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Original Article
a
Department of Neonatology, China Medical University Children’s Hospital, Taichung, Taiwan
b
Department of Genetics and Metabolism, China Medical University Children’s Hospital, Taichung,
Taiwan
c
School of Medicine, China Medical University, Taichung, Taiwan
d
Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
Received Jan 22, 2017; received in revised form Jun 21, 2017; accepted Jul 18, 2017
Available online 25 July 2017
Key Words Background: Previous studies have identified preterm birth and/or small for gestational age
metabolic outcome; (SGA) as risk factors for features of the metabolic syndrome, including high blood pressure, in-
preterm birth; sulin sensitivity and atherosclerosis, occurring later in life, with controversial results. We con-
small for gestational ducted this population-based cohort study to investigate metabolic outcomes in those with
age (SGA) former preterm birth and/or SGA status in Taiwan.
Methods: Data were obtained from Taiwan’s universal National Health Insurance Research
Database. From 1996 to 2004, 37,119 preterm infants, 3386 SGA infants, and 162,020 matched
controls were included. We investigated the risk of the metabolic disease, including hyperten-
sion, diabetes, and hyperlipidemia, which had been recorded by the end of 2008.
Results: The preterm and SGA cohort, combined into one, had a significantly increased risk of
developing metabolic disorders when compared with the comparison cohort (HR Z 2.46, 95%
CI Z 2.02e3.01). We observed that children with former preterm and SGA status in Taiwan had
a higher risk of developing hypertension (HR Z 3.24, 95% CI Z 1.58e6.67), Type 1 diabetes
mellitus (HR Z 1.80, 95% CI Z 1.05e3.07), Type 2 diabetes mellitus (HR Z 2.49, 95%
CI Z 1.98e3.14), and hyperlipidemia (HR Z 2.14, 95% CI Z 1.29e3.52).
Conclusion: Our study revealed the risk of metabolic disease in those with preterm birth
* Corresponding author. Department of Neonatology, China Medical University Children’s Hospital, 2, Yuh-Der Road, Taichung, 404,
Taiwan. Fax: þ886 4 2203 2798.
E-mail address: subh1168@gmail.com (B.-H. Su).
http://dx.doi.org/10.1016/j.pedneo.2017.07.007
1875-9572/Copyright ª 2017, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
148 Y.-T. Huang et al
and/or SGA. Further studies with a longer duration of follow-up are required to confirm if
there is a tendency for the metabolic syndrome to develop in this study cohort.
Copyright ª 2017, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).
2.3. Statistical analysis that in the preterm plus SGA cohort was 4.60 per 10,000
person-years (Table 2). In the preterm and SGA cohorts, the
To present the structure of the study cohort, we demon- incidence of metabolic disease was around 2-fold and 3-fold
strated the mean value and standard deviation (SD) of age greater than that in the comparison cohort (4.39 and 6.81
at each endpoint and numbers and percentages for cate- vs. 1.87 per 10,000 person-years, respectively). After
gorical demographic factors. To assess the differences in adjustment for age, gender, urbanization, and parental
distribution between the preterm plus SGA cohort and occupation, the preterm plus SGA cohort had a significantly
comparison cohort, we applied a t-test to age and a chi- increased risk of developing metabolic disease compared
square test to categorical variables. The incidence den- with the comparison cohort (HR Z 2.46, 95%
sity for each study cohort was calculated as the number of CI Z 2.02e3.01). Preterm and SGA infants had a 2.35-fold
metabolic disease events divided by the sum of follow-up (HR Z 2.35, 95% CI Z 1.90e2.89) and a 3.67-fold
years and expressed per 10,000 person-years. The cumu- (HR Z 3.67, 95% CI Z 2.33e5.78) increased risk of devel-
lative incidence curves for each cohort were measured by oping metabolic disease, respectively, compared with
the KaplaneMeier method and the differences in these normal infants.
incidence curves were further assessed by log-rank test. To Fig. 1 demonstrates the cumulative incidence curves of
demonstrate the association between preterm and/or SGA the comparison cohort, the preterm plus SGA cohort, the
infants and the risk of metabolic disease, the single vari- preterm cohort, and the SGA cohort. The cumulative inci-
able and multivariable Cox proportional hazards model was dence curves over 12 years’ follow-up of the preterm plus
used to measure the hazard ratios (HRs) and 95% confidence SGA, preterm, and SGA cohorts were significantly higher
intervals (CIs). than that of the comparison cohort (all p < 0.0001).
