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1.  Cord Blood C-peptide, Insulin, HbA1c, and Lipids Levels in Small- and Large-for-Gestational-Age Newborns 
Background
Small- and large-for-gestational-age (SGA, LGA) newborns are associated with metabolic syndrome in their later life. Cord blood C-peptide, insulin, glycosylated hemoglobin (HbA1c), and lipids levels may be altered in SGA and LGA newborns; however, the results are conflicting. Therefore, this study aimed to determine the effect of cord blood markers on SGA and LGA newborns.
Material/Methods
This was a prospective cohort study and included 2873 term newborns of non-diabetic women. Among these newborns, 83 (2.9%) were SGA, 2236 (77.8%) were appropriate-for-gestational-age (AGA), and 554 (19.3%) were LGA newborns. Cord blood C-peptide, insulin, HbA1c, triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels were measured. The chi-square, Kruskal-Wallis, and Mann-Whitney tests were used to analyze categorical variables and continuous variables, respectively. Multinomial logistic regression analysis was used to determine the independent effect of these variables on SGA and LGA newborns.
Results
Cord serum TG level was significantly higher in the SGA group than in AGA and LGA groups (p<0.05). The LGA group had significantly higher cord serum insulin level than AGA and SGA groups (p<0.05). After adjustment for confounding variables, including maternal age, parity, pre-pregnancy body mass index (BMI), education, annual household income, pregnancy-induced hypertension (PIH), mode of delivery, and newborn sex, high TG and insulin levels remained significantly associated with SGA and LGA newborns, respectively (p<0.05).
Conclusions
High cord serum TG and insulin levels are independently associated with SGA and LGA newborns, respectively.
doi:10.12659/MSM.890929
PMCID: PMC4226317  PMID: 25357084
Lipids; Insulin; Small-For-Gestational Age Newborns; Large-For-Gestational Age Newborns
2.  Fetal Growth and Risk of Stillbirth: A Population-Based Case–Control Study 
PLoS Medicine  2014;11(4):e1001633.
Radek Bukowski and colleagues conducted a case control study in 59 US hospitals to determine the relationship between fetal growth and stillbirth, and find that both restrictive and excessive growth could play a role.
Please see later in the article for the Editors' Summary
Background
Stillbirth is strongly related to impaired fetal growth. However, the relationship between fetal growth and stillbirth is difficult to determine because of uncertainty in the timing of death and confounding characteristics affecting normal fetal growth.
Methods and Findings
We conducted a population-based case–control study of all stillbirths and a representative sample of live births in 59 hospitals in five geographic areas in the US. Fetal growth abnormalities were categorized as small for gestational age (SGA) (<10th percentile) or large for gestational age (LGA) (>90th percentile) at death (stillbirth) or delivery (live birth) using population, ultrasound, and individualized norms. Gestational age at death was determined using an algorithm that considered the time-of-death interval, postmortem examination, and reliability of the gestational age estimate. Data were weighted to account for the sampling design and differential participation rates in various subgroups. Among 527 singleton stillbirths and 1,821 singleton live births studied, stillbirth was associated with SGA based on population, ultrasound, and individualized norms (odds ratio [OR] [95% CI]: 3.0 [2.2 to 4.0]; 4.7 [3.7 to 5.9]; 4.6 [3.6 to 5.9], respectively). LGA was also associated with increased risk of stillbirth using ultrasound and individualized norms (OR [95% CI]: 3.5 [2.4 to 5.0]; 2.3 [1.7 to 3.1], respectively), but not population norms (OR [95% CI]: 0.6 [0.4 to 1.0]). The associations were stronger with more severe SGA and LGA (<5th and >95th percentile). Analyses adjusted for stillbirth risk factors, subset analyses excluding potential confounders, and analyses in preterm and term pregnancies showed similar patterns of association. In this study 70% of cases and 63% of controls agreed to participate. Analysis weights accounted for differences between consenting and non-consenting women. Some of the characteristics used for individualized fetal growth estimates were missing and were replaced with reference values. However, a sensitivity analysis using individualized norms based on the subset of stillbirths and live births with non-missing variables showed similar findings.
Conclusions
Stillbirth is associated with both growth restriction and excessive fetal growth. These findings suggest that, contrary to current practices and recommendations, stillbirth prevention strategies should focus on both severe SGA and severe LGA pregnancies.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Pregnancy is usually a happy time, when the parents-to-be anticipate the arrival of a new baby. But, sadly, about 20% of pregnancies end in miscarriage—the early loss of a fetus (developing baby) that is unable to survive independently. Other pregnancies end in stillbirth—fetal death after 20 weeks of pregnancy (in the US; after 24 weeks in the UK). Stillbirths, like miscarriages, are common. In the US, for example, one in every 160 pregnancies ends in stillbirth. How women discover that their unborn baby has died varies. Some women simply know something is wrong and go to hospital to have their fears confirmed. Others find out when a routine check-up detects no fetal heartbeat. Most women give birth naturally after their baby has died, but if the mother's health is at risk, labor may be induced. Common causes of stillbirth include birth defects and infections. Risk factors for stillbirth include being overweight and smoking during pregnancy.
Why Was This Study Done?
Stillbirths are often associated with having a “small for gestational age” (SGA) fetus. Gestation is the period during which a baby develops in its mother's womb. Gestational age is estimated from the date of the woman's last menstrual period and/or from ultrasound scans. An SGA fetus is lighter than expected for its age based on observed distributions (norms) of fetal weights for gestational age. Although stillbirth is clearly associated with impaired fetal growth, the exact relationship between fetal growth and stillbirth remains unclear for two reasons. First, studies investigating this relationship have used gestational age at delivery rather than gestational age at death as an estimate of fetal age, which overestimates the gestational age of stillbirths and leads to errors in estimates of the proportions of SGA and “large for gestational age” (LGA) stillbirths. Second, many characteristics that affect normal fetal growth are also associated with the risk of stillbirth, and this has not been allowed for in previous studies. In this population-based case–control study, the researchers investigate the fetal growth abnormalities associated with stillbirth using a new approach to estimate gestational age and accounting for the effect of characteristics that affect both fetal growth and stillbirth. A population-based case–control study compares the characteristics of patients with a condition in a population with those of unaffected people in the same population.
What Did the Researchers Do and Find?
