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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 9 4252-4256
Copyright © 2002 by The Endocrine Society

Other Original Article

The Intrauterine Environment Is a Strong Determinant of Glucose Tolerance during the Neonatal Period, Even in Prematurity

I. P. Gray, P. A. Cooper, B. J. Cory, M. Toman and N. J. Crowther

Department of Chemical Pathology, University of the Witwatersrand and National Health Laboratory Service; and Department of Pediatrics, University of the Witwatersrand and Johannesburg General Hospital, 2193 Johannesburg, South Africa

Address all correspondence and requests for reprints to: Dr. N. J. Crowther, Department of Chemical Pathology, University of the Witwatersrand Medical School and National Health Laboratory Service, 7 York Road, Parktown 2193, Johannesburg, South Africa. E-mail: . nigelc{at}mail.saimr.wits.ac.za

Abstract

The aim of this study was to determine the contribution of birth weight and gestational age to glucose tolerance in premature neonates. The study group consisted of 100 premature and/or small-for-gestational age infants. Anthropometric measurements were performed both at birth and at the time of a standardized milk feed carried out at 19.6 ± 12.1 d (range, 1–65 d) after birth. Fasting and postprandial glucose and insulin levels were measured.

Birth weight, as a proxy mirror of the intrauterine environment, was found to influence the glucose concentration following a standardized milk feed (ß = -0.46; P = 0.01 for birth weight z-score with 60-min glucose level), whereas gestational age did not. Small-for-gestational age neonates had higher 60-min insulin levels than appropriate-for-gestational age neonates (115.4 ± 9.5 vs. 68.4 ± 14.2; P < 0.05) despite similar glucose levels. Neonates born of mothers who were on antihypertensive treatment were smaller and had a higher insulin secretory response than neonates from normotensive mothers. Postnatal growth velocity (kilograms per day) correlated with birth weight (ß = -0.65; P < 0.0001) and insulin resistance (ß = -0.31; P = 0.0004), independently of each other.

This study shows that glucose tolerance of the neonate is determined by weight attained at birth irrespective of gestational age and that maternal blood pressure may influence insulin sensitivity of the newborn. Furthermore, catch-up growth in neonates is determined by birth weight and insulin sensitivity.

THE THRIFTY PHENOTYPE hypothesis (1, 2) holds that low birth weight, a proxy indicator of impaired intrauterine nutrition, is causally related to the later development of the so-called diseases of lifestyle that afflict Westernized society. The spectrum includes obesity (3), hypertension (3, 4), glucose intolerance (1, 5), diabetes (2, 6), hyperlipidemia (6, 7), and insulin resistance (8, 9). In addition, short children and adults are more likely to be glucose intolerant (10, 11).

The proposed mechanism is related to the regulation of allometric growth with those organs most crucial for continued survival of the organism, in particular the brain, being favored over organs such as the pancreas (12, 13, 14), kidney (15), or endothelial cells (16).

However, data have also shown that glucose intolerance is related to the growth rate during childhood and that growth which does not track within the birth centile but crosses over into a higher centile is related to the development of insulin resistance (17, 18, 19). There is thus an argument about the relative importance of the intrauterine environment and the neonatal/childhood environment on determining the adult level of glucose tolerance. This clearly has implications for the design of interventions to attenuate these effects.

All but one (18) of the studies that have investigated the relationship between birth weight and glucose tolerance have excluded preterm births. Therefore, very little is known about the effect of gestational age on glucose tolerance. Premature births are common occurrences in the First World (20) and more so in developing countries such as South Africa (21, 22). Therefore, the aim of this study was to determine the effect of both birth weight and gestational age on the glucose tolerance of neonates.

Subjects and Methods

All studies were performed after written, informed consent was granted by the parents; the study protocol was approved by the Ethics Committee of the Faculty of Health Sciences, University of the Witwatersrand. The study represented one additional blood test to premature and small-for-gestational age (SGA) neonates, who are monitored routinely for hypoglycemia.

