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1.  Maternal Glycemia and Risk of Large-for-Gestational-Age Babies in a Population-Based Screening 
Diabetes Care  2009;32(12):2200-2205.
OBJECTIVE
Gestational diabetes is a risk factor for large-for-gestational-age (LGA) newborns, but many LGA babies are born to mothers with normal glucose tolerance. We aimed to clarify the association of maternal glycemia across the whole distribution with birth weight and risk of LGA births in mothers with normal glucose tolerance.
RESEARCH DESIGN AND METHODS
We undertook a population-based gestational diabetes screening in an urban area of Hungary in 2002–2005. All singleton pregnancies of mothers ≥18 years of age, without known diabetes or gestational diabetes (World Health Organization criteria) and data on a 75-g oral glucose tolerance test at 22–30 weeks of gestation, were included (n = 3,787, 78.9% of the target population). LGA was determined as birth weight greater than the 90th percentile using national sex- and gestational age–specific charts.
RESULTS
Mean ± SD maternal age was 30 ± 4 years, BMI was 22.6 ± 4.0 kg/m2, fasting blood glucose was 4.5 ± 0.5 mmol/l, and postload glucose was 5.5 ± 1.0 mmol/l. The mean birth weight was 3,450 ± 476 g at 39.2 ± 1.2 weeks of gestation. There was a U-shaped association of maternal fasting glucose with birth weight (Pcurve = 0.004) and risk of having an LGA baby (lowest values between 4 and 4.5 mmol/l, Pcurve = 0.0004) with little change after adjustments for clinical characteristics. The association of postload glucose with birth weight (P = 0.03) and the risk of an LGA baby (P = 0.09) was weaker and linear.
CONCLUSIONS
Both low and high fasting glucose values at 22–30 weeks of gestation are associated with increased risk of an LGA newborn. We suggest that the excess risk related to low glucose reflects the increased use of nutrients by LGA fetuses that also affects the mothers' fasting glucose.
doi:10.2337/dc09-1088
PMCID: PMC2782977  PMID: 19729526
2.  Insulin and Leptin Levels in Appropriate-for-Gestational-Age Infants of Diabetic Mother 
Iranian Journal of Pediatrics  2012;22(4):475-480.
Objective
Intensified management of gestational diabetes mellitus can normalize birth weight. However, it is still unknown whether intrauterine exposure to maternal diabetes is a risk factor for changing hormone levels involved in the development of insulin resistance in these infants. We compared insulin and leptin levels in appropriate for gestational age (AGA) infants of diabetic and non diabetic mothers.
Methods
We performed a cross-sectional study in the department of Neonatology of the Hospital of Gynecology-Pediatrics, in Leon, Mexico. We evaluated 182 full term AGA newborns (86 infants of diabetic and 96 of non-diabetic mothers). A venous blood sample was taken from cord blood immediately after the separation of the placenta and glucose, insulin and leptin levels were measured. In all diabetic mothers HbA1c was also evaluated immediately post-partum.
Findings
Leptin, insulin and insulin resistance index were significantly higher in infants of diabetic mothers. Leptin levels were positive correlated with insulin, parents‘ body mass index and age in the entire group. In infants of diabetic mothers only insulin levels showed a significantly correlation, whereas in those of non-diabetic mothers only mothers‘ age was significantly correlated with leptin levels.
Conclusion
AGA infants of diabetic mothers showed higher leptin, insulin levels and insulin resistance index than those of non-diabetic mothers.
PMCID: PMC3533147  PMID: 23429837
Diabetic Mother; Insulin; Leptin; Birthweight; Infant
3.  Retinol-Binding Protein 4: A Novel Adipokine Implicated In the Genesis of LGA in the Absence of Gestational Diabetes Mellitus 
Journal of perinatal medicine  2010;38(2):147-155.
Objective
Adipokines (cytokines produced by adipose tissue) play a major role in the control of body weight and energy distribution. Retinol-binding protein (RBP) 4, only recently recognized as an adipokine, has been proposed to modulate systemic insulin sensitivity. The goal of this study was to determine whether there is an association between maternal plasma RBP4 concentration and the birth of a large-for-gestational-age (LGA) newborn in women with and without gestational diabetes mellitus (GDM).
Study design
This cross-sectional study included pregnant women at term in the following groups: 1) normal pregnancy with an appropriate-for-gestational-age (AGA) neonate (n=64); 2) normal pregnancy with an LGA neonate (n=44); 3) GDM with an AGA neonate (n=55); and 4) GDM with an LGA neonate (n=42). Maternal plasma RBP4 concentration was determined by ELISA. Parametric and non-parametric statistics were used for analyses.
Results
1) Patients with GDM, either with AGA or LGA neonates, had a higher median plasma concentration of RBP4 than normal pregnant women who delivered an AGA neonate (p=0.01 and p=0.008, respectively); 2) mothers without GDM but with LGA neonates had a higher median plasma concentration of RBP4 than those with normal pregnancy and AGA newborns (p=0.001); 3) these findings remained significant after adjusting for maternal age, BMI and gestational age at blood sampling.
Conclusion
GDM is characterized by alterations in maternal circulating RBP4 concentrations akin to those of Type 2 DM. Retinol binding protein 4 concentrations in maternal plasma may play a role in accelerated fetal growth in the absence of overt carbohydrate intolerance.
doi:10.1515/JPM.2010.044
PMCID: PMC3426355  PMID: 20146659
metabolism; pregnancy; appropriate-for-gestational-age (AGA); adipokine; cytokine; adipose tissue; BMI; overweight; obesity; insulin resistance; insulin sensitivity
4.  Bone metabolism compensates for the delayed growth in small for gestational age neonates 
Organogenesis  2013;9(1):55-59.