The researchers investigated all the stillbirths and a sample of live births that occurred over 2.5 years at 59 hospitals in five US regions. They used a formula developed by the Stillbirth Collaborative Research Network to calculate the gestational age at death of the stillbirths. They categorized fetuses as SGA if they had a weight for gestational age within the bottom 10% (below the 10th percentile) of the population and as LGA if they had a weight for gestational age above the 90th percentile at death (stillbirth) or delivery (live birth) using population, ultrasound, and individualized norms of fetal weight for gestational age. Population norms incorporate weights for gestational age from normal pregnancies and from pregnancies complicated by growth abnormalities, whereas the other two norms include weights for gestational age from normal pregnancies only. Having an SGA fetus was associated with a 3- to 4-fold increased risk of stillbirth compared to having a fetus with “appropriate” weight for gestational age based on all three norms. LGA was associated with an increased risk of stillbirth based on the ultrasound and individualized norms but not the population norms. Being more severely SGA or LGA (below the 5th percentile or above the 95th percentile) was associated with an increased risk of stillbirth.
What Do These Findings Mean?
These findings indicate that, when the time of death is accounted for and norms for weight for gestational age only from uncomplicated pregnancies are used, stillbirth is associated with both restricted and excessive fetal growth. Overall, abnormal fetal growth was identified in 25% of stillbirths using population norms and in about 50% of stillbirths using ultrasound or individualized norms. Although the accuracy of these findings is likely to be affected by aspects of the study design, these findings suggest that, contrary to current practices, strategies designed to prevent stillbirth should focus on identifying both severely SGA and severely LGA fetuses and should use norms for the calculation of weight for gestational age based on normal pregnancies only. Such an approach has the potential to identify almost half of the pregnancies likely to result in stillbirth.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001633.
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on stillbirth
Tommy's, a UK nonprofit organization that funds research into stillbirth, premature birth, and miscarriage and provides information for parents-to-be, also provides information on stillbirth (including personal stories)
The UK National Health Service Choices website provides information about stillbirth (including a video about dealing with grief after a stillbirth)
MedlinePlus provides links to other resources about stillbirth (in English and Spanish)
Information about the Stillbirth Collaborative Research Network is available
doi:10.1371/journal.pmed.1001633
PMCID: PMC3995658  PMID: 24755550
3.  Effect of Maternal Factors and Fetomaternal Glucose Homeostasis on Birth Weight and Postnatal Growth 
Objective:
It is important to identify the possible risk factors for the occurrence of large for gestational age (LGA) in newborns and to determine the effect of birth weight and metabolic parameters on subsequent growth. We aimed to determine the effects of maternal weight, weight gain during pregnancy, maternal hemoglobin A1c (HbA1c), C-peptide and insulin as well as cord C-peptide and insulin levels on birth weight and postnatal growth during the first two years of life.
Methods:
Healthy, non-diabetic mothers and term singleton newborns were included in this prospective case-control cohort study. Fasting maternal glucose, HbA1c, C-peptide and insulin levels were studied. Cord blood was analyzed for C-peptide and insulin. At birth, newborns were divided into two groups according to birth size: LGA and appropriate for GA (AGA). Infants were followed at six-month intervals for two years and their length and weight were recorded.
Results:
Forty LGA and 43 AGA infants were included in the study. Birth weight standard deviation score (SDS) was positively correlated with maternal body mass index (BMI) before delivery (r=0.2, p=0.04) and with weight gain during pregnancy (r=0.2, p=0.04). In multivariate analyses, the strongest association with macrosomia was a maternal C-peptide level >3.85 ng/mL (OR=20). Although the LGA group showed decreased growth by the 6-month of follow-up, the differences between the LGA and AGA groups in weight and length SDS persisted over the 2 years of follow-up.
Conclusion:
The control of maternal BMI and prevention of overt weight gain during pregnancy may prevent excessive birth weight. The effect of the in utero metabolic environment on the weight and length SDS of infants born LGA persists until at least two years of age.
doi:10.4274/jcrpe.1914
PMCID: PMC4677550  PMID: 26831549
birth weight; glucose; insulin; large for gestational age; macrosomia
4.  Maternal Lipids as Strong Determinants of Fetal Environment and Growth in Pregnancies With Gestational Diabetes Mellitus  
Diabetes Care  2008;31(9):1858-1863.
OBJECTIVE—To determine the contribution of maternal glucose and lipids to intrauterine metabolic environment and fetal growth in pregnancies with gestational diabetes mellitus (GDM).
RESEARCH DESIGN AND METHODS—In 150 pregnancies, serum triglycerides (TGs), cholesterol, free fatty acids (FFAs), glycerol, insulin, and glucose were determined in maternal serum and cord blood during the 3rd trimester. Maternal glucose values came from oral glucose tolerance testing and glucose profiles. Measurements of fetal abdominal circumference (AC) were performed simultaneously with maternal blood sampling and birth weight, and BMI and neonatal fat mass were obtained following delivery.
RESULTS—Maternal TGs and FFAs correlated with fetal AC size (at 28 weeks: triglycerides, P = 0.001; FFAs, P = 0.02), and at delivery they correlated with all neonatal anthropometric measures (FFA: birth weight, P = 0.002; BMI, P = 0.001; fat mass, P = 0.01). After adjustment for confounding variables, maternal FFAs and TGs at delivery remained the only parameters independently related to newborns large for gestational age (LGA) (P = 0.008 and P = 0.04, respectively). Maternal FFA levels were higher in mothers with LGA newborns than in those with appropriate for gestational age (AGA) newborns (362.8 ± 101.7 vs. 252.4 ± 10.1, P = 0.002). Maternal levels of TGs, FFAs, and glycerol at delivery correlated with those in cord blood (P = 0.003, P = 0.004, and P = 0.005, respectively). Fetal triglyceride and cholesterol levels were negatively correlated with newborn birth weight (P = 0.001), BMI (P = 0.004), and fat mass (P = 0.001). TGs were significantly higher in small for gestational age (SGA) newborns compared with AGA or LGA newborns, while insulin-to-glucose ratio and FFAs were the highest in LGA newborns.
