Impact of early term and late preterm birth on infants’ neurodevelopment: evidence from a cohort study in Wuhan, China

Preterm birth (less than 37 weeks of gestation) is generally recognized as a major cause of neonatal morbidity and mortality [1]. However, the conventional 37-week cut-off for preterm and term birth has been considered relatively arbitrary in recent years. A growing number of researchers argue that gestational age over 37 weeks does not mean fetal maturity is enough to avoid morbidity [2]. It is indicated that early term infants (37–38^+ 6 weeks of gestation) have an increased risk of health problems than full term infants (39–41^+ 6 weeks of gestation). Risks that have been revealed in previous studies include respiratory morbidity, diabetes, obesity-related disorders, long-term developmental outcomes, and even mortality in infancy, childhood, and young adulthood [3‐7]. Late preterm birth (34–36^+ 6 weeks of gestation) is also under-recognized, while previous studies are mainly focused on health outcomes of extremely preterm infants (less than 28 weeks of gestation) [8]. Growing evidence has indicated that late preterm infants have a higher risk of morbidity and mortality than more mature infants [9, 10].

Notably, early term and late preterm births have been prevalent worldwide in recent years. It is estimated that early term and late preterm births account for 15 to 31% and 3 to 6% of all live-born infants, respectively [11, 12]. Despite the ascending proportion of late preterm and early term births, the prospective studies about their short-term and long-term health outcomes are insufficient, especially their impact on infants’ neurocognitive and motor developments. Although a few studies have investigated the association between late preterm birth and delayed neurodevelopment [13‐15], the results are still elusive [10]. Moreover, even fewer studies have investigated the relationship between early term birth and neurodevelopment [16, 17]. In addition, previous studies have mainly been devoted to exploring the long-term impacts of late preterm and early term birth on neurodevelopment [14, 18, 19]. In contrast, few have focused on their impact on neurodevelopment at the early stage of infancy [20], which is the optimum period for interventions, as targeted inventions in the early stages of neurodevelopmental delay will achieve the best benefits.

Given the limited reports and the existing inconclusive results on the impact of early term and late preterm birth on neurodevelopment during early infancy, this study aimed to investigate the effect of early term and late preterm birth on infants’ neurodevelopment within 6 months through a cohort study in Wuhan, China.

The distribution of demographic characteristics of participants in this study is shown in Table 1. Among the 4243 participants, 155 (3.65%) were late preterm, 1288 (30.36%) were early term, and 2800 (65.99%) were full term. Of the infants, 2.88% were low birth weight (< 2500 g), and 5.87% were macrosomia (≥ 4000 g). 56.02% of the infants were boys, and 43.98% were girls. A total of 48 (1.13%) infants had asphyxia at birth. There were significant differences in parental education level, the number of prenatal examinations, parity, mode of delivery, infant’s gender, and birth weight among the three groups of late preterm, early term, and full term infants (P < 0.01).

Table 2 presents late preterm birth and early term birth associations with DQ of different neurodevelopmental domains. The mean DQ of early term birth were 100.87, 105.63, 85.88, 87.63, and 88.13 in domains of gross motor, fine motor, adaptability, language, and social behavior, respectively, which were higher than those of late preterm infants (P < 0.01), and lower than full term infants (P < 0.01). The GLM analysis indicated that late preterm birth was significantly associated with decreased DQ in all domains: gross motor (β = − 17.42, 95% CI: − 21.15 to − 13.69), fine motor (β = − 23.61, 95% CI: − 28.52 to − 18.69), adaptability (β = − 10.10, 95% CI: − 13.82 to − 6.38), language (β = − 6.28, 95% CI: − 9.82 to − 2.74) and social behavior (β = − 5.99, 95% CI: − 9.59 to − 2.39). For early term birth, the statistically significant negative trend was only shown in the DQ of fine motor (β = − 2.01, 95% CI − 3.93 to − 0.09).

