Key Points

Question  Are specific phenotypes in preterm newborns associated with clinical, growth, and neurodevelopmental differences at age 2 years compared with term newborns?

Findings  In this cohort study of 6529 preterm and term newborns who were followed up from birth to age 2 years, 8 preterm-birth phenotypes were identified: no main maternal, fetal, or placental condition detected (35%); infections (21%); preeclampsia (12%); fetal distress (10%); intrauterine growth restriction (8%); severe maternal disease (6%); bleeding (5%); and congenital anomaly (4%). Each phenotype was associated with substantial differences in neonatal morbidity and infant outcomes.

Meaning  The study’s findings support the use of phenotypic classification for preterm births.

Abstract

Importance  The etiologic complexities of preterm birth remain inadequately understood, which may impede the development of better preventative and treatment measures.

Objective  To examine the association between specific preterm-birth phenotypes and clinical, growth, and neurodevelopmental differences among preterm newborns compared with term newborns up to age 2 years.

Design, Setting, and Participants  The INTERBIO-21st study included a cohort of preterm and term newborn singletons enrolled between March 2012 and June 2018 from maternity hospitals in 6 countries worldwide who were followed up from birth to age 2 years. All pregnancies were dated by ultrasonography. Data were analyzed from November 2019 to October 2020.

Exposures/Interventions  Preterm-birth phenotypes.

Main Outcomes and Measures  Infant size, health, nutrition, and World Health Organization motor development milestones assessed at ages 1 and 2 years; neurodevelopment evaluated at age 2 years using the INTERGROWTH-21st Neurodevelopment Assessment (INTER-NDA) tool.

Results  A total of 6529 infants (3312 boys [50.7%]) were included in the analysis. Of those, 1381 were preterm births (mean [SD] gestational age at birth, 34.4 [0.1] weeks; 5148 were term births (mean [SD] gestational age at birth, 39.4 [0] weeks). Among 1381 preterm newborns, 8 phenotypes were identified: no main maternal, fetal, or placental condition detected (485 infants [35.1%]); infections (289 infants [20.9%]); preeclampsia (162 infants [11.7%]); fetal distress (131 infants [9.5%]); intrauterine growth restriction (110 infants [8.0%]); severe maternal disease (85 infants [6.2%]); bleeding (71 infants [5.1%]); and congenital anomaly (48 infants [3.5%]). For all phenotypes, a previous preterm birth was a risk factor for recurrence. Each phenotype displayed differences in neonatal morbidity and infant outcomes. For example, infants with the no main condition detected phenotype had low neonatal morbidity but increased morbidity and hospitalization incidence at age 1 year (odds ratio [OR], 2.2; 95% CI, 1.8-2.7). Compared with term newborns, the highest risk of scoring lower than the 10th centile of INTER-NDA normative values was observed in the fine motor development domain among newborns with the fetal distress (OR, 10.6; 95% CI, 5.1-22.2) phenotype.

Conclusions and Relevance  Results of this study suggest that phenotypic classification may provide a better understanding of the etiologic factors and mechanisms associated with preterm birth than continuing to consider it an exclusively time-based entity.