CONCLUSIONS—In well-controlled GDM pregnancies, maternal lipids are strong predictors for fetal lipids and fetal growth. Infants with abnormal growth seem to be exposed to a distinct intrauterine environment compared with those with appropriate growth.
doi:10.2337/dc08-0039
PMCID: PMC2518359  PMID: 18606978
5.  Assessment of Antepartum Fetal Growth by Customized “GROW” Curves Versus Noncustomized Growth Curves in Correlation with Neonatal Growth Pattern 
Objective
To study the antepartum fetal growth between customized “GROW” curves and noncustomized growth curves with neonatal growth pattern.
Method
Fetal growth scans are performed between 30 and 35 weeks to singleton mother. Estimated fetal weights (EFWs) were determined using ultrasound variables (biparietal diameter, head circumference, abdominal circumference, and femur length). This EFW is plotted on SONOCARE software [noncustomized growth curves developed by Medialogic solutions (P) Ltd., Chennai, India] and customized “GROW” curves to determine the type of antenatal fetal growth as AGA, small for gestational age (SGA), or large for gestational age (LGA). The fetuses were followed longitudinally till birth, and the newborns’ growth patterns were determined according to birth weight at the gestational age of delivery (<10th percentile for gestational age as SGA and >90th percentile as LGA) and compared to antenatal prediction of fetal growth patterns determined by noncustomized growth curves and customized “GROW” curves.
Results
According to noncustomized growth curve at antenatal period, 93 % fetuses are AGA; 5.6 % are LGA, and 1 % are SGA. According to customized GROW curves, when the same EFW is plotted on GROW curves, 83 % are found to be AGA, 6.8 % LGA, and 10 % SGA. At postnatal period, according to newborn growth curve, 87.8 % are AGA, 8.8 % LGA, 3.4 % SGA. Sensitivity of customized “GROW” curves is more than that of noncustomized growth curves (45.45 vs. 18.18 %) for detection of SGA fetus.
Conclusion
Antenatal predictions of SGA baby by ultrasonography can be almost doubled with customized “GROW” curves than noncustomized growth curves. Customized GROW curves also better predict perinatal morbidities like neonatal jaundice and NICU admission. Antenatal serial fetal growth monitoring should be done with customized GROW curves.
doi:10.1007/s13224-014-0514-7
PMCID: PMC4061327  PMID: 24966503
Customized growth curves; Fetal growth
6.  Primary Prevention of Gestational Diabetes Mellitus and Large-for-Gestational-Age Newborns by Lifestyle Counseling: A Cluster-Randomized Controlled Trial 
PLoS Medicine  2011;8(5):e1001036.
In a cluster-randomized trial, Riitta Luoto and colleagues find that counseling on diet and activity can reduce the birthweight of babies born to women at risk of developing gestational diabetes mellitus (GDM), but fail to find an effect on GDM.
Background
Our objective was to examine whether gestational diabetes mellitus (GDM) or newborns' high birthweight can be prevented by lifestyle counseling in pregnant women at high risk of GDM.
Method and Findings
We conducted a cluster-randomized trial, the NELLI study, in 14 municipalities in Finland, where 2,271 women were screened by oral glucose tolerance test (OGTT) at 8–12 wk gestation. Euglycemic (n = 399) women with at least one GDM risk factor (body mass index [BMI] ≥25 kg/m2, glucose intolerance or newborn's macrosomia (≥4,500 g) in any earlier pregnancy, family history of diabetes, age ≥40 y) were included. The intervention included individual intensified counseling on physical activity and diet and weight gain at five antenatal visits. Primary outcomes were incidence of GDM as assessed by OGTT (maternal outcome) and newborns' birthweight adjusted for gestational age (neonatal outcome). Secondary outcomes were maternal weight gain and the need for insulin treatment during pregnancy. Adherence to the intervention was evaluated on the basis of changes in physical activity (weekly metabolic equivalent task (MET) minutes) and diet (intake of total fat, saturated and polyunsaturated fatty acids, saccharose, and fiber). Multilevel analyses took into account cluster, maternity clinic, and nurse level influences in addition to age, education, parity, and prepregnancy BMI. 15.8% (34/216) of women in the intervention group and 12.4% (22/179) in the usual care group developed GDM (absolute effect size 1.36, 95% confidence interval [CI] 0.71–2.62, p = 0.36). Neonatal birthweight was lower in the intervention than in the usual care group (absolute effect size −133 g, 95% CI −231 to −35, p = 0.008) as was proportion of large-for-gestational-age (LGA) newborns (26/216, 12.1% versus 34/179, 19.7%, p = 0.042). Women in the intervention group increased their intake of dietary fiber (adjusted coefficient 1.83, 95% CI 0.30–3.25, p = 0.023) and polyunsaturated fatty acids (adjusted coefficient 0.37, 95% CI 0.16–0.57, p<0.001), decreased their intake of saturated fatty acids (adjusted coefficient −0.63, 95% CI −1.12 to −0.15, p = 0.01) and intake of saccharose (adjusted coefficient −0.83, 95% CI −1.55 to −0.11, p  =  0.023), and had a tendency to a smaller decrease in MET minutes/week for at least moderate intensity activity (adjusted coefficient 91, 95% CI −37 to 219, p = 0.17) than women in the usual care group. In subgroup analysis, adherent women in the intervention group (n = 55/229) had decreased risk of GDM (27.3% versus 33.0%, p = 0.43) and LGA newborns (7.3% versus 19.5%, p = 0.03) compared to women in the usual care group.
Conclusions
The intervention was effective in controlling birthweight of the newborns, but failed to have an effect on maternal GDM.
Trial registration
Current Controlled Trials ISRCTN33885819
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Gestational diabetes mellitus (GDM) is diabetes that is first diagnosed during pregnancy. Like other types of diabetes, it is characterized by high levels of sugar (glucose) in the blood. Blood-sugar levels are normally controlled by insulin, a hormone that the pancreas releases when blood-sugar levels rise after meals. Hormonal changes during pregnancy and the baby's growth demands increase a pregnant woman's insulin needs and, if her pancreas cannot make enough insulin, GDM develops. Risk factors for GDM, which occurs in 2%–14% of pregnant women, include a high body-mass index (a measure of body fat), excessive weight gain or low physical activity during pregnancy, high dietary intake of polyunsaturated fats, glucose intolerance (an indicator of diabetes) or the birth of a large baby in a previous pregnancy, and a family history of diabetes. GDM is associated with an increased rate of cesarean sections, induced deliveries, birth complications, and large-for-gestational-age (LGA) babies (gestation is the time during which the baby develops within the mother). GDM, which can often be controlled by diet and exercise, usually disappears after pregnancy but increases a woman's subsequent risk of developing diabetes.
