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Original Investigation |

Preterm Birth and Random Plasma Insulin Levels at Birth and in Early Childhood

Guoying Wang, MD, PhD1; Sara Divall, MD2; Sally Radovick, MD2; David Paige, MD1; Yi Ning, MD, ScD3; Zhu Chen, PhD1; Yuelong Ji, MS1; Xiumei Hong, PhD1; Sheila O. Walker, PhD1; Deanna Caruso, MS1; Colleen Pearson, BA4; Mei-Cheng Wang, PhD5; Barry Zuckerman, MD4; Tina L. Cheng, MD6; Xiaobin Wang, MD, MPH, ScD1,6
[+] Author Affiliations
1Department of Population, Family and Reproductive Health, Center on Early Life Origins of Disease, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
2Division of Endocrinology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
3Division of Epidemiology, Department of Family Medicine and Population Health, Virginia Commonwealth University School of Medicine, Richmond
4Department of Pediatrics, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts
5Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
6Division of General Pediatrics and Adolescent Medicine, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland
JAMA. 2014;311(6):587-596. doi:10.1001/jama.2014.1.
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Importance  Although previous reports have linked preterm birth with insulin resistance in children and adults, it is not known whether altered insulin homeostasis is detectable at birth and tracks from birth through childhood.

Objective  To investigate whether preterm birth is associated with elevated plasma insulin levels at birth and whether this association persists into early childhood.

Design, Setting, and Participants  A prospective birth cohort of 1358 children recruited at birth from 1998 to 2010 and followed-up with prospectively from 2005 to 2012 at the Boston Medical Center in Massachusetts.

Main Outcomes and Measures  Random plasma insulin levels were measured at 2 time points: at birth (cord blood) and in early childhood (venous blood). The median age was 1.4 years (interquartile range [IQR], 0.8-3.3) among 4 gestational age groups: full term (≥39 wk), early term (37-38 wk), late preterm (34-36 wk), and early preterm (<34 wk).

Results  The geometric mean of insulin levels at birth were 9.2 µIU/mL (95% CI, 8.4-10.0) for full term; 10.3 µIU/mL (95% CI, 9.3-11.5) for early term; 13.2 µIU/mL (95% CI, 11.8-14.8) for late preterm; and 18.9 µIU/mL (95% CI, 16.6-21.4) for early preterm. In early childhood, these levels were 11.2 µIU/mL (95% CI, 10.3-12.0) for full term; 12.4 µIU/mL (95% CI, 11.3-13.6) for early term; 13.3 µIU/mL (95% CI, 11.9-14.8) for late preterm; and 14.6 µIU/mL (95% CI, 12.6-16.9) for early preterm. Insulin levels at birth were higher by 1.13-fold (95% CI, 0.97-1.28) for early term, 1.45-fold (95% CI, 1.25-1.65) for late preterm, and 2.05-fold (95% CI, 1.69-2.42) for early preterm than for those born full term. In early childhood, random plasma insulin levels were 1.12-fold (95% CI, 0.99-1.25) higher for early term, 1.19-fold (95% CI, 1.02-1.35) for late preterm, and 1.31-fold (95% CI, 1.10-1.52) for early preterm than those born full term. The association was attenuated after adjustment for postnatal weight gain and was not significant after adjustment for insulin levels at birth. Infants ranked in the top insulin tertile at birth were more likely to remain in the top tertile (41.2%) compared with children ranked in the lowest tertile (28.6%) in early childhood.

Conclusions and Relevance  There was an inverse association between gestational age and elevated plasma insulin levels at birth and in early childhood. The implications for future development of insulin resistance and type 2 diabetes warrant further investigation.

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Figure 1.
Flowchart of Initial Enrollment and Postnatal Follow-up of the Boston Birth Cohort and the Sample Included in the Analysis

Eligible mother-infant pairs were those who delivered a singleton live birth at the Boston Medical Center. Multiple-gestation pregnancies (eg, twins or triplets) or newborns with major birth defects were excluded. Early childhood age range was 0.5 to 6.5 years; median age was 1.4 years (interquartile range, 0.8-3.3). The Boston Birth Cohort initiated a rolling enrollment in 1998. The follow-up was initiated in 2003. Our study participants were a subset of the Boston Birth Cohort, thus the enrollment and follow-up are different than the Boston Birth Cohort.

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Figure 2.
Association of Plasma Insulin Levels at Birth With Gestational Age, Stratified by Birthweight for Gestational Age Category (n = 1117)

To convert insulin to pmol/mL, multiply by 6.945.The y-axis is the mean of logarithmically transformed insulin levels. Birthweight for gestational age was categorized into 3 groups: small for gestational age (birthweight, <10th percentile; n=174), large for gestational age (birthweight, ≥90th percentile; n=89), and appropriate for gestational age (birthweight, 10th-90th percentile; n=854) according to the local reference population.

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Figure 3.
Tracking of Plasma Insulin Levels From Birth to Early Childhood (n = 785)

To convert insulin to pmol/mL, multiply by 6.945.The y-axis is the mean of logarithmically transformed insulin levels. Age at insulin measurement was the age when the blood sample was obtained for the insulin measurement. Early childhood age range was 0.5 to 6.5 years; median, 1.4 years (interquartile range [IQR], 0.8-3.3). The participants were grouped as low, middle, and high tertile based on cord blood insulin levels. The median cord blood insulin levels were 4.8 µIU/mL (IQR, 2.9-6.9) for low tertile (n=261); 12.0 µIU/mL (IQR, 10.4-13.7) for middle tertile (n=260); and 24.0 µIU/mL (IQR, 18.6-33.8) for high tertile (n=264).

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