Association between birthweight discordance and extrauterine growth restriction among preterm twins: a national multi-center study in China

Background: This multicenter study investigated the association between birthweight discordance (BWD) and extrauterine growth restriction (EUGR) in preterm twins, and evaluated the modifying role of small for gestational age (SGA).

Methods: Data from 2,496 infants (1,248 twin pairs) admitted to 22 Chinese NICUs (2018–2020) were analyzed. BWD was calculated as the percentage difference in birthweight between larger and smaller twins, categorized into four groups (≤15%, 15%–20%, 20%–25%, >25%). EUGR was defined as discharge weight below the 10th percentile for corrected gestational age and sex (Fenton's chart). A generalized linear mixed model was employed to analyze the association between BWD and EUGR. Modification analysis was performed to assess the effect of SGA on this association.

Results: BWD of >25% was associated with a significantly increased risk of EUGR compared to BWD ≤15% (adjusted OR = 1.59, 95% CI: 1.05–2.41). Stratified analysis revealed a consistent association in SGA infants (OR = 1.38, 95% CI: 1.30–1.47).

Conclusion: Findings highlight BWD as a critical risk factor for EUGR, particularly in SGA twins. This association suggests that future research should investigate whether tailored monitoring and nutritional interventions in NICUs could help mitigate these growth disparities.

Introduction

Twin pregnancies account for approximately 2%–4% of all births and have significantly increased globally, particularly in middle-income and developing countries (1, 2). In China, the twinning rate rose from 2.84% to 3.22% between 2012 and 2020 (3). This trend carries substantial public health implications, as over half of all twin births are preterm (4), and twin pregnancies are associated with a threefold to sevenfold higher risk of perinatal morbidity and mortality compared to singleton pregnancies (5).

Birthweight discordance (BWD) is a key determinant of postnatal outcomes in twin pregnancies (6), typically defined as a birth weight difference of ≥20%–25% between the larger and smaller twin (7). It is a well-established risk factor for pregnancy outcomes, including preterm birth, and increased neonatal intensive care unit (NICU) admissions, and perinatal morbidity such as bronchopulmonary dysplasia (BPD), neonatal necrotizing enterocolitis (NEC), persistent patent ductus arteriosus (PDA) (8), and neonatal sepsis. Recent cohort studies have also linked BWD to adverse long-term developmental consequences (9–11). Improving the long-term prognosis for twins with significant BWD has become a new focus of research. Current evidence suggests that even short-term relative malnutrition during sensitive periods can significantly adversely affect subsequent development (12, 13). Extrauterine growth restriction (EUGR) describes inadequate growth during the sensitive postnatal period up to 40 weeks' corrected gestational age. This condition is consistently linked to adverse neurodevelopmental outcomes at 24 months (14–16).

EUGR is defined as the growth of preterm infants falls below the expected weight based on intrauterine growth rates [i.e., ≤10% of the expected weight for their gestational age (17)], which is still a serious problem among NICUs preterm infants (18). The pathophysiology of EUGR is multifactorial, with key risk factors including low birthweight, delayed achievement of full enteral feeding (FEF), BPD, and NEC (17, 19–21). These very conditions are frequently associated with BWD (8), suggesting a potential link between BWD and EUGR. Previous studies have described the growth patterns among discordant twins. Xiang et al. found the smaller infants among discordant twins had a higher risk of growth restriction in the first 6 months after birth (22), which was consistent with other research (23). However, the evidence of previous studies was insufficient to confirm the association between BWD and EUGR, due to the small sample sizes, different cut-off levels of BWD, and great heterogeneity. Therefore, the correlation between BWD and EUGR remains an unanswered question.

The relationship is further complicated by the high prevalence (25%–35%) of small for gestational age (SGA) infants in twins (24). SGA is a risk factor for EUGR in singletons, suggesting a persistence of poor growth from the intrauterine to the extrauterine environment (25, 26). While epidemiological studies reported inconsistent relationships of BWD with SGA among twins. Our previous study found higher rates of SGA in twins with higher BWD among 4,011 twin pairs (27). Another multicenter cohort study showed no association between BWD with SGA in 939 twins (28). The role of SGA in the association between BWD and EUGR remains unclear.

Using data from a nationwide multicenter study with NICU data, we propose two hypotheses: (1) higher BWD increases the odds of EUGR, and (2) SGA modifies the association between BWD and EUGR.

Methods

Study population and overall design

This national cross-sectional study, established by the Chinese Multicenter Birthweight Discordance Twins Collaborative Group (CBDC group), included 22 hospitals in 15 cities across 12 provinces/municipalities in China. All hospitals were government-designated tertiary class-A, with 20 affiliated with universities. Initially, a standardized protocol was developed for a pilot multi-center study in six cities in Guangdong Province. This protocol was later applied to other study sites. Detailed geographical distribution and specific demographic characteristics of participating centers are shown in Supplementary Figure S1. Trained data abstractors at each site collected patient data from medical records, ensuring patient identity remained confidential. Data were entered directly into a customized database (EpiData 3.1) with built-in error checking and a standard operation manual. The data were electronically transmitted to the coordinating center at the Third Affiliated Hospital of Guangzhou Medical University for integration and analysis. The CBDC database includes all live twin births from January 1, 2018, to December 31, 2020. This study conducted a secondary analysis of CBDC data for preterm twins admitted to participating NICUs with hospital stays of ≥7 days. From the initial 1,758 pairs of preterm twins in NICUs, we excluded 137 pairs with congenital malformations or genetic metabolic diseases, 58 pairs with twin to twin transfusion syndrome or twin anemia-polycythemia sequence, 66 pairs of monochorionic monoamniotic twins, and 249 pairs without discharge weight data (see Supplementary Figure S2). Finally, 1248 twin pairs (2,496 individuals) were eligible for analysis.