Why Was This Study Done?
Although lifestyle changes can be used to control GDM, it is not known whether similar changes can prevent GDM developing (“primary prevention”). In this cluster-randomized controlled trial, the researchers investigate whether individual intensified counseling on physical activity, diet, and weight gain integrated into routine maternity care visits can prevent the development of GDM and the occurrence of LGA babies among newborns. In a cluster-randomized controlled trial, groups of patients rather than individual patients are randomly assigned to receive alternative interventions, and the outcomes in different “clusters” are compared. In this trial, each cluster is a municipality in the Pirkanmaa region of Finland.
What Did the Researchers Do and Find?
The researchers enrolled 399 women, each of whom had a normal blood glucose level at 8–12 weeks gestation but at least one risk factor for GDM. Women in the intervention municipalities received intensified counseling on physical activity at 8–12 weeks' gestation, dietary counseling at 16–18 weeks' gestation, and further physical activity and dietary counseling at each subsequent antenatal visits. Women in the control municipalities received some dietary but little physical activity counseling as part of their usual care. 23.3% and 20.2% of women in the intervention and usual care groups, respectively, developed GDM, a nonstatistically significant difference (that is, a difference that could have occurred by chance). However, the average birthweight and the proportion of LGA babies were both significantly lower in the intervention group than in the usual care group. Food frequency questionnaires completed by the women indicated that, on average, those in the intervention group increased their intake of dietary fiber and polyunsaturated fatty acids and decreased their intake of saturated fatty acids and sucrose as instructed during counseling, The amount of moderate physical activity also tended to decrease less as pregnancy proceeded in the intervention group than in usual care group. Finally, compared to the usual care group, significantly fewer of the 24% of women in the intervention group who actually met dietary and physical activity targets (“adherent” women) developed GDM.
What Do These Findings Mean?
These findings indicate that intensified counseling on diet and physical activity is effective in controlling the birthweight of babies born to women at risk of developing GDM and encourages at least some of them to alter their lifestyle. However, the findings fail to show that the intervention reduces the risk of GDM because of the limited power of the study. The power of a study—the probability that it will achieve a statistically significant result—depends on the study's size and on the likely effect size of the intervention. Before starting this study, the researchers calculated that they would need 420 participants to see a statistically significant difference between the groups if their intervention reduced GDM incidence by 40%. This estimated effect size was probably optimistic and therefore the study lacked power. Nevertheless, the analyses performed among adherent women suggest that lifestyle changes might be a way to prevent GDM and so larger studies should now be undertaken to test this potential primary prevention intervention.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001036.
The US National Institute of Diabetes and Digestive and Kidney Diseases provides information for patients on diabetes and on gestational diabetes (in English and Spanish)
The UK National Health Service Choices website also provides information for patients on diabetes and on gestational diabetes, including links to other useful resources
The MedlinePlus Encyclopedia has pages on diabetes and on gestational diabetes; MedlinePlus provides links to additional resources on diabetes and on gestational diabetes (in English and Spanish)
More information on this trial of primary prevention of GDM is available
doi:10.1371/journal.pmed.1001036
PMCID: PMC3096610  PMID: 21610860
7.  Maternal obesity, diabetes mellitus and cord blood biomarkers in large-for-gestational age infants 
Infants born large-for-gestational age (LGA) are at risk for early childhood obesity. The aims of this study were to investigate factors associated with LGA status and their relationship to inflammatory biomarkers that have been implicated in the LGA infant at birth. Included were 364 mother-infant pairs enrolled as part of an ongoing longitudinal cohort study of infant birth weight being conducted at Boston Medical Center (BMC). LGA was defined as birth weight (BW) ≥90th percentile of the reference population at BMC (N=45). Appropriate-for-gestational age (AGA) was defined as BW<90th and >10th percentile (N=319). Cord blood IL-6, IL-8, TNF-alpha and RANTES levels were analyzed from a larger panel of immune biomarkers measured using multiplex immunoassay. Multivariate regression models were used to determine the associations between LGA status, maternal BMI and diabetes (DM), which included either gestational or type 2 diabetes (T2DM), and cord blood biomarkers, with adjustment for important demographic and clinical variables. Maternal pre-pregnancy BMI within the obesity range (≥30 kg/m2), as well as DM, were each associated with increased risk of LGA (OR=2.64, 95%CI 1.31-6.20; OR=5.58, 95%CI 2.06-15.13, respectively). Among the 4 biomarkers, only RANTES (regulated on activation, normal T cell express and secreted upon uptake), which is a chemokine secreted by white adipose tissue, was significantly increased in LGA infants (beta-coefficient=0.37; 95% CI: 0.09, 0.65; P<0.01). This association remained essentially unchanged after adjustment for maternal DM and BMI (beta-coefficient=0.37; 95% CI: 0.08, 0.65; P=0.01). Ponderal index (PI=BW×100/length3) was also positively correlated with RANTES. Cord blood RANTES is selectively elevated with fetal macrosomia, independent of maternal factors. Further investigation of RANTES as a marker of LGA and future childhood health is warranted.
PMCID: PMC3148069  PMID: 21814537
Birth weight; large-for-gestational age; cord blood; inflammation; obesity; diabetes
8.  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
9.  Is Asymmetric Dimethylarginine Associated with Being Born Small and Large for Gestational Age? 
Antioxidants & Redox Signaling  2014;20(15):2317-2322.