The goal of the present study is to investigate the relationship between anthropometric and bone metabolism markers in a sample of neonates and their mothers. A sample of 20 SGA (small for the gestational age), AGA (appropriate for the gestational age) and LGA (large for the gestational age) term neonates and their 20 mothers was analyzed at birth and at exit. Elisa method was used to measure the OPG (Osteoprotegerin), RANK (Receptor activator of nuclear factor-kappaB), RANKL (Receptor activator of nuclear factor-kappaB Ligand), IGF-1 (Insulin-like growth factor 1), IGFBP3 (Insulin-like Growth Factor Binding Protein 3) and Leptin levels. Birth weight and length were positively correlated with RANKL, IGF-1 and IGFBP3 and negatively with the ratio OPG/RANKL. SGA neonates presented lower RANKL values and higher OPG/RANKL ratio while LGA neonates had higher RANK levels than AGA neonates. Positive association was shown between neonatal IGFBP3 and maternal IGF-1 values and between neonatal and maternal RANK values at birth and at exit. These results reveal a remarkable upregulation of OPG/RANKL ratio in SGA neonates, pointing out the role of bone turnover in compensating for the delayed neonatal growth.
doi:10.4161/org.24251
PMCID: PMC3674041  PMID: 23538775
Leptin; neonates; RANKL; OPG; IGF-1
5.  VISFATIN IN HUMAN PREGNANCY: MATERNAL GESTATIONAL DIABETES VIS-À-VIS NEONATAL BIRTHWEIGHT 
Journal of perinatal medicine  2009;37(3):218-231.
Objective
Adipose tissue dysfunction, characterized by dysregulation of adipokines production and/or secretion, has been implicated in the pathophysiology of type-2 diabetes mellitus, a metabolic complication closely related to gestational diabetes mellitus (GDM). Recently, an association between circulating maternal visfatin, a novel adipokine with metabolic and immunoregulatory properties, and impaired glucose metabolism as well as with altered fetal growth, has been proposed. The aims of this study were to determine whether there is an association between maternal plasma visfatin concentration, GDM, and a large-for-gestational-age (LGA) newborn.
Study design
This cross-sectional study, included pregnant women at term in the following groups: 1) normal pregnancy and an appropriate-for-gestational-age (AGA) neonate (n=54); 2) normal pregnancy and an LGA newborn (n=47); 3) GDM and an AGA newborn (n=56); 4) GDM and an LGA newborn (n=45). The study population was further stratified by first trimester BMI (<25 vs. ≥25 kg/m2). Maternal plasma visfatin concentration was determined by ELISA. Parametric and non-parametric statistics were used for analysis.
Results
1) Among women who delivered an AGA neonate, the median maternal plasma concentration of visfatin was higher in patients with GDM than in those with a normal pregnancy; 2) Among women with a normal pregnancy, those who delivered an LGA neonate had a higher median maternal plasma visfatin concentration than those who delivered an AGA neonate; 3) among patients with normal BMI, there were no significant differences in the median maternal plasma visfatin concentration between the four study groups; and 4) maternal GDM, as well as delivery of an LGA neonate were independently associated with a higher maternal plasma visfatin concentrations.
Conclusion
The linkage between increased maternal circulating visfatin and the presence of GDM or delivery of an LGA neonate supports the hypothesis that perturbation of adipokines homeostasis may play a role in the pathophysiology of GDM or excess fetal growth.
doi:10.1515/JPM.2009.053
PMCID: PMC3504974  PMID: 19099366
Visfatin; gestational diabetes mellitus (GDM); large-for-gestational-age (LGA); appropriate-for-gestational-age (AGA); pre-B cell colony-enhancing factor (PBEF); adipokine; adipose tissue
6.  The paternal role in pre-eclampsia and giving birth to a small for gestational age infant; a population-based cohort study 
BMJ Open  2012;2(4):e001178.
Objective
To estimate the effect of partner change on risks of pre-eclampsia and giving birth to a small for gestational age infant.
Design
Prospective population study.
Setting
Sweden.
Participants
Women with their first and second successive singleton births in Sweden between 1990 and 2006 without pregestational diabetes and/or hypertension (n=446 459).
Outcome measures
Preterm (<37 weeks) and term (≥37 weeks) pre-eclampsia, and giving birth to a small for gestational age (SGA) infant. Risks were adjusted for interpregnancy interval, maternal age, body mass index, height and smoking habits in second pregnancy, years of involuntary childlessness before second pregnancy, mother's country of birth, years of formal education and year of birth. Further, when we calculated risks of SGA we restricted the study population to women with non-pre-eclamptic pregnancies.
Results
In women who had a preterm pre-eclampsia in first pregnancy, partner change was associated with a strong protective effect for preterm pre-eclampsia recurrence (OR 0.24; 95% CI 0.07 to 0.88). Similarly, partner change was also associated with a protective effect of recurrence of SGA birth (OR 0.75; 95% CI 0.67 to 0.84). In contrast, among women without SGA in first birth, partner change was associated with an increased risk of SGA in second pregnancy. Risks of term pre-eclampsia were not affected by partner change.