Subjects

Infants admitted to the neonatal unit who were premature or had a weight below the 10th centile were eligible for the study. All were of Black African origin. Because maternal dates are often inaccurate and early sonar examinations were not usually available, all infants had a Ballard score performed within 48 h of delivery. The Ballard score is the only viable technique of assessing gestational age in this population, who most commonly attend the maternity unit only from the late second trimester onward, if at all.

Once infants were tolerating enteral feeds, the parents were approached regarding enrollment into the study. One hundred infants (55 girls and 45 boys) were studied between the first and the 65th day of life (median, 17 d). Each individual was given a standardized formula milk (Nan, Nestlé, Vevey, Switzerland) meal of 21 ml/kg body weight after a 4-h fast. All the neonates finished the formula feed, and blood was taken by heel prick at fasting and 60 min after the feed was finished and analyzed for glucose and insulin concentrations. Insulin resistance was assessed using the homeostasis model assessment (HOMA) method (23), whereas insulin secretion was measured by using the insulinogenic index (24), which has been shown to be an accurate method of assessing ß-cell function (25, 26). The insulinogenic index was calculated as the ratio of the 60-min insulin increment (IU/ml) to the 60-min glucose increment (mmol/liter), i.e. {Delta}I/{Delta}G.

Routine measurements of weight, length, and head circumference were performed at birth; at the time of the milk tolerance test (MTT), weight, length, head circumference, crown-rump and sacrum-heel lengths, triceps and subscapular skinfold thickness were measured. Weight velocity between birth and the MTT was calculated and expressed as kilograms per day.

The glucose concentrations were measured using a commercially available enzymatic colorimetric method (Roche Molecular Biochemicals, Mannheim, Germany). Inter- and intra-assay coefficients of variation for glucose were 0.9% and 1.8%, respectively. Insulin was measured by enzyme-amplified immunoassay (Mercodia, Uppsala, Sweden); the lower limit of sensitivity for the ELISA was 7.3 pmol/liter, and the intra- and interassay coefficients of variation were 4% and 3.6%, respectively.

Statistics

Multiple regression analysis and one-way ANOVA were performed on the data, correcting for age of the neonate and gestational age. Fasting insulin data were not normally distributed and were log-transformed before analysis. The nonlogged and logged 1 h insulin levels were also not normally distributed and only became so by taking the square root. HOMA and insulinogenic index data were also log-transformed. Statistical analyses were performed using Statistica, version 5.0 (Statsoft Inc., Chicago, IL).

Data from a South African study have shown that fetal growth does not differ from that reported in European populations (27), and therefore birth weight was expressed as a SD (z) score (measured weight - population weight/population SD) using fetal growth data from a British study for which SD values were available (28).

Results

The number of SGA births were 86, and appropriate-for-gestational age (AGA) births were 14. SGA was defined as birth weight below the 10th centile, and AGA as birth weight between the 10th and 90th centiles (29). The range for Ballard scores was 26–40, with a median of 34.

The neonates finished the formula feed in a mean (±SD) of 10.2 ± 4.7 min (median, 10.0 min; range, 3.0–27.0 min) with 90% of the subjects finishing the feed in 5–15 min. No correlation was found between the time taken to finish the feed and the 60-min insulin or glucose levels.