Abstract
Low and high birth weights have been linked to increased susceptibility to cardiovascular and metabolic alterations. However, the natural history of cardiometabolic disturbances in children born small (SGA) and large (LGA) for gestational age is still unclear and no reliable biomarker of cardiovascular risk has definitively been identified in these subjects. Interestingly, asymmetric dimethylarginine (ADMA), antagonist of nitric oxide (NO) production, has been recognized as novel cardiovascular marker able to identify subjects at higher risk of health disturbances. Despite the well-described role of ADMA as a predictor of degenerative disease in adults, its potential application in pediatrics, and specifically in SGA and LGA children, has not been explored as only few data in preterm infants and SGA newborns are available. Therefore, we investigated potential alterations in circulating ADMA and NO levels in SGA and LGA children compared with those born appropriate (AGA) for gestational age. Of note, ADMA was significantly higher in SGA and LGA children than AGA peers. Intriguingly, SGA and LGA categories as well as insulin resistance were independently related to ADMA. Our observations lead to the intriguing hypothesis that ADMA could be involved in the development of cardiometabolic alterations in SGA and LGA children already during the prepubertal age. Antioxid. Redox Signal. 20, 2317–2322.
doi:10.1089/ars.2013.5787
PMCID: PMC4005497  PMID: 24350633
10.  Joint and Independent Associations of Gestational Weight Gain and Pre-Pregnancy Body Mass Index with Outcomes of Pregnancy in Chinese Women: A Retrospective Cohort Study 
PLoS ONE  2015;10(8):e0136850.
Objective
To explore the joint and independent effects of gestational weight gain (GWG) and pre-pregnancy body mass index (BMI) on pregnancy outcomes in a population of Chinese Han women and to evaluate pregnant women’s adherence to the 2009 Institute of Medicine (IOM) gestational weight gain guidelines.
Methods
This was a multicenter, retrospective cohort study of 48,867 primiparous women from mainland China who had a full-term singleton birth between January 1, 2011 and December 30, 2011. The independent associations of pre-pregnancy BMI, GWG and categories of combined pre-pregnancy BMI and GWG with outcomes of interest were examined using an adjusted multivariate regression model. In addition, women with pre-pregnancy hypertension were excluded from the analysis of the relationship between GWG and delivery of small-for-gestational-age (SGA) infants, and women with gestational diabetes (GDM) were excluded from the analysis of the relationship between GWG and delivery of large-for-gestational-age (LGA) infants.
Results
Only 36.8% of the women had a weight gain that was within the recommended range; 25% and 38.2% had weight gains that were below and above the recommended range, respectively. The contribution of GWG to the risk of adverse maternal and fetal outcomes was modest. Women with excessive GWG had an increased likelihood of gestational hypertension (adjusted OR 2.55; 95% CI = 1.92–2.80), postpartum hemorrhage (adjusted OR 1.30; 95% CI = 1.17–1.45), cesarean section (adjusted OR 1.31; 95% CI = 1.18–1.36) and delivery of an LGA infant (adjusted OR 2.1; 95% CI = 1.76–2.26) compared with women with normal weight gain. Conversely, the incidence of GDM (adjusted OR 1.64; 95% CI = 1.20–1.85) and SGA infants (adjusted OR 1.51; 95% CI = 1.32–1.72) was increased in the group of women with inadequate GWG. Moreover, in the obese women, excessive GWG was associated with an apparent increased risk of delivering an LGA infant. In the women who were underweight, poor weight gain was associated with an increased likelihood of delivering an SGA infant. After excluding the mothers with GDM or gestational hypertension, the ORs for delivery of LGA and SGA infants decreased for women with high GWG and increased for women with low GWG.
Conclusions
GWG above the recommended range is common in this population and is associated with multiple unfavorable outcomes independent of pre-pregnancy BMI. Obese women may benefit from avoiding weight gain above the range recommended by the 2009 IOM. Underweight women should avoid low GWG to prevent delivering an SGA infant. Pregnant women should therefore be monitored to comply with the IOM recommendations and should have a balanced weight gain that is within a range based on their pre-pregnancy BMI.
doi:10.1371/journal.pone.0136850
PMCID: PMC4552294  PMID: 26313941
11.  Infants born large-for-gestational-age display slower growth in early infancy, but no epigenetic changes at birth 
Scientific Reports  2015;5:14540.
We evaluated the growth patterns of infants born large-for-gestational-age (LGA) from birth to age 1 year compared to those born appropriate-for-gestational-age (AGA). In addition, we investigated possible epigenetic changes associated with being born LGA. Seventy-one newborns were classified by birth weight as AGA (10th–90th percentile; n = 42) or LGA (>90th percentile; n = 29). Post-natal follow-up until age 1 year was performed with clinical assessments at 3, 6, and 12 months. Genome-wide DNA methylation was analysed on umbilical tissue in 19 AGA and 27 LGA infants. At birth, LGA infants had greater weight (p < 0.0001), length (p < 0.0001), ponderal index (p = 0.020), as well as greater head (p < 0.0001), chest (p = 0.044), and abdominal (p = 0.007) circumferences than AGA newborns. LGA infants were still larger at the age of 3 months, but by age 6 months there were no more differences between groups, due to higher length and weight increments in AGA infants between 0 and 6 months (p < 0.0001 and p = 0.002, respectively). Genome-wide analysis showed no epigenetic differences between LGA and AGA infants. Overall, LGA infants had slower growth in early infancy, being anthropometrically similar to AGA infants by 6 months of age. In addition, differences between AGA and LGA newborns were not associated with epigenetic changes.
doi:10.1038/srep14540
PMCID: PMC4588582  PMID: 26419812
12.  Intrauterine growth restriction and congenital malformations: a retrospective epidemiological study 
Background
Intrauterine growth restriction (IUGR) and small for gestational age (SGA) birth have been considered possible indicators of the presence of malformations. The aim of this study is to evaluate such relationships in a population of newborns, along with other epidemiological and auxological parameters, in particular the ponderal index (PI).
Methods
We analyzed the birth data of 1093 infants, classified according to weight for gestational age as SGA, appropriate for gestational age (AGA) or large for gestational age (LGA). The prevalence of malformations was analyzed in relation to weight percentile at birth and SGA birth, maternal smoking, pregnancy diseases and PI.
Results
Our analysis showed no significant relationship between the prevalence of malformations and SGA birth. Maternal smoking and pregnancy diseases were strongly related to SGA birth, but not to a higher prevalence of malformations. PI, however, had a significant relationship with a higher prevalence of malformations, if analyzed as either a continuous variable or a categorical variable (cutoff: < 2.4).
Conclusions
The association between congenital malformations and birth weight for gestational age seems to be weak. As part of diagnostic screening for malformations in the neonatal period, PI could be considered a better predictor of risk than weight percentile.
doi:10.1186/1824-7288-39-23
PMCID: PMC3639199  PMID: 23578323
Congenital malformations; SGA; Weight percentile; Ponderal index
13.  Assessment of ten trace elements in umbilical cord blood and maternal blood: association with birth weight 
Background
Trace elements are an essential nutritional component for humans and inadequate tissue-concentrations may have a significant effect on fetal size.