Conclusions
There is a paternal effect on risks of preterm pre-eclampsia and giving birth to an SGA infant.
doi:10.1136/bmjopen-2012-001178
PMCID: PMC3432846  PMID: 22936817
7.  Impact of Insulin Resistance on Insulin-Like Growth Factor-1/Insulin Like Growth Factor-Binding Protein-3 Axis and on Early Weight Gain in Small for Gestational Age Infants 
Objective: To assess insulin-like growth factor-1 (IGF-1)/IGF-binding protein-3 (IGFBP-3) axis and insulin resistance (IR) and the relationship of these parameters with growth in appropriate for gestational age (AGA) and small for gestational age (SGA) infants at birth and in early infancy.
Methods: Postnatal blood samples for measurement of glucose, insulin, IGF-1, and IGFBP-3 were taken from 60 infants (30 AGA and 30 SGA) at birth and at one, three, and six months of age. Both SGA and AGA infants were divided into two groups: growing well and not growing well. Blood glucose, insulin, IGF-1, and IGFBP-3 values were assessed in all infants.
Results: Homeostasis model assessment-IR (HOMA-IR) values in well-growing SGA infants in the third and sixth months were found to be higher than in not well-growing SGA infants (3.9±0.8 vs. 1.0±0.3 at 3 months and 3.3±0.9 vs. 2.4±0.9 at 6 months, p<0.05). IGF-1 levels in well-growing SGA infants at 3 and 6 months were found to be higher than those in not well-growing SGA infants (83.80±44.50 vs. 73.50±17.60 ng/mL at 3 months and 95.12±50.74 vs. 87.67±22.91 ng/mL at 6 months, p<0.05). The IGF-1 values were significantly lower in well-growing SGA infants than in well-growing AGA infants (83.80±44.50 vs. 103.31±30.81 ng/mL at 3 months and 95.12±50.74 vs. 110.87±26.44 ng/mL at 6 months, p<0.05).
Conclusions: This study demonstrates the effects of accelerated early infant growth on IGF-1/IGFBP-3 axis in SGA-born infants.
Conflict of interest:None declared.
doi:10.4274/Jcrpe.867
PMCID: PMC3701915  PMID: 23748063
Well-growing; insulin-like growth factor/IGFBP-3 axis; insulin resistance; small for gestational
8.  Thyroid Function in Small for Gestational Age Newborns: A Review 
Several studies have shown that small for gestational age (SGA) babies have a different hormonal profile than those born with a birth weight appropriate for gestational age (AGA). Thyroid hormones play an important role in growth and neurocognitive development. Only few studies analyzed the concentrations of thyroid-stimulating hormone (TSH) and thyroxine (T4) during fetal and extrauterine life in SGA and AGA newborns, and the existing data on the possible alterations of these hormones in postnatal life are controversial. It remains to be established whether SGA newborns have different blood concentrations of thyroid hormones as compared with AGA infants and if so, whether these findings play a role in the development of obesity, short stature, hypertension, and diabetes - disorders, already known to be related with SGA birth. It has also not yet been established whether and when substitutive therapy with levothyroxine (LT4) should be initiated in preterm and full-term SGA newborns. Further trials are needed to determine the thyroid hormone profile in both preterm and full-term SGA newborns and also to evaluate the effectiveness and safety of LT4 treatment in these infants.
Conflict of interest:None declared.
doi:10.4274/Jcrpe.846
PMCID: PMC3608011  PMID: 23149390
small for gestational age; SGA; thyroid function
9.  Leptin and metabolic hormones in infants of diabetic mothers 
Ng, P | Lam, C | Lee, C | Wong, G | Fok, T | Wong, E | Ma, K | Chan, I
AIMS—To investigate the effect of maternal diabetes on leptin in term newborns and to determine whether leptin correlates with insulin and its associated biochemical parameters in support of the hypothesis that a functional "adipoinsular axis" might exist at this stage of development.
METHODS—A total of 116 term newborns were prospectively enrolled and categorised into three groups: 44 were infants of non-diabetic mothers (control group C); 41 were infants born to mothers with gestational diabetes on dietary treatment (group D); and 31 were infants born to mothers with gestational or pregestational diabetes on insulin treatment (group I).
RESULTS—No significant difference in serum leptin was observed between the three groups; the results of the study population were therefore pooled and analysed. Serum leptin correlated significantly with serum insulin, insulin:glucose ratio, birth weight, body length, body mass index, placenta weight, and maternal HbA1c. Female infants had significantly higher serum leptin than male infants. All parameters except placenta weight and body length remained significantly associated with serum leptin when multivariate stepwise regression analysis was applied. Subgroup analysis revealed a significant correlation between serum leptin and cortisol in group D.
CONCLUSIONS—There was no significant difference in serum leptin between infants born to diabetic and non-diabetic mothers, though infants born to mothers requiring insulin treatment had the highest median serum leptin concentrations. The significant association between serum leptin and insulin or insulin:glucose ratio supports the hypothesis that a functional adipoinsular axis might exist in term newborns. Furthermore, the significant correlation between maternal HbA1c and circulating leptin of the studied infants suggests that the clinical control of maternal diabetes could affect the regulation of serum leptin in these infants.

An active "adipoinsular axis" is likely to exist in term newborns. The clinical control of maternal diabetes may affect the regulation of serum leptin and possibly may also influence the growth of the fetus in utero
doi:10.1136/fn.83.3.F193
PMCID: PMC1721166  PMID: 11040167
10.  Serum Levels of Receptors for Advanced Glycation End Products in Normal-Weight and Obese Children Born Small and Large for Gestational Age 
Diabetes Care  2012;35(6):1361-1363.
OBJECTIVE
To assess potential alterations in soluble and endogenous secretory receptors for advanced glycation end products (sRAGE and esRAGE) in normal-weight (NW) and obese (Ob) children born small (SGA) and large (LGA) compared with appropriate for gestational age (AGA) subjects and to explore if birth weight (BW), insulin resistance (IR), and obesity represent independent risk factors.