Results of neurodevelopmental delay in different domains and the association with late preterm birth/early term birth are presented in Table 3. The neurodevelopmental delay rates among late preterm birth and early term birth infants were 56.77 and 22.67% in the gross motor domain, 56.13 and 29.04% in fine motor domain, 64.52 and 55.75% in adaptability domain, 52.26, and 50.85% in the language domain, 49.03 and 48.84% in social behavior development domain, respectively. They were all higher than the corresponding rates among full term infants. According to the results of the binary logistic regression model adjusted for potential confounders, late preterm birth infants had a significantly elevated risk of neurodevelopmental delay in domains of gross motor (adjusted OR = 3.82, 95% CI: 2.67 to 5.46), fine motor (adjusted OR = 3.51, 95% CI: 2.47 to 5.01) and adaptability (adjusted OR = 1.60, 95% CI: 1.12 to 2.29), whereas early term birth was significantly associated with delayed neurodevelopment in fine motor (adjusted OR = 1.22, 95% CI: 1.05 to 1.42).

We further explored the associations of late preterm birth and early term birth with neurodevelopment delay of different domains stratified by infants’ gender. As shown in Table 4, late preterm boys had a higher risk of neurodevelopment delay in three domains: gross motor (adjusted OR = 4.30, 95% CI: 2.75 to 6.71), fine motor (adjusted OR = 3.86, 95% CI: 2.49 to 5.99), and adaptability (adjusted OR = 1.64, 95% CI: 1.06 to 2.55); late preterm girls had a higher risk of neurodevelopment delay in 2 domains: gross motor (adjusted OR = 2.94, 95% CI: 1.59 to 5.44) and fine motor (adjusted OR = 2.91, 95% CI: 1.59 to 5.34). As for early term infants, the significant association was only found with fine motor development delay among girls (adjusted OR = 1.32, 95% CI: 1.05 to 1.65). The crude OR showed that late preterm birth was significantly associated with language delay among girls (crude OR = 1.81, 95% CI: 1.00 to 3.28). However, the association was no longer significant after adjusting for the potential confounding factors.

Table 5 shows the association of the specific gestational week with neurodevelopment delay of different domains. After adjusting for potential confounders, infants born between 34 and 37 weeks of gestation showed a higher risk of gross motor and fine motor development delay, and infants born between 34 and 35 weeks of gestation also had a higher risk of adaptability development delay. No significant association was found for language or social behavior development delay.

In this study, we explored the impact of early term and late preterm birth on the neurodevelopment of infants within 6 months. Our results indicated that late preterm birth was associated with decreased DQ in all neurological domains, and early term birth was associated with decreased DQ in the fine motor. Moreover, late preterm birth had an elevated risk of neurodevelopmental delay in gross motor, fine motor, and adaptability domains. In contrast, early term birth only showed an increased risk of developmental delay in the fine motor.

According to the Fetal Origins Hypothesis, the fetal intrauterine environment, associated with gestational length, has profound and long-term effects on children’s health and development [25]. Our current study showed that late preterm and early term infants exhibited poorer neurodevelopmental levels within 6 months compared with full term infants, enriching the evidence of the association between gestational length and neurodevelopment among children at the early stage. This result is consistent with previous studies conducted among older children [14, 26, 27]. A prospective longitudinal cohort study in Australia found that compared with term infants, moderate and late preterm children had a higher risk of developmental delay in cognitive, language, and motor domains at the age of 2 years [14]. A cohort study in China also suggested that early term birth was associated with an increased risk of delayed neurodevelopment in the psychomotor domain at 2 years old [17]. Neurodevelopmental delay in late preterm infants may be related to brain morphology and structure [28]. Late preterm infants have been reported to have less brain volume and lower differentiated myelination and neural connectivity than full term infants [29, 30]. It has been suggested that the period between 34^0/7 and 40^0/7 gestational weeks is a critical period for immature brain growth, in which cortical and white matter volumes are multiplied by two and five, respectively [31]. While early term birth between 37^0/7 and 38^0/7 gestational weeks is included in the critical period, the association between early term birth and neurodevelopmental delay may be also explained [31].