Objective
To measure ten trace elements in blood samples from mothers and their newborns, and assess their association with anthropometric characteristics at birth. The effects of other factors on fetal growth, such as biologic characteristics of the infant and mother, were analysed.
Methods
A cross-sectional study was conducted in the Hospital general, University of Valencia, Spain. Healthy pregnant women, and their full-term infants were selected (n = 54 paired samples). Infants were grouped according to birth weight: small for gestational age (SGA n = 11), appropriate (AGA n = 30), and large (LGA n = 13). Anthropometric and biologic characteristics of the infant and mother were recorded. Levels of ten essential elements: arsenic (As), barium (Ba), cobalt (Co), copper (Cu), chrome (Cr), iron (Fe), magnesium (Mg), manganese (Mn), selenium (Se) and zinc (Zn), in maternal and cord plasma samples were determined. Samples were obtained from the umbilical cord immediately after delivery and the samples of their mothers were drawn at 2–4 h after delivery.
Results
The analysis identified that cord blood Cu (p = 0.017) and maternal blood Ba and Mg (p = 0.027 and p = 0.002, respectively) concentrations were significantly higher among SGA infants compared to AGA and LGA infants. A multiple linear regression analysis showed that increased umbilical cord Cu concentration (adjusted β −146.4 g, 95 % CI −255 to −37.7; p = 0.009), maternal smoking during pregnancy (adjusted β −483.8 g, 95 % CI −811.7 to −155.9; p = 0.005), shorter gestational age (adjusted β 350.1 g, 95 % CI 244.5 to 455.8; p = 0.000), and female sex (adjusted β −374 g, 95 % CI −648 to −100; p = 0.009) were significantly associated with decreased birth weight. Maternal anaemia was positively associated with birth weight (adjusted β 362 g, 95 % CI 20.8 to 703.1; p = 0.038). No significant associations were found between maternal trace elements and birth weight in multivariate analysis.
Conclusions
We did not observe significant associations of cord blood trace elements other than Cu and maternal trace elements with birth weight in the multivariate analyses.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-015-0654-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s12967-015-0654-2
PMCID: PMC4562355  PMID: 26346609
Trace elements; Umbilical cord blood; Maternal blood; Copper; Birth weight
14.  Progression of Cardio-Metabolic Risk Factors in Subjects Born Small and Large for Gestational Age 
PLoS ONE  2014;9(8):e104278.
Background
Subjects born small (SGA) and large (LGA) for gestational age have an increased risk of cardio-metabolic alterations already during prepuberty. Nevertheless, the progression of their cardio-metabolic profile from childhood to adolescence has not been fully explored. Our aim was to assess potential changes in the cardio-metabolic profile from childhood to adolescence in subjects born SGA and LGA compared to those born appropriate (AGA) for gestational age.
Methods
This longitudinal study included 35 AGA, 24 SGA and 31 LGA subjects evaluated during childhood (mean age (±SD) 8.4±1.4 yr) and then re-assessed during adolescence (mean age 13.3±1.8 yr). BMI, blood pressure, insulin resistance (fasting insulin, HOMA-IR) and lipids were assessed. A cardio-metabolic risk z-score was applied and this consisted in calculating the sum of sex-specific z-scores for BMI, blood pressure, HOMA-IR, triglycerides and triglycerides:high-density lipoprotein cholesterol ratio.
Results
Fasting insulin and HOMA-IR were higher in SGA and LGA than AGA subjects both during childhood (all P<0.01) and adolescence (all P<0.01). Similarly, the clustered cardio-metabolic risk score was higher in SGA and LGA than AGA children (both P<0.05), and these differences among groups increased during adolescence (both P<0.05). Of note, a progression of the clustered cardio-metabolic risk score was observed from childhood to adolescence within SGA and within LGA subjects (both P<0.05).
Conclusions
SGA and LGA subjects showed an adverse cardio-metabolic profile during childhood when compared to AGA peers, with a worsening of this profile during adolescence. These findings indicate an overtime progression of insulin resistance and overall estimated cardiovascular risk from childhood to adolescence in SGA and LGA populations.
doi:10.1371/journal.pone.0104278
PMCID: PMC4130586  PMID: 25117750
15.  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
16.  Effect of different maternal metabolic characteristics on fetal growth in women with gestational diabetes mellitus 
Background: Fetal growth in diabetic pregnancies is a complex process and probably abnormalities in other metabolic pathways such as protein and lipid, as well as carbohydrate are responsible for delivering of macrosomic newborn.
Objective: The purpose of this study was to investigate the association between fetal growth and different maternal metabolic parameters in women with gestational diabetes mellitus (GDM) in comparison to control group.
Materials and Methods: This was a prospective cohort study conducted between March 2011 and May 2012, on 112 pregnant women with GDM and 159 healthy pregnant women. In order to determine of lipids or lipoproteins changes during pregnancy and to investigate any possible effects on fetal growth, lipid components, glucose and insulin levels were obtained in maternal serum three times in third trimester.
Results: Maternal serum glucose, total cholesterol (TC), low and high density lipoprotein (LDL-c, HDL-c) levels did not show any significant difference between two groups. While insulin, homeostasis model assessment-insulin resistance (HOMA-IR) and triglyceride (TG) values were detected to be significantly higher in the GDM cases especially after 32 weeks of gestation (p<0.001). After adjustment for confounding variables, maternal hypertriglyceridemia remained as a significant risk factor for delivering large for gestational age (LGA) newborns (p=0.04); and according to spearman test the increase of TG level was correlated with increase of insulin resistance and HOMA-IR (p<0.001, CI: 0.312).
Conclusion: Due to positive correlation of hypertriglyceridemia and hyperinsulinemia with newborn weight, it is possible to assume that elevated TGs levels in GDM cases is a reflection of variation in maternal insulin levels.
PMCID: PMC3941422  PMID: 24639763
Gestational diabetes mellitus; Macrosomia; Lipid
17.  Impact of Birth Weight and Early Infant Weight Gain on Insulin Resistance and Associated Cardiovascular Risk Factors in Adolescence 
PLoS ONE  2011;6(6):e20595.