A large proportion (50%) of the premature births were from mothers being treated for pregnancy-associated hypertension, and these neonates had lower birth weights (mean ± SD, 1.25 ± 0.19 kg) than neonates from mothers who were not hypertensive (1.42 ± 0.27 kg; P < 0.0005). All of the mothers for whom therapy for pregnancy-associated hypertension had been recorded (n = 7) in their admissions file were taking methyldopa (Aldomet) alone (n = 4) or in combination with hydralazine (Apresoline; n = 1), dihydralazine (Nepresol; n = 1), or hydralazine with prazosin (Minipress; n = 1). Three cases of abruptio placentae, one case of premature rupture of uterine membranes, and two cases of reduced fetal movement/fetal distress were reported. Cesarean sections (CS) were performed on 48% of the subjects, and the remainder were normal vaginal births (NVB). Babies born via CS were smaller than those delivered via NVB (1.26 ± 0.20 vs. 1.41 ± 0.32 kg; P < 0.001). Glucose and insulin levels did not differ between neonates from CS or NVB deliveries. However, the insulinogenic index level was higher in neonates from mothers treated for pregnancy-associated hypertension than in neonates from nontreated mothers (94 ± 17 vs. 64 ± 12; P < 0.05).

Table 1Go contains the anthropometric data for the study group. No statistically significant differences between sexes were observed, and therefore all statistical analyses were performed on a combined boy-girl data set.


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  		Table 1. Physical parameters at birth and at time of MMT

 
The SGA neonates had higher Ballard scores (P < 0.01) but similar birth weights and glucose levels compared with AGA neonates but higher insulin levels, being statistically significantly greater at the 1-h time point of the MTT (Table 2Go).

Table 3Go contains the results of the multiple regression analysis of the data set with Ballard score and age at the time of the MTT, both included as independent variables. Birth weight, birth weight z-score, and weight and length at the time of the MTT were negatively related to the 60-min glucose value. Insulin resistance, assessed using HOMA, was negatively related to weight at the time of the MTT. No correlations were found between Ballard scores and glucose, insulin, or HOMA values.


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  		Table 3. Multiple regression analyses

 
Children with the highest weight gain velocity were of the lowest birth weight and/or the most insulin sensitive; birth weight and HOMA exerted their influence on weight velocity independently of each other (Table 3Go).

Discussion

The thrifty phenotype hypothesis suggests that the etiology of type 2 diabetes involves the action of unknown factors during prenatal life that reduce fetal growth, islet ß-cell ontogeny, and insulin sensitivity (2). The best proof of this theory would therefore be to test glucose tolerance soon after birth, so ensuring that postnatal factors do not confound the analysis. The present investigation is the only study to have done this in humans, and the results show that a relationship between glucose tolerance and birth weight does exist in the neonate. This data strongly supports the role of the intrauterine environment as a major determinant of neonatal and potentially childhood and adulthood metabolism. Interestingly, this relationship is apparent in premature infants, and not only term infants as defined in the original studies. Thus, birth weight and birth weight z-score both correlated negatively with the 60-min glucose level, as did length at the time of the MTT. Previous studies have shown that short children and adults are more likely to be glucose-intolerant and diabetic (10, 11), and the present data strongly suggest that this relates to effects acting in utero.

The negative correlation between HOMA and weight at the time of the MTT and the higher insulin levels of SGA than AGA infants suggests that it is insulin resistance arising from fetal growth restriction rather than ß-cell dysfunction that is the first detectable event in the etiology of type 2 diabetes, as has been suggested in other studies (30, 31). The ß-cell insufficiency central to the thrifty phenotype hypothesis (2) is revealed only later in life in the presence of obesity, which further elevates the level of insulin resistance (32). This interaction between birth weight and obesity is demonstrated by studies showing that type 2 diabetes is more common in individuals of low birth weight who become obese as adults (1, 33, 34).

No correlations were observed between gestational age and any of the measured metabolic variables, as also observed in a recent study on preterm neonates in whom glucose tolerance was assessed at 9–12 yr of age (18); weight attained rather than length of gestation at the time of birth is therefore more important in determining glucose tolerance. This is emphasized by the finding that SGA neonates, despite having higher Ballard scores and similar birth weights and glucose levels, have higher insulin levels than AGA neonates. In addition, birth weight when expressed relative to the mean birth weight of a large population as a z-score correlates negatively with the 60-min glucose level. This relationship is weaker when birth weight is used as the independent variable. The present study therefore suggests that prematurity will be less detrimental if neonates are close to the appropriate weight for their gestational age. A major determinant of birth weight (35) and glucose tolerance (36) of the offspring is maternal food intake, and therefore an adequate diet during pregnancy may protect against the later development of type 2 diabetes in full term and premature neonates.

