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1.  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
2.  Chronic Hypertension Related to Risk for Preterm and Term Small-for-Gestational-Age Births 
Obstetrics and gynecology  2008;112(2 Pt 1):290-296.
Objective:
Evidence relating chronic hypertension to risk of small for gestational age (SGA) births is conflicting. To identify factors associated with SGA that may involve a placental pathogenesis, we related chronic hypertension and other maternal factors that may be markers of endothelial dysfunction to preterm compared with term SGA births.
Methods:
Chronic hypertension, diabetes, body mass index, age, and subfertility were related to risk of term and preterm SGA births in the Danish National Birth Cohort (n=81,008). SGA births were those with a birth weight adjusted for gestational age greater than 2 standard deviations below the mean based on fetal growth curves.
Results:
Risk of preterm SGA increased 5.5-fold (95% CI 3.2-9.4) and risk of term SGA increased 1.5-fold (1.0-2.2) among women with definite chronic hypertension. Risk of preterm SGA but not term SGA was increased among women less than 20 (odds ratio [OR] 2.8, 95% CI: 1.1-6.8) or greater than 36 (OR 2.0 , 95% CI:1.3-3.1) years of age and among those with at least 2 early spontaneous abortions (OR 2.0, CI:1.3-3.3). Smoking, parity, time to pregnancy greater than 12 months, and underweight status were similarly related to term and preterm SGA. Overweight status, obesity, and presence of diabetes were unrelated to either SGA subtype.
Conclusions:
Chronic hypertension, young or older maternal age, and recurrent early spontaneous abortions increased risk for preterm SGA. These factors may involve abnormal placentation and likely represent a pathogenesis distinct from that leading to term SGA.
doi:10.1097/AOG.0b013e31817f589b
PMCID: PMC2596352  PMID: 18669725
3.  Risk of childhood undernutrition related to small-for-gestational age and preterm birth in low- and middle-income countries 
International journal of epidemiology  2013;42(5):10.1093/ije/dyt109.
Background
Low- and middle-income countries continue to experience a large burden of stunting; 148 million children were estimated to be stunted, around 30–40% of all children in 2011. In many of these countries, foetal growth restriction (FGR) is common, as is subsequent growth faltering in the first 2 years. Although there is agreement that stunting involves both prenatal and postnatal growth failure, the extent to which FGR contributes to stunting and other indicators of nutritional status is uncertain.
Methods
Using extant longitudinal birth cohorts (n = 19) with data on birth-weight, gestational age and child anthropometry (12–60 months), we estimated study-specific and pooled risk estimates of stunting, wasting and underweight by small-for-gestational age (SGA) and preterm birth.
Results
We grouped children according to four combinations of SGA and gestational age: adequate size-for-gestational age (AGA) and preterm; SGA and term; SGA and preterm; and AGA and term (the reference group). Relative to AGA and term, the OR (95% confidence interval) for stunting associated with AGA and preterm, SGA and term, and SGA and preterm was 1.93 (1.71, 2.18), 2.43 (2.22, 2.66) and 4.51 (3.42, 5.93), respectively. A similar magnitude of risk was also observed for wasting and underweight. Low birthweight was associated with 2.5–3.5-fold higher odds of wasting, stunting and underweight. The population attributable risk for overall SGA for outcomes of childhood stunting and wasting was 20% and 30%, respectively.
Conclusions
This analysis estimates that childhood undernutrition may have its origins in the foetal period, suggesting a need to intervene early, ideally during pregnancy, with interventions known to reduce FGR and preterm birth.
doi:10.1093/ije/dyt109
PMCID: PMC3816349  PMID: 23920141
Foetal growth restriction; preterm birth; stunting; wasting; childhood
4.  Genetic Markers of Adult Obesity Risk Are Associated with Greater Early Infancy Weight Gain and Growth 
PLoS Medicine  2010;7(5):e1000284.
Ken Ong and colleagues genotyped children from the ALSPAC birth cohort and showed an association between greater early infancy gains in weight and length and genetic markers for adult obesity risk.