Background
Low birth weight followed by accelerated weight gain during early childhood has been associated with adverse metabolic and cardiovascular outcomes later in life. The aim of this study was to examine the impact of early infant weight gain on glucose metabolism and cardiovascular risk factors in adolescence and to study if the effect differed between adolescents born small for gestational age (SGA) vs. appropriate for gestational age (AGA).
Methodology/Principal Findings
Data from 30 SGA and 57 AGA healthy young Danish adolescents were analysed. They had a mean age of 17.6 years and all were born at term. Data on early infant weight gain from birth to three months as well as from birth to one year were available in the majority of subjects. In adolescence, glucose metabolism was assessed by a simplified intravenous glucose tolerance test and body composition was assessed by dual-energy X-ray absorptiometry. Blood pressures as well as plasma concentrations of triglycerides and cholesterol were measured. Early infant weight gain from birth to three months was positively associated with the fasting insulin concentration, HOMA-IR, basal lipid levels and systolic blood pressure at 17 years. There was a differential effect of postnatal weight gain on HOMA-IR in AGA and SGA participants (P for interaction = 0.03). No significant associations were seen between postnatal weight gain and body composition or parameters of glucose metabolism assessed by the simplified intravenous glucose tolerance test. In subgroup analysis, all associations with early infant weight gain were absent in the AGA group, but the associations with basal insulin and HOMA-IR were still present in the SGA group.
Conclusion
This study suggests that accelerated growth during the first three months of life may confer an increased risk of later metabolic disturbances – particularly of glucose metabolism – in individuals born SGA.
doi:10.1371/journal.pone.0020595
PMCID: PMC3107215  PMID: 21655104
18.  Risk Factors and Adverse Perinatal Outcomes among Term and Preterm Infants Born Small-for-Gestational-Age: Secondary Analyses of the WHO Multi-Country Survey on Maternal and Newborn Health 
PLoS ONE  2014;9(8):e105155.
Background
Small for gestational age (SGA) is not only a major indicator of perinatal mortality and morbidity, but also the morbidity risks in later in life. We aim to estimate the association between the birth of SGA infants and the risk factors and adverse perinatal outcomes among twenty-nine countries in Africa, Latin America, the Middle East and Asia in 359 health facilities in 2010–11.
Methods
We analysed facility-based, cross-sectional data from the WHO Multi-country Survey on Maternal and Newborn Health. We constructed multilevel logistic regression models with random effects for facilities and countries to estimate the risk factors for SGA infants using country-specific birthweight reference standards in preterm and term delivery, and SGA’s association with adverse perinatal outcomes. We compared the risks and adverse perinatal outcomes with appropriate for gestational age (AGA) infants categorized by preterm and term delivery.
Results
A total of 295,829 singleton infants delivered were analysed. The overall prevalence of SGA was highest in Cambodia (18.8%), Nepal (17.9%), the Occupied Palestinian Territory (16.1%), and Japan (16.0%), while the lowest was observed in Afghanistan (4.8%), Uganda (6.6%) and Thailand (9.7%). The risk of preterm SGA infants was significantly higher among nulliparous mothers and mothers with chronic hypertension and preeclampsia/eclampsia (aOR: 2.89; 95% CI: 2.55–3.28) compared with AGA infants. Higher risks of term SGA were observed among sociodemographic factors and women with preeclampsia/eclampsia, anaemia and other medical conditions. Multiparity (> = 3) (AOR: 0.88; 95% CI: 0.83–0.92) was a protective factor for term SGA. The risk of perinatal mortality was significantly higher in preterm SGA deliveries in low to high HDI countries.
Conclusion
Preterm SGA is associated with medical conditions related to preeclampsia, but not with sociodemographic status. Term SGA is associated with sociodemographic status and various medical conditions.
doi:10.1371/journal.pone.0105155
PMCID: PMC4132094  PMID: 25119107
19.  PRETERM BIRTH AND FETAL GROWTH RESTRICTION IN HIV-INFECTED BRAZILIAN PREGNANT WOMEN 
Introduction:
Maternal HIV infection and related co-morbidities may have two outstanding consequences to fetal health: mother-to-child transmission (MTCT) and adverse perinatal outcomes. After Brazilian success in reducing MTCT, the attention must now be diverted to the potentially increased risk for preterm birth (PTB) and intrauterine fetal growth restriction (IUGR).
Objective:
To determine the prevalence of PTB and IUGR in low income, antiretroviral users, publicly assisted, HIV-infected women and to verify its relation to the HIV infection stage.
Patients and Methods:
Out of 250 deliveries from HIV-infected mothers that delivered at a tertiary public university hospital in the city of Vitória, state of Espírito Santo, Southeastern Brazil, from November 2001 to May 2012, 74 single pregnancies were selected for study, with ultrasound validated gestational age (GA) and data on birth dimensions: fetal weight (FW), birth length (BL), head and abdominal circumferences (HC, AC). The data were extracted from clinical and pathological records, and the outcomes summarized as proportions of preterm birth (PTB, < 37 weeks), low birth weight (LBW, < 2500g) and small (SGA), adequate (AGA) and large (LGA) for GA, defined as having a value below, between or beyond the ±1.28 z/GA score, the usual clinical cut-off to demarcate the 10th and 90th percentiles.
Results:
PTB was observed in 17.5%, LBW in 20.2% and SGA FW, BL, HC and AC in 16.2%, 19.1%, 13.8%, and 17.4% respectively. The proportions in HIV-only and AIDS cases were: PTB: 5.9 versus 27.5%, LBW: 14.7% versus 25.0%, SGA BW: 17.6% versus 15.0%, BL: 6.0% versus 30.0%, HC: 9.0% versus 17.9%, and AC: 13.3% versus 21.2%; only SGA BL attained a significant difference. Out of 15 cases of LBW, eight (53.3%) were preterm only, four (26.7%) were SGA only, and three (20.0%) were both PTB and SGA cases. A concomitant presence of, at least, two SGA dimensions in the same fetus was frequent.