Criteria for discharge

Infants were considered eligible for discharge upon meeting all of the following criteria, which from the guidelines of the American Academy of Pediatrics (29): 1) Physiological stability without respiratory support, and freedom from clinically significant apnea and bradycardia for at least 5 days; 2) Ability to maintain normal body temperature in an open crib; 3) Consistent weight gain on full oral feeding without the need for supplemental tube feeding; 4) Resolution of major acute diseases.

Definitions

BWD was defined as the percentage difference in birthweight between the larger and smaller twin using the formula: (larger birthweight - smaller birthweight)/larger birthweight × 100%, with a cut-off of >20%. Participants were categorized into four groups: ≤15%, >15%–20%, >20%–25%, and >25%, as previous studies (30). EUGR was defined as a discharge weight below the 10th percentile for the same corrected gestational age and gender, according to the Fenton growth chart (31). SGA was defined as birthweight below the 10th percentile for Chinese twins, specific to gestational age (GA) and chorion (32). Diagnoses of BPD, NEC, PDA, and neonatal sepsis were established by Practical Neonatology (5th edition) (33). The standardized feeding protocol was developed following the Clinical Application Guidelines for Neonatal Nutritional Support in China (34). FEF was defined as enteral feeding volume of 150 ml per kilogram of body weight per day, or 110 kcal per kilogram of body weight per day, or exclusive breast-feeding, whichever occurred first (35). Weights at birth and discharge were converted to z-score using the Fenton growth charts. To better evaluate the longitudinal growth of the infants, the difference between discharge and birth weight z-scores (Δz-score) was calculated.

Covariates

The collected data included maternal age (<35 years, ≥35 years), education level (high school and below, college degree and above), multiparity, use of assisted reproductive technology (ART), cesarean delivery, twin chorionicity (dichorionic diamniotic (DCDA), monochorionic diamniotic (MCDA)), and complications such as gestational diabetes (GDM) and hypertensive disorder complicating pregnancy (HDP). Neonatal data included GA (<31⁺⁶ weeks, 32–36⁺⁶ weeks) and complications like BPD, NEC, PDA, or neonatal sepsis. Nutritional information included the time to achieve of FEF and the duration of hospital stay.

Statistical analysis

We calculated mean (SD) or median (IQR) values for continuous variables and percentages for categorical variables. Characteristics were compared across BWD groups using rank sum or χ² tests as appropriate.

Cases with any missing value in the demographic characteristics, adjusted confounders were excluded from the multivariate analysis. Of the 2,496 individuals, 15(0.60%) had incomplete data and were removed. We explored the association between BWD (both continuous and categorical) and EUGR by treating twins as separate individuals. To account for within-twin correlations, a generalized linear mixed model was used, treating twin pairs and hospitalization area as random effects (36). The main model included maternal age, GDM, HDP, ART, chorionicity, GA, infant gender, complications, FEF days, and hospital stay duration as fixed effects. Multicollinearity was assessed by calculating the Variance Inflation Factor (VIF) for each predictor. A VIF >10 was considered indicative of severe multicollinearity that required remediation (37), All VIF values in our model were below 3. The potential effect modification of SGA on the BWD-EUGR association was evaluated with multiplicative interaction terms in the model, adjusted for the same covariates. Stratified analysis based on the SGA infants was performed.

Sensitivity analyses included: (1) using a generalized additive model (GAM) to assess non-linear associations (38); (2) using stratified analyses by maternal and neonatal characteristics (maternal age, chorioamniotic sac type, GDM, HDP, GA and neonatal complications) with interaction terms; and (3) using ordinal regression with random effects to analyze the BWD-EUGR association, considering geographical birth areas as random effects, and twins without EUGR were the reference category.

Statistical analyses were performed using R version 4.2.2. All tests were 2-sided, with P < 0.05 considered significant.

Results

Characteristics of study subjects

The study population comprised 2,496 individuals with twin pregnancies: 1,772 (70.99%) infants with BWD ≤15%, 246 (9.86%) infants with BWD >15%–20%, 196 (7.85%) infants with BWD >20%–25% and 282 (11.30%) infants with BWD >25%. And 1,137 (45.55%) of them were diagnosed with EUGR. Infants with higher BWD had higher rates of cesarean delivery, MCDA, HDP, SGA, EUGR and neonatal complications than those with lower BWD. No statistical differences were observed among advanced maternal age, mother education levels, GA, infant's gender and other characteristics across different degree of BWD (P > 0.05) (Table 1).

Table 1

Table 1. Characteristics of study participants (infants).

