRI score difference could be attributed to the gap in PDI at the age of 1. The smaller twins accepted preschool education inevitably under pressure from parents, who wanted to narrow the gap after the BSID assessment. Some studies on the monochorionic twin cohort [24, 25] reported fetal growth restriction results in lower neurocognitive scores in early childhood and significant differences in size.

Typically, the general indicators can affect IQ scores, among which the prenatal environment is discussed previously [26]. The high pregnancy S/D value can predict fetal intrauterine distress and poor perinatal outcomes [27]; however, whether subtle variations in the routine ultrasound detection are associated with long-term cognitive and motor abilities is yet to be elucidated. The occurrence of fetal distress might lead to neonatal asphyxia. Chronic asphyxia can cause cerebral and hypoxia, affecting the children’s quality of later life. We found that the IQ-L group had a higher pregnancy S/D value and perinatal asphyxia rate than the IQ-H group. The current study carried out univariate analysis and multivariate linear regression analysis to control the confounding factors, and the ROC curve was drawn for an intuitive picture of the possible factors affecting the IQ. The pregnancy S/D value comprised the maximum AUC, followed by asphyxia, pointing to a link with IQ. Therefore, additional clinical cases will be collected in future studies to verify the influence of pregnancy S/D value and neonatal asphyxia on children’s IQ scores. As the smaller twins’ body size grew with age, the basic and complex skills improved, especially fine motion abilities. This could explain the association of body weight with intelligence level at the age of 1, although the effect diminished at the age of 6.

Nevertheless, we did not analyze other physical indicators, such as head, chest, and abdomen circumferences. The assessments of intelligence development were only performed on 1- and 7-year-olds due to the lack of cooperation from children. Furthermore, we could not keep track of all the twins to assess whether they have narrowed the gap in physical parameters during adolescence.

In summary, birth weight differences in twins sustain an impact on the children’s physical growth in height and weight from birth to preschool age, causing psychomotor developmental differences at the age of 1. However, the differences in psychomotor development narrowed gradually at the age of 6.