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.

Objective: To assess the association of maternal HIV infection and antiretroviral therapy (ART) with perinatal outcomes among women with accurate pregnancy dating and birth weights. Design: Prospective pregnancy cohort study in Soweto, South Africa. Methods: Gestational age was estimated by first-trimester ultrasound and birth weight was measured in a standardised manner within 24 hours of birth. The primary composite outcome "adverse perinatal outcome" included preterm birth, low birth weight, small for gestational age, stillbirth and neonatal death. Specific adverse perinatal outcomes were secondary outcomes. Logistic regression models adjusted for multiple confounders. Results: Of 633 women included in the analysis, 229 (36.2%) were HIV-positive and 404 (63.8%) HIV-negative. Among 125 HIV-positive women who provided detailed information on HIV and ART, 96.7% had clinical stage 1 of HIV disease and 98.4% were on ART during pregnancy, mostly WHO-recommended efavirenz-based ART. Among 109 HIV-positive women with information on timing of ART initiation, 38 (34.9%) initiated ART preconception and 71 (65.1%) antenatally. No newborns were HIV-positive. In univariable analysis, maternal HIV infection was associated with increased risk of the composite "adverse perinatal outcome" (OR 1.44; 95%CI 1.03, 2.03), neonatal death (OR 6.15; 95%CI 1.27, 29.88) and small for gestational age (OR 1.55; 95%CI 1.01, 2.37). After adjusting for confounders, maternal HIV infection remained associated with "adverse perinatal outcome" (adjusted OR (AOR)1.47; 95%CI 1.01, 2.14) and neonatal death (AOR 7.82; 95%CI 1.32, 46.42). No associations with timing of ART initiation were observed. Conclusion: Despite high ART coverage, good maternal health, and very low vertical HIV transmission rate, maternal HIV infection remained associated with increased risk of adverse perinatal outcomes. Larger studies using first trimester ultrasound for pregnancy dating are needed to further assess associations with specific adverse perinatal outcomes.