Association between BWD and EUGR

Table 2 presents the ORs for the association between BWD, both as a continuous variable and in categories, and the risk of extrauterine growth restriction (EUGR). The twin pairs-level random intercept variance was 1.29 [intraclass correlation (ICC) = 0.26] and the hospitalization area-level random intercept variance was 0.32 (ICC = 0.07). After adjusting for potential confounding factors, each 1% increment in BWD was associated with a 1.02-fold increase (95% CI: 1.00, 1.03) in the risk of individual EUGR. Additionally, BWD was subdivided into four distinct categories to further investigate this relationship. Compared to a BWD of ≤15%, the adjusted OR of EUGR for a BWD >25% was 1.59 (95% CI: 1.05, 2.41), with a significant p value for trend (P _{for trend} < 0.01).

Table 2

Table 2. Associations between BWD and individual EUGR.

Furthermore, Supplementary Figure S3 illustrates the results of a smooth curve fitting based on a GAM model. The smooth curve fitting between BWD and EUGR revealed an inverted U-shaped relationship, with a turning point around 34.8% BWD (EDF = 3.00, P = 0.007). Before this turning point, the risk of EUGR increased with the increase in BWD. After reaching the turning point, further increases in BWD led to a decreased risk of EUGR. The maximum likelihood method identified the turning point of the smooth curve at BWD = 34.8%, adjusted for confounders. Additionally, the BWD value at which the curve intersected the horizontal axis was 20% for EUGR, which was considered the significant threshold for the dichotomous variable.

SGA on the association between BWD and EUGR

The significant interaction P-value (<0.001) for the association of BWD across EUGR was found. In the stratified analyses (Table 3), we found a positive significant association (OR = 1.38, 95% CI: 1.30–1.47, P < 0.01) between the cut-off levels of BWD and EUGR among SGA infants. While we did not find similar associations among infants of non-SGA (OR = 0.75, 95% CI: 0.49–1.14).

Table 3

Table 3. Modification of SGA on the associations between the cut-off level of BWD and individual EUGR.

Sensitivity analyses

As Supplementary Table S1 shows, the association between the cut-off levels of BWD and EUGR remained robust when restricting to infants born with a GA of 32–36⁺⁶ weeks or DCDA, or infants whose mothers were of advanced age, or without GDM, or without HDP. The output of ordinal regression with random effects analysis was computed to analyze the association between BWD and EUGR group (Supplementary Table S2). Compared with the BWD<15% group, twins with the highest BWD (>25%) had a higher risk of being EUGR (AOR = 1.49, 95% CI 1.11–1.99, P_{for trend}<0.01) after adjusting for confounders. Moreover, compared to a BWD of ≤15%, the adjusted OR of Δz-score for a BWD >25% was 0.09 (95% CI: 0.02, 0.16), with a significant p value for trend (P _{for trend} <0.01) (Supplementary Table S3).

Discussion

In this national multicenter study of twins, we found that each 1% increase in BWD was associated with a 1.02-fold increase in the risk of EUGR, with an adjusted OR of 1.59 for BWD >25% compared to BWD ≤15%, and the smooth curve fitting indicated an inverted U-shaped relationship with a turning point at 34.8% BWD. The association between BWD and EUGR was significant among SGA infants but not in non-SGA infants, and remained robust under various sensitivity analyses.

The 45.55% incidence of EUGR in our study is higher than in previous Chinese reports (30.2%–43.1%) (39, 40), possibly due to differences in the study population and sample size. While some BWD may represent normal physiological variation, the precise threshold for significant BWD remains controversial, with current thresholds ranging from 15% to 30% (8, 41). Our research is the first to use EUGR as an outcome indicator to explore the threshold of BWD, revealing that when BWD is greater than 15%, a higher BWD is positively associated with individual EUGR among NICU twins after adjusting for confounders. Moreover, we identified a significant threshold of 20% for BWD, consistent with previous studies (42). Different thresholds have been proposed to define high discordance as a predictor of neonatal morbidity and mortality. The American College of Obstetricians and Gynecologists considers 20% BWD as significant growth discordance (43), while the National Institute for Health and Care Excellence suggests a cutoff of 25% (44). These varying thresholds may be due to the heterogeneity of study populations and neonatal outcomes. Furthermore, our results showed a non-linear relationship between BWD and EUGR, with an inflection point at 34.8% BWD, indicating that the correlation is meaningful when BWD is below this threshold. This finding may be influenced by the smaller sample size for BWD >34.8% (n = 90, 3.61%), as supported by previous epidemiological studies showing that twins with higher BWD are at increased risk of fetal death (7, 45, 46).

Although the mechanism linking BWD and EUGR is not well-established, a comparable “two-hit process” of metaflammation may be identified. While unequal placental sharing plays an indispensable role in the pathophysiology of BWD (47), the associated placental malperfusion can trigger fetal growth restriction through pathways like oxidative stress and inflammation (48). We speculate that this initial insult (49, 50), combined with the postnatal challenges of prematurity and the NICU environment as a second hit, contributes to EUGR in infants who experienced BWD.

Existing evidence on growth patterns among twins with BWD and SGA remains limited and inconclusive. In this study, we identified a statistically significant interaction between SGA and BWD, specifically noting that infants with SGA exhibited more pronounced detrimental associations between BWD and EUGR. Hence, our findings align with Yang et al.'s cohort study of 150 twin pairs, which linked BWD and SGA to disordered gut microbiota and later metabolic health (51), noting that Oscillospira (enriched in SGA infants) is associated with leanness or lower weight in later life (19, 52). Additionally, SGA infants among BWD twins, who had a higher risk of neonatal morbidity during hospitalization (53), may impair nutrient intake and elevate EUGR risk (40, 54). Placental and maternal factors in BWD disproportionately restrict growth in the smaller twins, as reported by Puccio et al. (20), further explaining the differential effect of BWD on EUGR in SGA vs. non-SGA infants.