Statistical analysis was performed with SAS 9.4 software Table 3 shows the independent effects of preterm plus
(SAS Institute, Cary, NC, USA). The cumulative incidence SGA, preterm, and SGA on the individual and combined risk
curve was also drawn with SAS 9.4. A two-sided p-value of of the components of metabolic disease. Relative to the
less than 0.05 was considered to indicate significance. comparison cohort, all three subgroups had a higher inci-
dence rate of combined metabolic parameters (HR Z 2.46,
95% CI Z 2.02e3.01; HR Z 2.35, 95% CI Z 1.90e2.89;
3. Results HR Z 3.67, 95% CI Z 2.33e5.78, respectively). The pre-
term plus SGA cohort had an association with increased risk
In this study, we analyzed the data from 37,119 preterm of developing hypertension (HR Z 3.24, 95%
infants, 3386 SGA infants, and 162,020 matched controls CI Z 1.58e6.67) and the preterm cohort had a 3.28-fold
(Table 1). There was no significant difference between the higher risk of hypertension (HR Z 3.28, 95%
preterm plus SGA cohort and the comparison cohort CI Z 1.57e6.87). There was a 2.49-fold increased risk of
(p > 0.05), distributed by gender, urbanization, and type 2 DM (HR Z 2.49, 95% CI Z 1.98e3.14), a 1.80-fold risk
parental occupation. At the study endpoint, the mean age of type 1 DM (HR Z 1.80, 95% CI Z 1.05e3.07), and a 2.14-
of the comparison cohort was 0.5 years greater than that of fold risk of hyperlipidemia (HR Z 2.14, 95%
the preterm plus SGA cohort (8.6 years vs. 8.1 years, CI Z 1.29e3.52) relative to the comparison cohort. We
p < 0.0001). attempted to obtain data on prescription orders for Amlo-
The incidence of developing metabolic disease in the dipine for hypertension. The result revealed that few hy-
comparison cohort was 1.87 per 10,000 person-years, and pertensive children had been treated with Amlodipine (two
Table 1 Comparison of demographics between 4 cohorts of preterm, small for gestational age (SGA), preterm & SGA and
controls.
Variable Preterm SGA Preterm& SGA Controls p-value
N Z 37,119 N Z 3386 N Z 40,505 N Z 162,020
N (%) N (%) N (%) N (%)
Mean age of 8.04 (3.2) 8.7 (3.0) 8.1 (3.2) 8.6 (2.6) <0.0001
follow-up years (SD)a
Sex
Female 16,420 (44.2) 1901 (56.1) 18,321 (45.2) 73,284 (45.2) >0.99
Male 20,699 (55.8) 1485 (43.9) 22,184 (54.8) 88,736 (54.8)
Urbanization
1 (highest) 10,647 (28.7) 1059 (31.3) 11,706 (28.9) 46,824 (28.9) >0.99
2 11,054 (29.8) 1022 (30.2) 12,076 (29.8) 48,304 (29.8)
3 6927 (18.7) 552 (16.3) 36,976 (22.8) 9244 (22.8)
4 (lowest) 8491 (22.9) 753 (22.2) 9244 (22.8) 36,976 (22.8)
Parental occupations
White collar 21,509 (57.9) 1958 (57.8) 23,467 (57.9) 93,868 (57.9) >0.99
Blue collar 9572 (25.8) 864 (25.5) 10,436 (25.8) 41,744 (25.8)
Others 6038 (16.3) 564 (16.7) 6602 (16.3) 26,408 (16.3)
a
t test.
150 Y.-T. Huang et al
Table 2 Incidence rates and relative risks of metabolic disease for 4 cohorts of preterm, small for gestational age (SGA),
preterm & SGA and controls by multivariate Cox proportional hazards regression model.