RESEARCH DESIGN AND METHODS
We categorized 130 prepubertal children into six groups according to BW and obesity and evaluated sRAGE, esRAGE, and homeostasis model assessment of IR.
RESULTS
sRAGE and esRAGE were lower in Ob SGA and LGA children than Ob AGA subjects (all P < 0.05), and in NW SGA and LGA children than NW AGA subjects (all P < 0.05). Interestingly, BW and IR were significantly and independently related to RAGE.
CONCLUSIONS
sRAGE and esRAGE are decreased in SGA and LGA children, and BW and IR seem to play an important role in the reduction of RAGE.
doi:10.2337/dc11-2302
PMCID: PMC3357256  PMID: 22511256
11.  Aorta Structural Alterations in Term Neonates: The Role of Birth and Maternal Characteristics 
BioMed Research International  2013;2013:459168.
Aim. To evaluate the influence of selected maternal and neonatal characteristics on aorta walls in term, appropriately grown-for-gestational age newborns. Methods. Age, parity, previous abortions, weight, height, body mass index before and after delivery, smoking, and history of hypertension, of diabetes, of cardiovascular diseases, and of dyslipidemia were all assessed in seventy mothers. They delivered 34 males and 36 females healthy term newborns who underwent ultrasound evaluation of the anteroposterior infrarenal abdominal aorta diameter (APAO), biochemical profile (glucose, insulin, total cholesterol, HDL and LDL cholesterol, triglycerides, fibrinogen, and D-dimers homeostasis model assessment [HOMAIR]index), and biometric parameters. Results. APAO was related to newborn length (r = +0.36; P = 0.001), head circumference (r = +0.37; P = 0.001), gestational age (r = +0.40, P = 0.0005), HOMA index (r = +0.24; P = 0.04), and D-dimers (r = +0.33, P = 0.004). Smoke influenced APAO values (odds ratio: 1.80; confidence interval 95%: 1.05–3.30), as well as diabetes during pregnancy (r = +0.42, P = 0.0002). Maternal height influenced neonatal APAO (r = +0.47, P = 0.00003). Multiple regression analysis outlined neonatal D-dimers as still significantly related to neonatal APAO values. Conclusions. Many maternal and neonatal characteristics could influence aorta structures. Neonatal D-dimers are independently related to APAO.
doi:10.1155/2013/459168
PMCID: PMC3741912  PMID: 23984364
12.  Oxidative stress in term small for gestational age neonates born to undernourished mothers: a case control study 
BMC Pediatrics  2004;4:14.
Background
The objective of this study was to assess the status of oxidative stress in term small for gestational age (SGA) newborn infants born to undernourished mothers by estimating levels of erythrocyte superoxide dismutase (SOD), catalase, reduced glutathione, and serum malondialdehyde (MDA) in cord blood and comparing them to healthy appropriate for gestational age (AGA) controls. This was done in a case control design at a tertiary level teaching hospital.
Methods
We included 20 singleton healthy SGA newborn infants born between 38–40 weeks to undernourished mothers with a) post-pregnancy weight < 50 kg or height < 145 cm AND b) hemoglobin < 8.0 g/dL or serum albumin < 2.5 g/dL. An equal number of age and sex matched AGA newborn infants born to healthy mothers served as Controls. Mothers with other risk factors and newborns with complications during delivery or immediate newborn period were excluded. MDA, SOD, catalase and reduced glutathione were measured in the cord blood of all neonates and compared between the groups (unpaired t test); levels were also correlated to maternal weight, height, hemoglobin, and albumin by both univariate (pearsonian correlation) and multivariate (multiple regression) analysis.
Results
The activity of MDA was increased (5.33 ± 0.72 vs 2.55 ± 0.22 nmol/mL; P < 0.0001) while levels of superoxide dismutase (493.6 ± 54.9 vs. 786.8 ± 79.1 U/g Hb; P < 0.0001), catalase (1.48 ± 0.24 vs. 2.31 ± 0.20 U/g Hb; P < 0.0001) and reduced glutathione (2.84 ± 0.37 vs 6.42 ± 0.23 Umol/g Hb, P < 0.0001) were decreased in term SGA born to undernourished mothers as compared to term AGA born to healthy mothers. On univariate analysis, all the markers of oxidative stress correlated significantly with maternal parameters (P < 0.005). On multivariate analysis, maternal albumin and hemoglobin accounted for maximum correlation with the markers of oxidative stress.
Conclusions
Intrauterine malnutrition is associated with significant oxidative stress in small for gestational age neonates born at term to malnourished mothers.
doi:10.1186/1471-2431-4-14
PMCID: PMC487903  PMID: 15260886
13.  Fetal macrosomia related to maternal poorly controlled type 1 diabetes strongly impairs serum lipoprotein concentrations and composition 
Journal of Clinical Pathology  2000;53(12):917-923.
Aims—To determine the effects of fetal macrosomia related to maternal type 1 diabetes on the lipid transport system.
Methods—Serum lipoprotein concentrations and composition and lecithin:cholesterol acyltransferase (LCAT) activity were investigated in macrosomic newborns (mean birth weight, 4650 g; SEM, 90) and their mothers with poorly controlled type 1 diabetes, in appropriate for gestational age newborns (mean birth weight, 3616 g; SEM, 68) and their mothers with well controlled type 1 diabetes, and macrosomic (mean birth weight, 4555 g; SEM, 86) or appropriate for gestational age (mean birth weight, 3290 g; SEM, 45) newborns and their healthy mothers.