To date, no international consensus regarding the ideal growth pattern for preterm infants (55). According to previous studies, it is safe and feasible to use the traditional definition of EUGR (<10th percentile for corrected GA) as a growth aim before determining more accurate targets through large-scale studies (12, 14, 56). To prevent EUGR, expert consensus on the growth development monitoring and nutritional management of preterm infants have been issued by both the European Society of Pediatric Gastroenterology, Hepatology and Nutrition, and the Preterm Committee of Neonatology Branch of Chinese Medical Doctor Association (57, 58). However, these guidelines only classify risk levels based on GA, birthweight, or postnatal complications, without considering twins, who had higher risk of lower GA, lower birthweight, or more postnatal complications. A recent review suggested that SGA infants of multiple pregnancies should be distinguished in future guidelines and that specific nutrition recommendations for appropriate weight gain should be given (59). Our results further provided comprehensive evidence regarding the association between BWD and the risk of EUGR, as well as the modifying effect of SGA. By controlling for important confounders and conducting multiple sensitivity analyses based on national data, our findings indicate that twins with different BWD, as well as infants with or without SGA, exhibit different growth patterns. These observed differences point to potential underlying variations in metabolic needs and justify future research to determine if targeted clinical interventions and individualized care strategies would be beneficial.

Strengths and limitations

The strengths of our study include a large national sample size and comprehensive information on maternal characteristics and neonatal complications, which ensured the robustness of our findings. However, several potential limitations merit further discussion. First, in a cross-sectional survey, it is not possible to fully establish the causal nature of BWD relative to the development of EUGR, cautioning against drawing causal inferences. However, there is a temporal relationship between BWD and EUGR, which helps avoid the phenomenon of cause-effect inversion. Second, the lack of detailed data regarding factors such as fluid intake in the first week, protein energy ratio, milk administration speed, reasons for fasting, and other variables makes it impossible to comprehensively analyze the nutritional status of this study population. Although we adjusted for time to enteral nutrition in the main models, future prospective studies that collect nutritional intake of infants are needed. Third, although applying singleton-based Fenton references to twins may underestimate postnatal growth restriction, we used the Δz-score to validate the association between higher BWD and a lower change in weight Z-score from birth to discharge. Finally, our study did not examine the correlation of BWD with linear growth or head circumference. Future studies should incorporate these critical anthropometric measures to provide a more holistic view of postnatal growth patterns in discordant twins.

Conclusion

In this present study, BWD was associated with higher odds of EUGR in preterm twins, and the association was pronounced among SGA infants. Future well-designed with long-term follow-up researches are needed to confirm our findings.

Data availability statement

The data analyzed in this study is subject to the following licenses/restrictions: The data are available from the corresponding author on reasonable request. Requests to access these datasets should be directed to Qiliang Cui,Y3VpcWxfZ3lzeUAxNjMuY29t.

Ethics statement

The studies involving humans were approved by This study protocol was reviewed and approved by the Ethical Review Committee for Biomedical Research, the Third Affiliated Hospital of Guangzhou Medical University, approval number ([2020] No.097), which was recognized by all participating hospitals. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements.

Author contributions

QC: Data curation, Formal analysis, Funding acquisition, Methodology, Validation, Visualization, Writing – original draft. BS: Data curation, Formal analysis, Methodology, Validation, Writing – original draft. LL: Formal analysis, Writing – review & editing. DL: Investigation, Resources, Writing – original draft. JZ: Formal analysis, Writing – review & editing. SR: Investigation, Resources, Writing – original draft. KH: Investigation, Resources, Writing – original draft. WS: Investigation, Resources, Writing – original draft. ZC: Investigation, Resources, Writing – original draft. JL: Investigation, Resources, Writing – original draft. CY: Investigation, Resources, Writing – original draft. GL: Investigation, Resources, Writing – original draft. HoJ: Investigation, Resources, Writing – original draft. HR: Investigation, Resources, Writing – original draft. JQ: Investigation, Resources, Writing – original draft. XW: Investigation, Resources, Writing – original draft. YZ: Investigation, Resources, Writing – original draft. XL: Investigation, Resources, Writing – original draft. HaJ: Investigation, Resources, Writing – original draft. SH: Investigation, Resources, Writing – original draft. FW: Investigation, Resources, Writing – original draft. WZ: Investigation, Resources, Writing – original draft. XY: Investigation, Resources, Writing – original draft. YW: Investigation, Resources, Writing – original draft. NL: Investigation, Resources, Writing – original draft. XT: Conceptualization, Data curation, Funding acquisition, Methodology, Project administration, Supervision, Writing – review & editing. QC: Conceptualization, Methodology, Project administration, Supervision, Writing – review & editing.

Funding

The author(s) declared that financial support was received for this work and/or its publication. This work was supported by the Basic research project of Guangzhou Science and Technology Bureau; Guangzhou Municipal Health and Wellness Science (No. 2023A03J0382) and Technology Project - General Guidance Project in Western Medicine Category (No. 20231A011087). Key Areas Research and Development Programs of Guangdong (No. 2023B0303040001).