Event PYs IR Crude HR Adjusted HR
95% CI 95% CI
Controls 260 1,391,969 1.87 reference reference
Preterm 131 298,540 4.39 2.35 (1.91, 2.90) 2.35 (1.90, 2.89)
SGA 20 29,366 6.81 3.63 (2.30, 5.72) 3.67 (2.33, 5.78)
Preterm & SGA 151 327,906 4.60 2.47 (2.02, 3.02) 2.46 (2.02, 3.01)
Model adjusted by sex, urbanization and parental occupation.
Metabolic disease: any one of hypertension, diabetes mellitus, or hyperlipidemia.
PYs: person-years; IR: incidence rate, per 10,000 person-years.
4. Discussion
Table 3 Incidence rates and relative risks of types of metabolic disease for 4 cohorts of preterm, small for gestational age
(SGA), preterm & SGA and controls by multivariate Cox proportional hazards regression analysis.
Type of event Controls Preterm & SGA Preterm SGA
Event IR Event IR HR (95% CI) Event IR HR (95% CI) Event IR HR (95% CI)
Overall 260 1.87 151 4.60 2.46 (2.02, 3.01) 131 4.39 2.35 (1.90, 2.89) 20 6.81 3.67 (2.33, 5.78)
Hypertension 17 0.12 13 0.40 3.24 (1.58, 6.67) 12 0.40 3.28 (1.57, 6.87) 1 0.34 2.83 (0.38, 21.3)
Hypertension 2 0.01 1 0.03 2.10 (0.19, 23.1) 1 0.03 2.28 (0.21, 25.1) 0 0.00 e
þ amlodipine
Diabetes
Type 2 DM 197 1.42 116 3.54 2.49 (1.98, 3.14) 101 3.38 2.38 (1.87, 3.03) 15 5.11 3.65 (2.16, 6.18)
Type 1 DM 45 0.32 19 0.58 1.80 (1.05, 3.07) 17 0.57 1.76 (1.01, 3.08) 2 0.68 2.12 (0.51, 8.74)
Hyperlipidemia 46 0.33 23 0.70 2.14 (1.29, 3.52) 19 0.64 1.94 (1.14, 3.32) 4 1.36 4.02 (1.44, 11.2)
Model adjusted by sex, urbanization and parental occupation.
PYs: person-years; IR: incidence rate, per 10,000 person-years.
Table 4 Incidence rates and relative risks of metabolic disease stratified by demographic factors for 4 cohorts of preterm,
small for gestational age (SGA), preterm & SGA and controls by multivariate Cox proportional hazards regression analysis.
Demographic factors Controls Preterm & SGA Preterm SGA
Event IR Event IR HR (95% CI) Event IR HR (95% CI) Event IR HR (95% CI)
Sex
Female 94 1.48 68 4.55 3.06 (2.24, 4.18) 58 4.36 2.94 (2.12, 4.08) 10 6.07 3.99 (2.08, 7.67)
Male 166 2.19 83 4.65 2.12 (1.63, 2.76) 73 4.41 2.01 (1.53, 2.65) 10 7.76 3.51 (1.85, 6.64)
Urbanization
Urban 184 2.25 108 5.57 2.48 (1.96, 3.14) 91 5.18 2.30 (1.79, 2.95) 17 9.37 4.31 (2.62, 7.09)
Rural 76 1.33 43 3.21 2.42 (1.67, 3.52) 40 3.26 2.46 (1.68, 3.61) 3 2.67 2.02 (0.64, 6.40)
Parental occupations
White collar 173 2.16 97 5.13 2.37 (1.85, 3.04) 82 4.76 2.19 (1.69, 2.85) 15 8.81 4.25 (2.50, 7.20)
Blue collar 52 1.41 33 3.81 2.71 (1.75, 4.19) 31 3.92 2.81 (1.80, 4.38) 2 2.62 1.78 (0.43, 7.33)
Others 35 1.56 31 4.04 2.57 (1.50, 4.42) 18 3.81 2.43 (1.38, 4.29) 3 6.37 3.98 (1.22, 13.0)
Model adjusted by sex, urbanization and parental occupation.