Additionally, the prior study has shown a linear correlation between gestational age and birth fetal brain volume [32], supporting the present findings that longer gestation was associated with improved neurodevelopment at the early stage in infants. In line with these findings, a prospective study investigating 232 full term infants in Germany also found that infants with longer gestation had better cognitive and motor development within 1 year old [26]. Moreover, another study in Chilean also reported that the longer pregnancy was associated with higher mental and motor scores of BSID among term infants at 1 year of age [33]. It is suggested that longer gestation can benefit the infants’ neurodevelopment. Specifically, our results showed that infants born at 37 gestational weeks had a significantly elevated risk of neurodevelopment delay in gross motor and fine motor, compared with full term birth infants. This result supports the arguments of the conventional cut-off of 37 gestational weeks for preterm birth. However, taking gestational age as a continuum representing the risk level connected with adverse outcomes may be more appropriate than taking the term and preterm birth as a dichotomy [34]. More attention should be paid to the consequences of gestational length among term infants.

The present study found that late preterm birth mainly influenced infants’ neurodevelopmental delay of gross motor, fine motor, and adaptability during the early stage. In contrast, early term birth was associated with neurodevelopmental delay of fine motor. These findings may suggest that there may be different potential mechanisms under the impact of gestational age for different neurodevelopmental domains, and different neurodevelopmental modules may have different developmental critical periods. It has been shown that sensory axons are usually myelinated before motor axons, and myelination generally extends from the center to the periphery, from the dorsal to the ventral [35]. It seems that the sensory module may develop before the motor module and the gross motor module before the fine motor module. Our results suggest no significant difference between gestational age and neurodevelopmental delay of language at the early stage, which was inconsistent with results of some previous studies [36]. The inconsistency may be related to the physiological age of infants. Unlike most studies focused on the neurodevelopment of infants at least one-year-old, the present study was devoted to assessing the neurodevelopmental level within 6 months. In fact, to the best of our knowledge, there are a growing number of studies evaluating neurodevelopment in infants around 6 months of age [37‐39]. A study had shown that infants with neurodevelopmental delays would have better neurodevelopmental outcomes in future if interventions were given at 6 months of age [40]. This might highlight the importance of early identification and intervention of high-risk infants to promote an improved neurodevelopmental outcome.

Further, we investigated the influence of late preterm birth and early term birth with neurodevelopmental delay stratified by infants’ gender. Late preterm birth was associated with a higher risk of delay in 3 domains (gross motor, fine motor, and adaptability) in boys. In contrast, adaptability developmental delay was not observed among late preterm girls. Moreover, the association of early term birth with fine motor developmental delay was only detected in girls. Prior studies have shown that fetal gender may play an essential role in regulating the influence of prenatal exposure on neurodevelopment [41, 42]. Male fetuses are more sensitive to early exposure to risk factors than female fetuses [43]. Wu et al. found that the association between early term birth and the neurodevelopmental delay was more significant in male infants [17]. The results indicated that the impact and mechanism of gestational age on neurodevelopment at an early stage could be different for boys and girls, which needs to be examined and identified in the future.

The main strength of this study is the relatively large sample size compared with previous studies, which included information collected from pregnancy through 6 months after birth. Moreover, we were able to adjust for some potential confounding factors that may impact infants’ neurodevelopment in the present study. Furthermore, the assessment of infants’ neurodevelopment was under strict quality control, making the results more reliable. However, several limitations of this study need to be concerned. First, infants’ neurodevelopment was only assessed within 6 months in this study. As individual neuropsychological development is a long-term process and can be affected by various biological and psychosocial factors, further follow-up is required to identify the neurodevelopmental status of early term and late preterm birth infants in the future. Second, the participants in this study came from a single center of tertiary hospital, limiting our findings’ generalizability to the broader population. Third, although the revised GDS is widely used for neurodevelopmental assessment and diagnosis in China, it is not commonly used in western countries, which increases the difficulty of comparing the results among different studies worldwide.

In conclusion, we conducted a prospective cohort study in Wuhan, China to evaluate the impact of early term and late preterm birth on infants’ neurodevelopment at the early stage, and found the evidence that late preterm birth mainly elevated the risk of neurodevelopmental delay of gross motor, fine motor, and adaptability. In contrast, early term birth was associated with an increased risk of fine motor developmental delay within 6 months. We found that longer gestation benefits the infants’ gross and fine motor development at an early stage even among term infants. Further research is needed to determine the effectiveness and necessity of the interventions at the early stage for early term and late preterm infants who had suspected neurodevelopmental delay.