Acknowledgments

We thank all the infants' caregivers who willingly participated in our study. We also appreciate the neonatal units in the hospitals and centers for their cooperation.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The reviewer [QW] declared a shared parent affiliation with the author(s) [QC, BS, XT, QC] to the handling editor at the time of review.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fped.2025.1709824/full#supplementary-material

Footnote

Abbreviations ART, assisted reproductive technology; BPD, bronchopulmonary dysplasia; BWD, birthweight discordance; CBDC, Chinese Multicenter Birthweight Discordance Twins Collaborative Group; DCDA, dichorionic diamniotic; EUGR, extrauterine growth restriction; FEF, full enteral feeding; GA, gestational age; GAM, generalized additive model; GDM, gestational diabetes; HDP, hypertensive disorder complicating pregnancy; MCDA, monochorionic diamniotic; NEC, neonatal necrotizing enterocolitis; NICU neonatal intensive care units; PDA, persistent patent ductus arteriosus; SGA, small gestational age.

References

1. Kilicarslan N, Gurbuz H, Tasgoz FN, Karaca U, Karasu D, Gamli M. Factors influencing neonatal outcomes in twin pregnancies undergoing cesarean section: a cross-sectional study. Rev Assoc Med Bras (1992). (2023) 69(5):e20221464. doi: 10.1590/1806-9282.20221464

PubMed Abstract | Crossref Full Text | Google Scholar

2. Santana DS, Surita FG, Cecatti JG. Multiple pregnancy: epidemiology and association with maternal and perinatal morbidity. Rev Bras Ginecol Obstet. (2018) 40(9):554–62. doi: 10.1055/s-0038-1668117

PubMed Abstract | Crossref Full Text | Google Scholar

3. Chen P, Li M, Mu Y, Wang Y, Liu Z, Li Q, et al. Temporal trends and adverse perinatal outcomes of twin pregnancies at differing gestational ages: an observational study from China between 2012 and 2020. BMC Pregnancy Childbirth. (2022) 22(1):467. doi: 10.1186/s12884-022-04766-0

PubMed Abstract | Crossref Full Text | Google Scholar

4. Canada PHAo. Congenital Anomalies in Canada: 2022. Ottawa: Public Health Infobase (2022). Available online at: https://www.canada.ca/en/public-health/services/injury-prevention/health-surveillance-epidemiology-division/maternal-infant-health.html (Accessed March 07, 2022).

5. Hack KE, Derks JB, Elias SG, Franx A, Roos EJ, Voerman SK, et al. Increased perinatal mortality and morbidity in monochorionic versus dichorionic twin pregnancies: clinical implications of a large Dutch cohort study. BJOG. (2008) 115(1):58–67. doi: 10.1111/j.1471-0528.2007.01556.x

PubMed Abstract | Crossref Full Text | Google Scholar

6. Miller J, Chauhan SP, Abuhamad AZ. Discordant twins: diagnosis, evaluation and management. Am J Obstet Gynecol. (2012) 206(1):10–20. doi: 10.1016/j.ajog.2011.06.075

PubMed Abstract | Crossref Full Text | Google Scholar

7. D'Antonio F, Odibo AO, Prefumo F, Khalil A, Buca D, Flacco ME, et al. Weight discordance and perinatal mortality in twin pregnancy: systematic review and meta-analysis. Ultrasound Obstet Gynecol. (2018) 52(1):11–23. doi: 10.1002/uog.18966

PubMed Abstract | Crossref Full Text | Google Scholar

8. Di Mascio D, Acharya G, Khalil A, Odibo A, Prefumo F, Liberati M, et al. Birthweight discordance and neonatal morbidity in twin pregnancies: a systematic review and meta-analysis. Acta Obstet Gynecol Scand. (2019) 98(10):1245–57. doi: 10.1111/aogs.13613

PubMed Abstract | Crossref Full Text | Google Scholar

9. Swamy RS, McConachie H, Ng J, Rankin J, Korada M, Sturgiss S, et al. Cognitive outcome in childhood of birth weight discordant monochorionic twins: the long-term effects of fetal growth restriction. Arch Dis Child Fetal Neonatal Ed. (2018) 103(6):F512–6. doi: 10.1136/archdischild-2017-313691

PubMed Abstract | Crossref Full Text | Google Scholar

10. Edmonds CJ, Isaacs EB, Cole TJ, Rogers MH, Lanigan J, Singhal A, et al. The effect of intrauterine growth on verbal IQ scores in childhood: a study of monozygotic twins. Pediatrics. (2010) 126(5):e1095–101. doi: 10.1542/peds.2008-3684

PubMed Abstract | Crossref Full Text | Google Scholar

11. Hack KE, Koopman-Esseboom C, Derks JB, Elias SG, de Kleine MJ, Baerts W, et al. Long-term neurodevelopmental outcome of monochorionic and matched dichorionic twins. PLoS One. (2009) 4(8):e6815. doi: 10.1371/journal.pone.0006815

PubMed Abstract | Crossref Full Text | Google Scholar

12. Gounaris AK, Sokou R. Nutrition and growth of preterm neonates during hospitalization: impact on childhood outcomes. Nutrients. (2024) 16(2):218-23. doi: 10.3390/nu16020218

