[Association between birth order and early neurodevelopmental outcomes in preterm twins]

Objective: To explore the association between birth order and early neurodevelopmental outcomes in preterm twin infants. Methods: A retrospective cohort study was conducted on 2 251 of twin neonates admitted to the Department of Neonatology, Children's Hospital of Chongqing Medical University, from January 2020 to December 2024. Clinical data including general characteristics, perinatal outcomes, and neurodevelopmental assessments (cranial ultrasonography, amplitude-integrated electroencephalography (aEEG) and the test of infant motor performance (TIMP) during hospitalization and follow-up up to corrected age ≤4 months, were collected and analyzed. Each pair of preterm twins was grouped into first-born and second-born groups according to birth order. Subgroup analyses were performed according to chorionicity (monochorionic, dichorionic), gestational age at birth (28-31, 32-33, 34-36 weeks), and mode of delivery (vaginal delivery, cesarean section). Paired t test, Wilcoxon signed-rank test, McNemar test or exact McNemar test were used for paired comparisons, and a multivariable regression model accounting for within-pair of twins clustering was further constructed to evaluate the association between birth order and early neurodevelopmental outcomes. Results: A total of 225 twin pairs were enrolled, with a gestational age of (33.9±1.8) weeks. Birth weight was (2 002±389) g in first-born twins and (1 956±363) g in second-born twins; the proportion of males was 52.9% (119/225) and 49.8% (112/225), respectively. The second-born group had higher rates of the first minute Apgar score <7 and respiratory failure compared with the first-born group (both P<0.05), along with lower blood-gas pH and base excess (both P<0.05). There were no differences between the first-born and second-born groups in ventriculomegaly (8.6% (19/221) vs. 12.2% (27/221)) or periventricular-intraventricular hemorrhage (23.1% (51/221) vs. 19.5% (43/221)) (both P>0.05). The second-born twins had lower odds of achieving higher aEEG Burdjalov scores (cumulative OR=0.48, 95%CI 0.33-0.72, P<0.001). No significant deviation of the within-pair TIMP Z-score difference from 0 was observed during hospitalization (P=0.537). In longitudinal analysis (corrected age ≤4 month), the time slope had no difference (β=0.01,95%CI -0.02-0.04, P=0.637). Subgroup analyses showed that lower odds of higher Burdjalov scores for second-borns remained statistical difference in monochorionic twins (cumulative OR=0.34,95%CI 0.14-0.79,P=0.013), dichorionic twins (cumulative OR=0.52,95%CI 0.33-0.82,P=0.005), the gestational age of 32-33 week at birth subgroup (cumulative OR=0.40,95%CI 0.19-0.87, P=0.021), the gestational age 34-36 weeks at birth subgroup (cumulative OR=0.56,95%CI 0.34-0.94,P=0.027), and the cesarean section subgroup (cumulative OR=0.49,95%CI 0.32-0.73,P=0.001), whereas no statistical difference were observed in the gestational age of 28-31 weeks at birth or the birth via vaginal delivery subgroup (all P>0.05). Across all subgroups, no statistical difference was found in periventricular-intraventricular hemorrhage (all P>0.05), and in ventriculomegaly after correction (all q>0.05). In the birth via vaginal delivery subgroup, the difference in TIMP Z-scores compared to 0 had no statistical difference after correction (q=0.269). During the follow-up period, there were no trends in the change of TIMP Z-scores over time (all P>0.05). Conclusions: Birth order was associated with brain functional maturity among preterm twins. Enhanced aEEG monitoring and neurodevelopmental follow-up are recommended for high-risk newborns, including preterm and multiple births, to facilitate early detection and intervention, thus reducing the risk of impaired brain development.