Pregnancy-associated hypertension leads to lower birth weight, as shown in this and previous studies (37, 38). Therefore, the high prevalence of low birth weight in the Black population of South Africa (39, 40) may be due to a combination of poor maternal nutrition and hypertension, the latter of which is very common in this group (41). Low birth weight is associated with insulin resistance (9, 42, 43), which in turn can give rise to type 2 diabetes and hypertension in adult life (44), and a number of studies have shown associations between birth weight and the incidence of both these diseases (6, 33, 34). The possibility that pregnancy-associated hypertension may play a role in the etiology of insulin resistance and associated disorders is supported by the higher prevalence of low birth weight (39, 40), preeclampsia (45, 46), type 2 diabetes (47, 48), and hypertension (41) in the Black than White South African population and also by studies demonstrating that Black obese women are more insulin resistant than their White South African counterparts (49, 50). Furthermore, the present study shows that the insulinogenic index was higher in neonates from hypertensive mothers, which suggests that these infants require a higher insulin secretory response to maintain euglycemia. In addition, a study has shown that maternal blood pressure correlates positively with blood pressure of the offspring but negatively with birth weight (51). It is interesting to note that low birth weight (52, 53), preeclampsia (52, 54, 55), hypertension (56, 57), and type 2 diabetes (58, 59) are all more prevalent in African Americans than European Americans, and that the former group is more insulin resistant than the latter (60, 61).

In this study, growth during the early days of life was greatest in the infants of lowest birth weight or highest insulin sensitivity. Considering the role of insulin as a growth factor (62), this is perhaps unsurprising and low birth weight is known to lead to catch-up growth of the neonate (63). Further evidence that insulin may play a role in catch-up growth comes from a study showing that red blood cell insulin receptor affinity is increased in children undergoing catch-up growth (64) and from a study demonstrating that a positive correlation exists between catch-up growth rate and insulin levels (65). The stronger association of weight velocity with birth weight than with HOMA (Table 3Go) suggests that in low birth weight neonates weight may be more influential on the subsequent growth rate than insulin sensitivity.

A previous investigation has shown that catch-up growth is associated with increased body mass index in 5-yr-old children (66), and therefore catch-up growth may be one mechanism by which low weight at birth may predispose to obesity (67, 68).

The most accurate method for determining gestational age is from ultrasound scans performed early in pregnancy. However, this was not possible in the present study, and therefore Ballard scores were used. The Ballard score is based on physical examination of the baby within 48 h of birth to assess both neuromuscular and physical maturity of the neonate (69). A number of investigations have shown that the Ballard score correlates very well with ultrasound measurement (69, 70, 71), and therefore we consider the estimates of gestational age in the present study as being sufficiently accurate.

In conclusion, these data demonstrate clearly the founding influence of the intrauterine environment and, in particular, the importance of weight attained at birth irrespective of gestational age on determining glucose tolerance of the neonate. Also, maternal hypertension may influence insulin sensitivity of the newborn. Furthermore, catch-up growth of the neonate is determined by birth weight and insulin sensitivity, but independently of one another, and may play a role in predisposing to childhood obesity in low birth weight individuals.


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  		Table 2. Birth weight, Ballard score, glucose and insulin levels in AGA and SGA neonates

 
Acknowledgments

Footnotes

This research was funded by the National Health Laboratory Service and the Medical Research Council of South Africa.

Abbreviations: AGA, Appropriate-for-gestational age; CS, cesarean section; HOMA, homeostasis model assessment; MTT, milk tolerance test; NVB, normal vaginal births; SGA, small-for-gestational age.

Received December 10, 2001.

Accepted June 7, 2002.

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