PubMed Abstract | Crossref Full Text | Google Scholar

13. Leppänen M, Lapinleimu H, Lind A, Matomäki J, Lehtonen L, Haataja L, et al. Antenatal and postnatal growth and 5-year cognitive outcome in very preterm infants. Pediatrics. (2014) 133(1):63–70. doi: 10.1542/peds.2013-1187

PubMed Abstract | Crossref Full Text | Google Scholar

14. Shah PS, Wong KY, Merko S, Bishara R, Dunn M, Asztalos E, et al. Postnatal growth failure in preterm infants: ascertainment and relation to long-term outcome. J Perinat Med. (2006) 34(6):484–9. doi: 10.1515/JPM.2006.094

PubMed Abstract | Crossref Full Text | Google Scholar

15. Casey PH, Whiteside-Mansell L, Barrett K, Bradley RH, Gargus R. Impact of prenatal and/or postnatal growth problems in low birth weight preterm infants on school-age outcomes: an 8-year longitudinal evaluation. Pediatrics. (2006) 118(3):1078–86. doi: 10.1542/peds.2006-0361

PubMed Abstract | Crossref Full Text | Google Scholar

16. Gounaris AK, Sokou R, Gounari EA, Panagiotounakou P, Grivea IN. Extrauterine growth restriction and optimal growth of very preterm neonates: state of the art. Nutrients. (2023) 15(14):3231-9. doi: 10.3390/nu15143231

PubMed Abstract | Crossref Full Text | Google Scholar

17. Clark RH, Thomas P, Peabody J. Extrauterine growth restriction remains a serious problem in prematurely born neonates. Pediatrics. (2003) 111(5 Pt 1):986–90. doi: 10.1542/peds.111.5.986

PubMed Abstract | Crossref Full Text | Google Scholar

18. Tozzi MG, Moscuzza F, Michelucci A, Lorenzoni F, Cosini C, Ciantelli M, et al. Extrauterine growth restriction (EUGR) in preterm infants: growth patterns, nutrition, and epigenetic markers. A pilot study. Front Pediatr. (2018) 6:408. doi: 10.3389/fped.2018.00408

PubMed Abstract | Crossref Full Text | Google Scholar

19. Goodrich JK, Waters JL, Poole AC, Sutter JL, Koren O, Blekhman R, et al. Human genetics shape the gut microbiome. Cell. (2014) 159(4):789–99. doi: 10.1016/j.cell.2014.09.053

PubMed Abstract | Crossref Full Text | Google Scholar

20. Puccio G, Giuffré M, Piccione M, Piro E, Malerba V, Corsello G. Intrauterine growth pattern and birthweight discordance in twin pregnancies: a retrospective study. Ital J Pediatr. (2014) 40:43. doi: 10.1186/1824-7288-40-43

PubMed Abstract | Crossref Full Text | Google Scholar

21. Alam Machado RC, Brizot ML, Liao AW, Krebs VL, Zugaib M. Early neonatal morbidity and mortality in growth-discordant twins. Acta Obstet Gynecol Scand. (2009) 88(2):167–71. doi: 10.1080/00016340802649808

PubMed Abstract | Crossref Full Text | Google Scholar

22. Xiang H, Huang X, Zhu J, Chen J, Zhou P, Zhou T, et al. Physical growth and intelligence development of discordant dizygotic twins from birth to preschool age: a prospective cohort study. Ital J Pediatr. (2022) 48(1):162. doi: 10.1186/s13052-022-01354-y

PubMed Abstract | Crossref Full Text | Google Scholar

23. Mazkereth R, Miron E, Leibovitch L, Kuint J, Strauss T, Maayan-Metzger A. Growth parameters of discordant preterm twins during the first year of life. J Matern Fetal Neonatal Med. (2014) 27(17):1795–9. doi: 10.3109/14767058.2014.880688

PubMed Abstract | Crossref Full Text | Google Scholar

24. Fox NS, Rebarber A, Klauser CK, Roman AS, Saltzman DH. Intrauterine growth restriction in twin pregnancies: incidence and associated risk factors. Am J Perinatol. (2011) 28(4):267–72. doi: 10.1055/s-0030-1270116

PubMed Abstract | Crossref Full Text | Google Scholar

25. Figueras-Aloy J, Palet-Trujols C, Matas-Barceló I, Botet-Mussons F, Carbonell-Estrany X. Extrauterine growth restriction in very preterm infant: etiology, diagnosis, and 2-year follow-up. Eur J Pediatr. (2020) 179(9):1469–79. doi: 10.1007/s00431-020-03628-1

PubMed Abstract | Crossref Full Text | Google Scholar

26. Gidi NW, Goldenberg RL, Nigussie AK, McClure E, Mekasha A, Worku B, et al. Incidence and associated factors of extrauterine growth restriction (EUGR) in preterm infants, a cross-sectional study in selected NICUs in Ethiopia. BMJ Paediatr Open. (2020) 4(1):e000765. doi: 10.1136/bmjpo-2020-000765

PubMed Abstract | Crossref Full Text | Google Scholar

27. Shi BJ, Cui QL, Tan XH, Pan QJ, Chen Q, Lin LL. Occurrence of live-born twins with birth weight-discordance and its relationship to the adverse birth outcomes. Zhonghua Er Ke Za Zhi. (2022) 60(10):1038–44. doi: 10.3760/cma.j.cn112140-20220507-00432