Results—In mothers with well controlled type 1 diabetes, serum lipids, apolipoproteins, and lipoproteins were comparable with those of healthy mothers. Similarly, in their infants, these parameters did not differ from those of appropriate for gestational age newborns. Serum triglyceride, very low density lipoprotein (VLDL), apolipoprotein B100 (apo B100), and high density lipoprotein (HDL) triglyceride concentrations were higher, whereas serum apo A-I and HDL3 concentrations were lower in mothers with diabetes and poor glycaemic control than in healthy mothers. Their macrosomic newborns had higher concentrations in all serum lipids and lipoproteins, with high apo A-I and apo B100 values compared with appropriate for gestational age newborns. In macrosomic infants of healthy mothers, there were no significant differences in lipoprotein profiles compared with those of appropriate for gestational age infants. LCAT activity was similar in both groups of mothers and newborns.
Conclusion—Poorly controlled maternal type 1 diabetes and fetal macrosomia were associated with lipoprotein abnormalities. Macrosomic lipoprotein profiles related to poor metabolic control of type 1 diabetes appear to have implications for later metabolic diseases.
Key Words: apolipoproteins • lipids • lipoproteins • lecithin:cholesterol acyltransferase • fetal macrosomia • maternal type 1 diabetes
doi:10.1136/jcp.53.12.917
PMCID: PMC1731132  PMID: 11265176
14.  Markers of collagen metabolism and insulin-like growth factor binding protein-1 in term infants 
AIM—To study the relation between fetal growth and markers of collagen metabolism and insulin-like growth factor binding protein-1 (IGFBP-1) in term infants.
METHODS—Cord vein plasma was obtained from 67 term infants of gestational age 37.1-41.7 weeks (39 appropriate for gestational age (AGA), 11 large for gestational age (LGA; relative birth weight ⩾ 2.0 SD), and 17 small for gestational age (SGA; relative birth weight ⩽ −2.0 SD)) for analysis of markers of metabolism of collagen type I (PICP and ICTP) and III (PIIINP) and of IGFBP-1.
RESULTS—Negative correlations existed between gestational age and PICP (r = −0.294, p = 0.0158), ICTP (r = −0.338, p = 0.0052), and PIIINP (r = −0.432, p = 0.0003). These correlations were also found in SGA infants (all p < 0.05). IGFBP-1 showed negative correlations with birth weight and relative birth weight (r = −0.644, p = 0.0001, and r = −0.693, p = 0.0001 respectively) but not with gestational age (p>0.05).
CONCLUSIONS—In the term fetus, collagen metabolism is primarily dependent on maturity and not on intrauterine growth status, whereas IGFBP-1 reflects intrauterine growth independently of maturity.


doi:10.1136/fn.83.1.F17
PMCID: PMC1721109  PMID: 10873165
15.  Comparisons of mortality and pre-discharge respiratory outcomes in small-for-gestational-age and appropriate-for-gestational-age premature infants 
BMC Pediatrics  2004;4:9.
Background
There are differences in the literature regarding outcomes of premature small-for-gestational-age (SGA) and appropriate-for gestational-age (AGA) infants, possibly due to failure to take into account gestational age at birth.
Objective
To compare mortality and respiratory morbidity of SGA and AGA premature newborn infants.
Design/Methods
A retrospective study was done of the 2,487 infants born without congenital anomalies at ≤36 weeks of gestation and admitted to the neonatal intensive care unit (NICU) at John Dempsey Hospital, between Jan. 1992 and Dec. 1999. Recent (1994–96) U.S. birth weight percentiles for gestational age (GA), race and gender were used to classify neonates as SGA (<10th percentile for GA) or AGA (10th–90th percentile for GA). Using multivariate logistic regression and survival analyses to control for GA, SGA and AGA infants were compared for mortality and respiratory morbidity.
Results
Controlling for GA, premature SGA infants were at a higher risk for mortality (Odds ratio 3.1, P = 0.001) and at lower risk of respiratory distress syndrome (OR = 0.71, p = 0.02) than AGA infants. However multivariate logistic regression modeling found that the odds of having respiratory distress syndrome (RDS) varied between SGA and AGA infants by GA. There was no change in RDS risk in SGA infants at GA ≤ 32 wk (OR = 1.27, 95% CI 0.32 – 1.98) but significantly decreased risk for RDS at GA > 32 wk (OR = 0.41, 95% CI 0.27 – 0.63; p < 0.01). After controlling for GA, SGA infants were observed to be at a significantly higher risk for developing chronic lung disease as compared to AGA infants (OR = 2.2, 95% CI = 1.2 – 3.9, P = 0.01). There was no significant difference between SGA and AGA infants in total days on ventilator. Among infants who survived, mean length of hospital stay was significantly higher in SGA infants born between 26–36 wks GA than AGA infants.
Conclusions
Premature SGA infants have significantly higher mortality, significantly higher risk of developing chronic lung disease and longer hospital stay as compared to premature AGA infants. Even the reduced risk of RDS in infants born at ≥32 wk GA, (conferred possibly by intra-uterine stress leading to accelerated lung maturation) appears to be of transient effect and is counterbalanced by adverse effects of poor intrauterine growth on long term pulmonary outcomes such as chronic lung disease.
doi:10.1186/1471-2431-4-9
PMCID: PMC434508  PMID: 15186501
16.  Birth weight- and fetal weight-growth restriction: impact on neurodevelopment 
Early human development  2012;88(9):765-771.
