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Comparative Study
. 2021 May 1;175(5):483-493.
doi: 10.1001/jamapediatrics.2020.6087.

Association Between Preterm-Birth Phenotypes and Differential Morbidity, Growth, and Neurodevelopment at Age 2 Years: Results From the INTERBIO-21st Newborn Study

Jose Villar  1   2 , María C Restrepo-Méndez  1   2 , Rose McGready  3   4 , Fernando C Barros  5 , Cesar G Victora  6 , Shama Munim  7 , Aris T Papageorghiou  1   2 , Roseline Ochieng  8 , Rachel Craik  1 , Hellen C Barsosio  9   10 , James A Berkley  11 , Maria Carvalho  8 , Michelle Fernandes  1   12 , Leila Cheikh Ismail  1   13 , Ann Lambert  1   2 , Shane A Norris  14 , Eric O Ohuma  1   15 , Alan Stein  16   17 , Chrystelle O O Tshivuila-Matala  1   14   18 , Krina T Zondervan  1   19 , Adele Winsey  1 , Francois Nosten  3   4 , Ricardo Uauy  20 , Zulfiqar A Bhutta  21 , Stephen H Kennedy  1   2
Affiliations
Comparative Study

Association Between Preterm-Birth Phenotypes and Differential Morbidity, Growth, and Neurodevelopment at Age 2 Years: Results From the INTERBIO-21st Newborn Study

Jose Villar et al. JAMA Pediatr. .

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Villar reported receiving grants from the Bill and Melinda Gates Foundation during the conduct of the study. Dr Victora reported receiving grants from the Bill and Melinda Gates Foundation during the conduct of the study. Dr Papageorghiou reported receiving grants from the Bill and Melinda Gates Foundation during the conduct of the study and grants from the Bill and Melinda Gates Foundation, the European Research Council, and the National Institute of Health Research; personal fees from the British Journal of Obstetrics and Gynaecology, Intelligent Ultrasound, the National Health Service of the United Kingdom, and Ultrasound Diagnostic Services; being a cofounder, shareholder, and senior advisor of Intelligent Ultrasound; being a paid scientific advisor for Oxford University Innovation; and being a deputy editor-in-chief of the British Journal of Obstetrics and Gynaecology outside the submitted work. Dr Ochieng reported receiving grants from the University of Oxford during the conduct of the study. Dr Lambert reported receiving grants from the Bill and Melinda Gates Foundation during the conduct of the study. Dr Tshivuila-Matala reported receiving a scholarship and stipend for living expenses from the Rhodes Trust during the conduct of the study. Dr Winsey reported receiving grants from the Nuffield Department of Women’s and Reproductive Health during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Mean z Scores at Birth and Ages 1 and 2 Years According to Preterm-Birth Phenotype
A-D, Mean values. Gestational age- and sex-specific centiles at birth were compared with the international INTERGROWTH-21st newborn size standards and reference charts for very preterm size at birth., Age- and sex-specific centiles at ages 1 and 2 years were compared with the international World Health Organization Child Growth Standards. P < .001 for all comparisons based on analysis of variance. IUGR indicates intrauterine growth restriction; NMCD, no main condition detected.
Figure 2.
Figure 2.. Severe Neonatal Morbidity Index According to Preterm-Birth Phenotype
The Severe Neonatal Morbidity Index includes bronchopulmonary dysplasia, hypoxic-ischemic encephalopathy, sepsis, neonatal anemia (requiring transfusion), periventricular hemorrhage or leukomalacia, retinopathy of prematurity, necrotizing enterocolitis (Bell stage 2 or higher), and patent ductus arteriosus (requiring pharmacologic treatment or surgery). There were no cases of severe neonatal morbidity in newborns with the severe maternal disease phenotype. Odds ratios are based on comparisons with the NMCD phenotype. The 95% CIs were based on robust SEs. IUGR indicates intrauterine growth restriction; NMCD, no main condition detected.
Figure 3.
Figure 3.. Median Age for Developmental Achievement of Walking Alone According to Preterm-Birth Phenotype
Horizontal lines represent interquartile ranges. For comparison, the 25th and 75th centiles of the WHO periods of achievement for the same developmental milestone are shown in the shaded area (with the median age represented by a broken vertical line). IUGR indicates intrauterine growth restriction; NMCD, no main condition detected; and WHO, World Health Organization.
See this image and copyright information in PMC

Comment in

References

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