PubMed Abstract | Crossref Full Text | Google Scholar

28. D'Antonio F, Thilaganathan B, Laoreti A, Khalil A. Birth-weight discordance and neonatal morbidity in twin pregnancy: analysis of STORK multiple pregnancy cohort. Ultrasound Obstet Gynecol. (2018) 52(5):586–92. doi: 10.1002/uog.18916

PubMed Abstract | Crossref Full Text | Google Scholar

29. American Academy of Pediatrics Committee on Fetus and Newborn. Hospital discharge of the high-risk neonate. Pediatrics. (2008) 122(5):1119–26. doi: 10.1542/peds.2008-2174

PubMed Abstract | Crossref Full Text | Google Scholar

30. Blickstein I, Kalish RB. Birthweight discordance in multiple pregnancy. Twin Res. (2003) 6(6):526–31. doi: 10.1375/136905203322686536

PubMed Abstract | Crossref Full Text | Google Scholar

31. Fenton TR, Kim JH. A systematic review and meta-analysis to revise the fenton growth chart for preterm infants. BMC Pediatr. (2013) 13:59. doi: 10.1186/1471-2431-13-59

PubMed Abstract | Crossref Full Text | Google Scholar

32. Chen J, Zhang J, Liu Y, Wei X, Yang Y, Zou G, et al. Fetal growth standards for Chinese twin pregnancies. BMC Pregnancy Childbirth. (2021) 21(1):436. doi: 10.1186/s12884-021-03926-y

PubMed Abstract | Crossref Full Text | Google Scholar

33. Qiu X YH, Shao X. Practical Neonatology. 5th ed. Beijing: People’s Medical Publishing House (2018).

Google Scholar

34. Pediatrics Group of the Chinese Society of Parenteral and Enteral Nutrition CMA, Neonatology Group of the Chinese Society of Pediatrics CMA, Neonatal Surgery Group of the Chinese Society of Pediatric Surgery CMA. Clinical application guidelines for neonatal nutritional support in China. Chin J Pediatr Surg. (2013) 34:782–7. doi: 10.3760/cma.j.issn.0253-3006.2013.10.016

Crossref Full Text | Google Scholar

35. Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Darmaun D, Decsi T, et al. Enteral nutrient supply for preterm infants: commentary from the European society of paediatric gastroenterology, hepatology and nutrition committee on nutrition. J Pediatr Gastroenterol Nutr. (2010) 50(1):85–91. doi: 10.1097/MPG.0b013e3181adaee0

PubMed Abstract | Crossref Full Text | Google Scholar

36. Bonat WH, Hjelmborg JVB. Multivariate generalized linear models for twin and family data. Behav Genet. (2022) 52(2):123–40. doi: 10.1007/s10519-021-10095-3

PubMed Abstract | Crossref Full Text | Google Scholar

37. James G, Witten D, Hastie T, Tibshirani R. An Introduction to Statistical Learning, with Applications in R. New York: Springer (2021).

Google Scholar

38. Hastie T, Tibshirani R. Generalized additive models for medical research. Stat Methods Med Res. (1995) 4(3):187–96. doi: 10.1177/096228029500400302

PubMed Abstract | Crossref Full Text | Google Scholar

39. Zhao T, Feng HM, Caicike B, Zhu YP. Investigation into the current situation and analysis of the factors influencing extrauterine growth retardation in preterm infants. Front Pediatr. (2021) 9:643387. doi: 10.3389/fped.2021.643387

PubMed Abstract | Crossref Full Text | Google Scholar

40. Wang YS, Shen W, Wu F, Mao J, Liu L, Chang YM, et al. Factors influencing extrauterine growth retardation in singleton-non-small for gestational age infants in China: a prospective multicenter study. Pediatr Neonatol. (2022) 63(6):590–8. doi: 10.1016/j.pedneo.2022.04.013

PubMed Abstract | Crossref Full Text | Google Scholar

41. Lin D, Fan D, Wu S, Chen G, Li P, Ma H, et al. The effect of gestational weight gain on perinatal outcomes among Chinese twin gestations based on institute of medicine guidelines. BMC Pregnancy Childbirth. (2019) 19(1):262. doi: 10.1186/s12884-019-2411-7

PubMed Abstract | Crossref Full Text | Google Scholar

42. Vergani P, Locatelli A, Ratti M, Scian A, Pozzi E, Pezzullo JC, et al. Preterm twins: what threshold of birth weight discordance heralds major adverse neonatal outcome? Am J Obstet Gynecol. (2004) 191(4):1441–5. doi: 10.1016/j.ajog.2004.05.053

PubMed Abstract | Crossref Full Text | Google Scholar

43. American College of Obstetricians and Gynecologists Committee on Practice Bulletins-Obstetrics; Society for Maternal-Fetal Medicine; ACOG Joint Editorial Committee. ACOG Practice bulletin #56: multiple gestation: complicated twin, triplet, and high-order multifetal pregnancy. Obstet Gynecol. (2004) 104(4):869–83. doi: 10.1097/00006250-200410000-00046

PubMed Abstract | Crossref Full Text | Google Scholar

44. National Collaborating Centre for Ws, Children’s H. National Institute for Health and Clinical Excellence: Guidance. Multiple Pregnancy: The Management of Twin and Triplet Pregnancies in the Antenatal Period. London: RCOG Press (2011).