Background
The newborn classified as growth-restricted on birth weight curves, but not on fetal weight curves, is classified prenatally as small for gestational age (SGA), but postnatally as appropriate for gestational age (AGA).
Aims
To see (1) to what extent the neurodevelopmental outcomes at 24 months corrected age differed among three groups of infants (those identified as SGA based on birth weight curves (B-SGA), those identified as SGA based on fetal weight curves only (F-SGA), and the referent group of infants considered AGA, (2) if girls and boys were equally affected by growth restriction, and (3) to what extent neurosensory limitations influenced what we found.
Study design
Observational cohort of births before the 28 week of gestation. Outcome measures: Mental Development Index (MDI) and Psychomotor Development Index (PDI) of the Bayley Scales of Infant Development II.
Results
B-SGA, but not F-SGA girls were at an increased risk of a PDI < 70 (OR=2.8; 95% CI: 1.5, 5.3) compared to AGA girls. B-SGA and F-SGA boys were not at greater risk of low developmental indices than AGA boys. Neurosensory limitations diminished associations among girls of B-SGA with low MDI, and among boys B-SGA and F-SGA with PDI < 70.
Conclusions
Only girls with the most severe growth restriction were at increased risk of neurodevelopmental impairment at 24 months corrected age in the total sample. Neurosensory limitations appear to interfere with assessing growth restriction effects in both girls and boys born preterm.
doi:10.1016/j.earlhumdev.2012.04.004
PMCID: PMC3694609  PMID: 22732241
17.  Two hour blood glucose levels in at-risk babies: An audit of Canadian guidelines 
Paediatrics & Child Health  2009;14(4):238-244.
BACKGROUND:
The Canadian guidelines recommend blood glucose (BG) screening starting at 2 h of age in asymptomatic ‘at-risk’ babies (including small-for-gestational-age [SGA] and large-for-gestational-age [LGA] infants), with intervention cut-offs of 1.8 mmol/L and 2.6 mmol/L. The present study reviews and audits this practice in full-term newborn populations.
METHODS:
A literature review meta-analyzed BG values in appropriate-for-gestational age (AGA) term newborns to establish normal 1 h, 2 h and 3 h values. A clinical review audited screening of ‘at-risk’ SGA and LGA term newborns, evaluating both clinical burden and validity.
RESULTS:
The review included six studies, although none clearly defined the plasma glucose standard. The pooled mean (plasma) BG level in AGA babies 2 h of age was 3.35 mmol/L (SD=0.77), significantly higher than 1 h levels (3.01 mmol/L, SD=0.96). In the audit, 78 SGA and 142 LGA babies each had an average of 6.0 and 4.7 BG tests, respectively. The mean 2 h BG levels for SGA (3.42 mmol/L, SD=1.02) and LGA (3.31 mmol/L, SD=0.66) babies did not differ significantly from the AGA pooled mean. Receiver operating characteristic curves showed that 2 h BG levels in LGA and SGA babies predicted later hypoglycemia (defined as a BG level lower than 2.6 mmol/L), but sensitivities and specificities were poor.
CONCLUSIONS:
Published 2 h BG levels for AGA babies are higher than 1 h values and are similar to audited 2 h levels in SGA and LGA babies. Clinically, 2 h levels are predictive of later hypoglycemia but may require repeat BG testing. Audit is an important tool to validate national guidelines, to minimize their burden and to maximize their utility.
PMCID: PMC2690537  PMID: 20357922
Blood glucose; Hypoglycemia; Large for gestational age; Neonatal; Normal values; Plasma glucose; Small for gestational age
18.  Association of Second and Third Trimester Weight Gain in Pregnancy with Maternal and Fetal Outcomes 
PLoS ONE  2013;8(1):e54704.
Objective
To investigate the association between weekly weight gain, during the second and third trimesters, classified according to the 2009 Institute of Medicine (IOM/NRC) recommendations, and maternal and fetal outcomes.
Methods
Gestational weight gain was evaluated in 2,244 pregnant women of the Brazilian Study of Gestational Diabetes (Estudo Brasileiro do Diabetes Gestacional – EBDG). Outcomes were cesarean delivery, preterm birth and small or large for gestational age birth (SGA, LGA). Associations between inadequate weight gain and outcomes were estimated using robust Poisson regression adjusting for pre-pregnancy body mass index, trimester-specific weight gain, age, height, skin color, parity, education, smoking, alcohol consumption, gestational diabetes and hypertensive disorders in pregnancy.
Results
In fully adjusted models, in the second trimester, insufficient weight gain was associated with SGA (relative risk [RR] 1.72, 95% confidence interval [CI] 1.26–2.33), and excessive weight gain with LGA (RR 1.64, 95% CI 1.16–2.31); in third trimester, excessive weight gain with preterm birth (RR 1.70, 95% CI 1.08–2.70) and cesarean delivery (RR 1.21, 95% CI 1.03–1.44). Women with less than recommended gestational weight gain in the 2nd trimester had a lesser risk of cesarean deliveries (RR 0.82, 95% CI 0.71–0.96) than women with adequate gestational weight gain in this trimester.
Conclusion
Though insufficient weight gain in the 3rd trimester was not associated with adverse outcomes, other deviations from recommended weight gain during second and third trimester were associated with adverse pregnancy outcomes. These findings support, in part, the 2009 IOM/NRC recommendations for nutritional monitoring during pregnancy.
doi:10.1371/journal.pone.0054704
PMCID: PMC3559868  PMID: 23382944
19.  Maternal and Pregnancy Related Predictors of Cardiometabolic Traits in Newborns 
PLoS ONE  2013;8(2):e55815.