PYs: person-years; Incidence rate: incidence rate, per 10,000 person-years.
postnatal “catch-up” in body weight may contribute to children were treated with Amlodipine, possibly indicating
some extent.22 that hypertension in most of the children in this cohort
Prematurity may also increase the risk of hypertension could be well- controlled by non-pharmacological inter-
via decreased glomerulogenesis, which is independent of vention, such as exercise, weight reduction, and diet con-
birth weight.4,23 This phenomenon may thus explain our trol in this relatively short-term follow-up.
results of no significant increase in the risk of hypertension Preterm birth was linked with a modestly increased risk
in the SGA cohort but a significant increase in the preterm of diabetes (both type 1 and 2 diabetes mellitus) in young
plus SGA cohort and preterm cohort. A meta-analysis of 10 Swedish adults. These findings reveal the important public
studies with 3083 individuals from eight countries reported health issues, given the increasing number of infants sur-
an association of prematurity with adolescent and adult viving preterm birth and the huge morbid burden of dia-
blood pressure (measured at the average age of 18 years).4 betes.24 Small-for-age babies are more likely to have
Those who were born prematurely had higher systolic blood metabolic abnormalities associated with hypertension or
pressures with statistical significance (2.5 mmHg), regard- later-developing coronary disease, accompanied by
less of weight. The results could be partly attributed to increased insulin resistance,25 diabetes mellitus, and
altered programming of nephron numbers, which are hyperlipidemia,26 especially in those with higher abdominal
adversely affected by developmental stressors, such as (visceral) adiposity.
maternal, fetal, and childhood under- or over-nutrition.14 Those with VLBW had significantly higher blood pressure,
The findings mentioned above provided inconclusive evi- higher fasting insulin, 2-h insulin, and 2-h glucose concen-
dence of birth weight and/or prematurity contributing to trations as well as a higher HOMA-IR index reflecting
blood pressure levels in later life. increased insulin resistance, compared with young adults
In the current study, we attempted to correlate the who had been born at term, implying a higher risk for
severity of hypertension with prescription orders of Amlo- progression of type 2 diabetes and cardiovascular mortality.
dipine. We used the prescription code for Amlodipine These differences were neither attributable to adult body
because it is the most frequently prescribed antihyper- size nor composition, nor to fat distribution. Thus, VLBW
tensive agent. The results revealed that few hypertensive appeared to be associated with signs of insulin resistance
152 Y.-T. Huang et al
and impaired glucose regulation in early adulthood. How- exercise, weight reduction, and diet control. Further
ever, some have suggested that young adults with VLBW studies with longer follow-up times are required to confirm
would appear to benefit from early-targeting preventive if there is a tendency for the metabolic syndrome to
interventions, such as prevention of rapid weight gaining develop in this study cohort.
during childhood.27,28 The correlation between low birth
weight at term and adverse profile of later insulin meta-
Conflicts of interest
bolism and glucose regulation has been validated.29 Sub-
jects with intrauterine growth retardation tended to have
The authors have no conflicts of interest relevant to this
more severe impaired insulin sensitivity than subjects with
article.
appropriate birth weight at gestational age. This difference
was foreseen in the subjects’ prepubertal childhood30,31 or
later in their young adulthood.32,33 Acknowledgement
Prematurity (with both appropriate and small for
gestational age) has been proven to have reduced in insulin This study is supported in part by Taiwan Ministry of Health
sensitivity and secretion capacity, with or without early and Welfare Clinical Trial and Research Center of Excel-
accelerated or poor postnatal growth.8,34 In our study, we lence (MOHW104-TDU-B-212-113002), Bureau of Health
analyzed the risks of type 1 DM and type 2 DM individually Promotion (DOH99-HP-1205), China Medical University
due to the different pathophysiology, and observed a higher Hospital, Academia Sinica Taiwan Biobank Stroke Bio-
incidence both of type 1 DM and type 2 DM in the preterm signature Project (BM104010092).
plus SGA cohort and the preterm cohort than the compar-
ison cohort, which was not only consistent with previously
study findings but also expanded our knowledge of adverse References
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