Google Scholar

45. Saccone G, Khalil A, Thilaganathan B, Glinianaia SV, Berghella V, D'Antonio F. Weight discordance and perinatal mortality in monoamniotic twin pregnancy: analysis of MONOMONO, NorSTAMP and STORK multiple-pregnancy cohorts. Ultrasound Obstet Gynecol. (2020) 55(3):332–8. doi: 10.1002/uog.20357

PubMed Abstract | Crossref Full Text | Google Scholar

46. Boghossian NS, Saha S, Bell EF, Brumbaugh JE, Shankaran S, Carlo WA, et al. Birth weight discordance in very low birth weight twins: mortality, morbidity, and neurodevelopment. J Perinatol. (2019) 39(9):1229–40. doi: 10.1038/s41372-019-0427-5

PubMed Abstract | Crossref Full Text | Google Scholar

47. Townsend R, Khalil A. Twin pregnancy complicated by selective growth restriction. Curr Opin Obstet Gynecol. (2016) 28(6):485–91. doi: 10.1097/GCO.0000000000000326

PubMed Abstract | Crossref Full Text | Google Scholar

48. Burton GJ, Jauniaux E. Pathophysiology of placental-derived fetal growth restriction. Am J Obstet Gynecol. (2018) 218(2s):S745–61. doi: 10.1016/j.ajog.2017.11.577

PubMed Abstract | Crossref Full Text | Google Scholar

49. Ernst LM. Maternal vascular malperfusion of the placental bed. APMIS. (2018) 126(7):551–60. doi: 10.1111/apm.12833

PubMed Abstract | Crossref Full Text | Google Scholar

50. Burton GJ, Fowden AL, Thornburg KL. Placental origins of chronic disease. Physiol Rev. (2016) 96(4):1509–65. doi: 10.1152/physrev.00029.2015

PubMed Abstract | Crossref Full Text | Google Scholar

51. Yang J, Hou L, Wang J, Xiao L, Zhang J, Yin N, et al. Unfavourable intrauterine environment contributes to abnormal gut microbiome and metabolome in twins. Gut. (2022) 71(12):2451–62. doi: 10.1136/gutjnl-2021-326482

PubMed Abstract | Crossref Full Text | Google Scholar

52. Tims S, Derom C, Jonkers DM, Vlietinck R, Saris WH, Kleerebezem M, et al. Microbiota conservation and BMI signatures in adult monozygotic twins. ISME J. (2013) 7(4):707–17. doi: 10.1038/ismej.2012.146

PubMed Abstract | Crossref Full Text | Google Scholar

53. Haimovich Y, Ascher-Landsberg J, Azem F, Mandel D, Mimouni FB, Many A. Neonatal outcome of preterm discordant twins. J Perinat Med. (2011) 39(3):317–22. doi: 10.1515/jpm.2011.013

PubMed Abstract | Crossref Full Text | Google Scholar

54. Sun M, Lu J, Sun M, Zheng Y, Zhu Q, Liu C. Analysis of extrauterine growth retardation and related risk factors in 132 premature infants. Pak J Med Sci. (2022) 38(6):1644–8. doi: 10.12669/pjms.38.6.5864

PubMed Abstract | Crossref Full Text | Google Scholar

55. Lapillonne A, Griffin IJ. Feeding preterm infants today for later metabolic and cardiovascular outcomes. J Pediatr. (2013) 162(3 Suppl):S7–16. doi: 10.1016/j.jpeds.2012.11.048

PubMed Abstract | Crossref Full Text | Google Scholar

56. González-López C, Solís-Sánchez G, Lareu-Vidal S, Mantecón-Fernández L, Ibáñez-Fernández A, Rubio-Granda A, et al. Variability in definitions and criteria of extrauterine growth restriction and its association with neurodevelopmental outcomes in preterm infants: a narrative review. Nutrients. (2024) 16(7):968-81. doi: 10.3390/nu16070968

Crossref Full Text | Google Scholar

57. Embleton ND, Jennifer Moltu S, Lapillonne A, van den Akker CHP, Carnielli V, Fusch C, et al. Enteral nutrition in preterm infants (2022): a position paper from the ESPGHAN committee on nutrition and invited experts. J Pediatr Gastroenterol Nutr. (2023) 76(2):248–68. doi: 10.1097/MPG.0000000000003642

PubMed Abstract | Crossref Full Text | Google Scholar

58. Nutritional Committee of Neonatology Branch of Chinese Medical Doctor Association, Preterm Committee of Neonatology Branch of Chinese Medical Doctor Association; Editorial Committee of Chinese Journal of Contemporary Pediatrics. Expert consensus on enteral nutrition management of preterm infants (2024). Chin J Contemp Pediatr. (2024) 26(6):541–52. doi: 10.7499/j.issn.1008-8830.2402039

Crossref Full Text | Google Scholar

59. Kosmeri C, Giapros V, Rallis D, Balomenou F, Serbis A, Baltogianni M. Classification and special nutritional needs of SGA infants and neonates of multiple pregnancies. Nutrients. (2023) 15(12):2736–47. doi: 10.3390/nu15122736

PubMed Abstract | Crossref Full Text | Google Scholar