Background
The influence of multiple maternal and pregnancy characteristics on offspring cardiometabolic traits at birth is not well understood and was evaluated in this study.
Methods and Findings
The Family Atherosclerosis Monitoring In earLY life (FAMILY) Study prospectively evaluated 11 cardiometabolic traits in 901 babies born to 857 mothers. The influence of maternal age, health (pre-pregnancy weight, blood pressure, glycemic status, lipids), health behaviors (diet, activity, smoking) and pregnancy characteristics (gestational age at birth, gestational weight gain and placental-fetal ratio) were examined. Greater gestational age influenced multiple newborn cardiometabolic traits including cord blood lipids, glucose and insulin, body fat and blood pressure. In a subset of 442 singleton mother/infant pairs, principal component analysis grouped 11 newborn cardiometabolic traits into 5 components (anthropometry/insulin, 2 lipid components, blood pressure and glycemia), accounting for 74% of the variance of the 11 outcome variables. Determinants of these components, corrected for sex and gestational age, were examined. Baby anthropometry/insulin was independently predicted by higher maternal pre-pregnancy weight (standardized estimate 0.30) and gestational weight gain (0.30; both p<0.0001) and was inversely related to smoking during pregnancy (−0.144; p = 0.01) and maternal polyunsaturated to saturated fat intake (−0.135;p = 0.01). Component 2 (HDL-C/Apo Apolipoprotein1) was inversely associated with maternal age. Component 3 (blood pressure) was not clustered with any other newborn cardiometabolic trait and no associations with maternal pregnancy characteristics were identified. Component 4 (triglycerides) was positively associated with maternal hypertension and triglycerides, and inversely associated with maternal HDL and age. Component 5 (glycemia) was inversely associated with placental/fetal ratio (−0.141; p = 0.005). LDL-C was a bridging variable between the lipid factors and glycemia.
Conclusions
Maternal health, health behaviours and placenta to fetal weight ratio are associated with newborn cardiometabolic traits over and above gestational age. Future investigations are needed to determine if these factors remain important determinants of cardiometabolic health throughout childhood.
doi:10.1371/journal.pone.0055815
PMCID: PMC3572188  PMID: 23418462
20.  Leisure-time Physical Activity in Pregnancy and the Birth Weight Distribution: Where is the effect? 
BACKGROUND
Leisure-time physical activity (LTPA) is recommended during pregnancy and has been associated with lower risk of delivering a large infant. We sought to characterize the effect of LTPA across the entire birth weight distribution.
METHODS
Women enrolled in the Pregnancy Outcomes and Community Health (POUCH) Study (1998–2004) were followed-up in 2007. Follow-up efforts were extensive for a subcohort and minimal for the remainder (non-subcohort). Thus, 596 subcohort and 418 non-subcohort women who delivered at term participated. Offspring were categorized as small-, appropriate-, or large-for-gestational-age (SGA, AGA, and LGA, respectively) based on gender and gestational age-specific birth weight z-scores (BWz). At follow-up, women recalled pregnancy LTPA and were classified as inactive, insufficiently active or meeting LTPA recommendations. Linear, logistic, and quantile regression analyses were conducted separately by subcohort status.
RESULTS
Meeting LTPA recommendations decreased odds of LGA significantly among the non-subcohort (aOR=0.30, 95%CI: 0.14–0.64) and non-significantly among the subcohort (aOR=0.68, 95%CI: 0.34–1.34). In quantile regression, meeting LTPA recommendations reduced BWz among the upper quantiles in the non-subcohort.
CONCLUSIONS
LTPA during pregnancy lowered odds of LGA and reduced BWz among the upper quantiles, without shifting the entire distribution. LTPA during pregnancy may be useful for reducing risks of large fetal size.
PMCID: PMC4051283  PMID: 22207373
exercise; prenatal; maternal; fetal macrosomia; cohort studies
21.  Maternal nutritional risk factors for small for gestational age babies in a developed country: a case-control study 
Aims: To assess the effect of maternal diet during pregnancy on the risk of delivering a baby who is small for gestational age (SGA).
Methods: Case-control study of 844 cases (SGA) and 870 controls (appropriate size for gestational age (AGA)). Only term (37+ completed weeks of gestation) infants were included. Retrospective food frequency questionnaires were completed at birth on the diet at the time of conception and in the last month of pregnancy.
Results: At the time of conception, mothers of AGA infants ate significantly more servings of carbohydrate rich food and fruit, and were more likely to have taken folate and vitamin supplements than mothers of SGA infants. There was some evidence that mothers of AGA infants also ate more servings of dairy products, meat, and fish (0.05 < p < 0.1). However, after adjustment for maternal ethnicity, smoking, height, weight, hypertension, and occupation, fish intake (p  =  0.04), carbohydrate-rich foods (p  =  0.04), and folate supplementation (p  =  0.02) were associated with a reduced risk of SGA. In the last month of pregnancy, only iron supplementation was associated with a reduced risk of SGA (p  =  0.05) after adjustment for potential confounders.
Conclusions: This study suggests that small variations in maternal diets within the normal range during pregnancy in developed countries are associated with differences in birth weight.
doi:10.1136/adc.2003.036970
PMCID: PMC1721755  PMID: 15321964
22.  Determinants of Insulin Resistance in Infants at Age 1 Year 
Diabetes Care  2012;35(8):1795-1797.
OBJECTIVE
The offspring of women with gestational diabetes mellitus (GDM) display a propensity for the early accrual of cardiometabolic risk factors, including insulin resistance, in childhood and adolescence. Thus, we sought to identify early life determinants of insulin resistance in infants of women with and without GDM.