Conclusions:
The proportions of preterm birth and low birth weight were higher than the local and Brazilian prevalence and a trend was observed for higher proportions of SGA fetal dimensions than the expected population distribution in this small casuistry of newborn from the HIV-infected, low income, antiretroviral users, and publicly assisted pregnant women. A trend for higher prevalence of PTB, LBW and SGA fetal dimensions was also observed in infants born to mothers with AIDS compared to HIV-infected mothers without AIDS.
doi:10.1590/S0036-46652015000200003
PMCID: PMC4435008  PMID: 25923889
Pregnancy; HIV; Infant; Preterm birth; Fetal weight; Low birth weight; Small for gestational age
20.  TCF7L2 rs7903146 variant does not associate with smallness for gestational age in the French population 
BMC Medical Genetics  2007;8:37.
Background
In adults, the TCF7L2 rs7903146 T allele, commonly associated with type 2 diabetes (T2D), has been also associated with a lower body mass index (BMI) in T2D individuals and with a smaller waist circumference in subjects with impaired glucose tolerance.
Methods
The present association study aimed at analyzing the contribution of the rs7903146 SNP to smallness for gestational age (SGA) and metabolic profiles in subjects with SGA or appropriate for gestational age birth weight (AGA). Two groups of French Caucasian subjects were selected on birth data: SGA (birth weight < 10th percentile; n = 764), and AGA (25th < birth weight < 75th percentile; n = 627). Family-based association tests were also performed in 3,012 subjects from 628 SGA and AGA pedigrees.
Results
The rs7903146 genotypic distributions between AGA (30.7%) and SGA (29.0%) were not statistically different (allelic OR = 0.92 [0.78–1.09], p = 0.34). Family association-based studies did not show a distortion of T allele transmission in SGA subjects (p = 0.52). No significant effect of the T allele was detected on any of the metabolic parameters in the SGA group. However, in the AGA group, trends towards a lower insulin secretion (p = 0.03) and a higher fasting glycaemia (p = 0.002) were detected in carriers of the T allele.
Conclusion
The TCF7L2 rs7903146 variant neither increases the risk for SGA nor modulates birth weight and young adulthood glucose homeostasis in French Caucasian subjects born with SGA.
doi:10.1186/1471-2350-8-37
PMCID: PMC1920504  PMID: 17593304
21.  Subtle increases in heart size persist into adulthood in growth restricted babies: the Cardiovascular Risk in Young Finns Study 
Open Heart  2015;2(1):e000265.
Background and objectives
Impaired fetal growth is associated with increased cardiovascular morbidity and mortality in adulthood. We sought to determine whether adults born with intrauterine growth restriction have primary maladaptive changes in cardiac structure.
Methods
Study participants were adults (34–49 years) who attended the 31-year follow-up of the Cardiovascular Risk in Young Finns Study (longitudinal cohort). Transthoracic echocardiograms and demographic and cardiovascular risk surveys were completed for 157 adults born small for gestational age (SGA, birth weight <10th population centile) and 627 born average for gestational age (average for gestational age (AGA), birth weight 50th–90th population centile).
Results
Those born growth restricted had subtly enlarged hearts with indexed left ventricular (LV) end-systolic and end-diastolic diameters slightly greater in the SGA individuals than the AGA group (LVESD 18.7 mm/m2 SGA vs 18.1 mm/m2 AGA, p<0.01; LVEDD 27.5 mm/m2 SGA vs 26.6 mm/m2 AGA, p<0.01); LV base-to-apex length (47.4 mm/m2 SGA vs 46.0 mm/m2 AGA, p<0.01); LV basal diameter (26.4 mm/m2 SGA vs 25.7 mm/m2 AGA, p<0.01); and right ventricular base-to-apex length (40.1 mm/m2 SGA vs 39.2 mm/m2 AGA, p=0.02). LV stroke volume was greater in those born AGA (74.5 mL SGA vs 78.8 mL AGA, p<0.01), with no significant difference in cardiac output (5 L/min SGA vs 5.2 L/min AGA, p=0.06), heart rate, diastolic indices or sphericity index.
Conclusions
Adults born SGA have some statistically significant but subtle changes in cardiac structure and function, which are less marked than have been described in childhood, and are unlikely to play a pathogenic role in their elevated cardiovascular risk.
doi:10.1136/openhrt-2015-000265
PMCID: PMC4555072  PMID: 26339495
CARDIAC FUNCTION
22.  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
23.  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
24.  Intrauterine growth pattern and birthweight discordance in twin pregnancies: a retrospective study 
Background
Twins, compared to singletons, have an increased risk of perinatal mortality and morbidity, due mainly to a higher prevalence of preterm birth and low birthweight. Intrauterine growth restriction (IUGR) is also common and can affect one or both fetuses. In some cases, however, one twin is much smaller than the other (growth discordance). Usually, high birthweight discordance is associated with increased perinatal morbidity. The aim of this study is to describe the epidemiological features of a population of twins at birth, with particular reference to the interpretation and clinical effects of birthweight discordance.
Methods
We evaluated retrospectively the clinical features of 70 infants born from twin pregnancies and assessed birthweight discordance in 31 pregnancies where both twins were followed at our institution. Discordance was treated both as a continuous and a categorical variable, using a cutoff of 18%. Possible relationships between birthweight discordance and other variables, such as maternal age, gestational age, birthweight percentile, number of SGA newborns in the pair, Hematocrit (Ht) discordance and neonatal anemia, prevalence of malformations, neonatal morbidity and death, were analyzed.
Results
In our cohort birthweight percentile decreased slightly with increasing gestational age. Birthweight discordance, on the contrary, increased slightly with the increase of gestational age.
A high discordance is associated to the presence of one SGA twin, with the other AGA or LGA. In our population, all 6 pregnancies in which discordance exceeded 18% belonged to this category (one SGA twin).
Ht discordance at birth is associated to the presence of neonatal anemia in a twin, but it is not significantly related to weight discordance.
Finally, in our case history, weight discordance is not associated in any way with the prevalence of malformations, morbidity and mortality.
Conclusions
Birthweight discordance is an important indicator of complications that act asymmetrically on the two fetuses, affecting intrauterine growth in one of them, and usually determining the birth of a SGA infant.
Our case history shows a significant statistical association between pair discordance and IUGR in one of the twins, but we could not demonstrate any relationship between discordance and the prevalence of malformations, morbidity and mortality.
doi:10.1186/1824-7288-40-43
PMCID: PMC4018970  PMID: 24887062
Twins; Birthweight discordance; SGA; Weight percentile; Neonatal anemia
25.  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

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