RESEARCH DESIGN AND METHODS
In total, 104 full-term, singleton infants born to women with (n = 36) and without (n = 68) GDM were evaluated at age 1 year, with insulin resistance assessed by homeostasis model (HOMA-IR).
RESULTS
HOMA-IR at 1 year did not differ between infants born to mothers with and without GDM (P = 0.74). The sole independent predictor of infant HOMA-IR in the non-GDM group was birth weight (t = 3.33, P = 0.002). In contrast, weight gain in the 1st year was the only independent predictor of HOMA-IR in infants of women with GDM (t = 2.19, P = 0.039).
CONCLUSIONS
In the 1st year of life, weight gain in infants born to women with GDM is associated with insulin resistance, unlike in their peers.
doi:10.2337/dc12-0173
PMCID: PMC3402255  PMID: 22699283
23.  Recruiting Latina Families in a Study of Infant Iron Deficiency: A Description of Barriers, Study Adjustments and Review of the Literature 
Background
Maternal minority status is a risk factor for iron deficiency in infancy and pregnancy. Because language and cultural differences may limit research participation, a prospective study examining iron deficiency included maternal minority status as an inclusionary criterion. Cognizant of potential barriers to recruitment, goals were to quantify eligible Latina enrollees and refusals, examine participation barriers, and devise possible solutions.
Methods
Mothers and their full-term newborns were eligible if the women were anemic, diabetic during pregnancy, of minority and/or lower socioeconomic status, and/or delivered an infant outside the average weight range for gestational age. Self-reported ethnicity and reasons for participation refusal were documented.
Results
During the first 18 months, 255 mothers and their infants were enrolled. Based on inclusionary criteria and the percentage of minority women admitted to the birthing center in a year, we anticipated 25% minority enrollees, with 16.3% Latina. Although 27% minority enrollment was obtained, only 8% were Latina (P < 0.01). System barriers, researcher perception barriers, and participant perception barriers were encountered. Over the next 8 months, addressing these recruitment barriers improved Latina enrollment.
Conclusion
Enrollment barriers are significant hurdles to overcome, but with increased understanding and effort, more successful inclusion of Latina families can be achieved.
PMCID: PMC3148080  PMID: 21473510
24.  Genetic factors associated with small for gestational age birth and the use of human growth hormone in treating the disorder 
The term small for gestational age (SGA) refers to infants whose birth weights and/or lengths are at least two standard deviation (SD) units less than the mean for gestational age. This condition affects approximately 3%–10% of newborns. Causes for SGA birth include environmental factors, placental factors such as abnormal uteroplacental blood flow, and inherited genetic mutations. In the past two decades, an enhanced understanding of genetics has identified several potential causes for SGA. These include mutations that affect the growth hormone (GH)/insulin-like growth factor (IGF)-1 axis, including mutations in the IGF-1 gene and acid-labile subunit (ALS) deficiency. In addition, select polymorphisms observed in patients with SGA include those involved in genes associated with obesity, type 2 diabetes, hypertension, ischemic heart disease and deletion of exon 3 growth hormone receptor (d3-GHR) polymorphism. Uniparental disomy (UPD) and imprinting effects may also underlie some of the phenotypes observed in SGA individuals. The variety of genetic mutations associated with SGA births helps explain the diversity of phenotype characteristics, such as impaired motor or mental development, present in individuals with this disorder. Predicting the effectiveness of recombinant human GH (hGH) therapy for each type of mutation remains challenging. Factors affecting response to hGH therapy include the dose and method of hGH administration as well as the age of initiation of hGH therapy. This article reviews the results of these studies and summarizes the success of hGH therapy in treating this difficult and genetically heterogenous disorder.
doi:10.1186/1687-9856-2012-12
PMCID: PMC3511163  PMID: 22587301
Growth hormone; Small for gestational age; Insulin-like growth factor; Acid-labile subunit deficiency; Uniparental disomy
25.  Prothrombotic State, Cardiovascular, and Metabolic Syndrome Risk Factors in Prepubertal Children Born Large for Gestational Age 
Diabetes Care  2010;33(11):2468-2470.
OBJECTIVE
To evaluate metabolic syndrome and cardiovascular disease risk factors in prepubertal children born large for gestational age (LGA) to nondiabetic, nonobese mothers.
RESEARCH DESIGN AND METHODS
At 6–7 years of age, the comparison of various factors was made between 31 LGA and 34 appropriate-for-gestational-age (AGA) children: fibrinogen, antithrombin III, protein C and S, fasting insulin, glucose, homeostasis assessment model of insulin resistance (HOMA-IR) index, adiponectin, leptin, visfatin, IGF-1, IGF-binding protein (IGFBP)-1, IGFBP-3, lipids, and the genetic factors V Leiden G1691A mutation, prothrombin 20210A/G polymorphism, and mutation in the enzyme 5,10-methylenetetrahydrofolate-reductase gene (MTHFR-C677T).
RESULTS
LGA children had higher levels of leptin (P < 0.01), fasting insulin (P < 0.01), and HOMA-IR (P < 0.01), but lower IGFBP-3 (P = 0.0001), fibrinogen (P = 0.0001), and lipoprotein(a) (P < 0.001) than AGA children. Significantly more LGA children were homozygous for the MTHFR-C677T mutation (P = 0.0016).
CONCLUSIONS
Being born LGA to nondiabetic, nonobese mothers is associated with diverse effects on cardiometabolic risk factors at prepuberty.
doi:10.2337/dc10-1190
PMCID: PMC2963515  PMID: 20724652

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