Background
Genome-wide studies have identified several common genetic variants that are robustly associated with adult obesity risk. Exploration of these genotype associations in children may provide insights into the timing of weight changes leading to adult obesity.
Methods and Findings
Children from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort were genotyped for ten genetic variants previously associated with adult BMI. Eight variants that showed individual associations with childhood BMI (in/near: FTO, MC4R, TMEM18, GNPDA2, KCTD15, NEGR1, BDNF, and ETV5) were used to derive an “obesity-risk-allele score” comprising the total number of risk alleles (range: 2–15 alleles) in each child with complete genotype data (n = 7,146). Repeated measurements of weight, length/height, and body mass index from birth to age 11 years were expressed as standard deviation scores (SDS). Early infancy was defined as birth to age 6 weeks, and early infancy failure to thrive was defined as weight gain between below the 5th centile, adjusted for birth weight. The obesity-risk-allele score showed little association with birth weight (regression coefficient: 0.01 SDS per allele; 95% CI 0.00–0.02), but had an apparently much larger positive effect on early infancy weight gain (0.119 SDS/allele/year; 0.023–0.216) than on subsequent childhood weight gain (0.004 SDS/allele/year; 0.004–0.005). The obesity-risk-allele score was also positively associated with early infancy length gain (0.158 SDS/allele/year; 0.032–0.284) and with reduced risk of early infancy failure to thrive (odds ratio  = 0.92 per allele; 0.86–0.98; p = 0.009).
Conclusions
The use of robust genetic markers identified greater early infancy gains in weight and length as being on the pathway to adult obesity risk in a contemporary birth cohort.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The proportion of overweight and obese children is increasing across the globe. In the US, the Surgeon General estimates that, compared with 1980, twice as many children and three times the number of adolescents are now overweight. Worldwide, 22 million children under five years old are considered by the World Health Organization to be overweight.
Being overweight or obese in childhood is associated with poor physical and mental health. In addition, childhood obesity is considered a major risk factor for adult obesity, which is itself a major risk factor for cancer, heart disease, diabetes, osteoarthritis, and other chronic conditions.
The most commonly used measure of whether an adult is a healthy weight is body mass index (BMI), defined as weight in kilograms/(height in metres)2. However, adult categories of obese (>30) and overweight (>25) BMI are not directly applicable to children, whose BMI naturally varies as they grow. BMI can be used to screen children for being overweight and or obese but a diagnosis requires further information.
Why Was This Study Done?
As the numbers of obese and overweight children increase, a corresponding rise in future numbers of overweight and obese adults is also expected. This in turn is expected to lead to an increasing incidence of poor health. As a result, there is great interest among health professionals in possible pathways between childhood and adult obesity. It has been proposed that certain periods in childhood may be critical for the development of obesity.
In the last few years, ten genetic variants have been found to be more common in overweight or obese adults. Eight of these have also been linked to childhood BMI and/or obesity. The authors wanted to identify the timing of childhood weight changes that may be associated with adult obesity. Knowledge of obesity risk genetic variants gave them an opportunity to do so now, without following a set of children to adulthood.
What Did the Researchers Do and Find?
The authors analysed data gathered from a subset of 7,146 singleton white European children enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC) study, which is investigating associations between genetics, lifestyle, and health outcomes for a group of children in Bristol whose due date of birth fell between April 1991 and December 1992. They used knowledge of the children's genetic makeup to find associations between an obesity risk allele score—a measure of how many of the obesity risk genetic variants a child possessed—and the children's weight, height, BMI, levels of body fat (at nine years old), and rate of weight gain, up to age 11 years.
They found that, at birth, children with a higher obesity risk allele score were not any heavier, but in the immediate postnatal period they were less likely to be in the bottom 5% of the population for weight gain (adjusted for birthweight), often termed “failure to thrive.” At six weeks of age, children with a higher obesity risk allele score tended to be longer and heavier, even allowing for weight at birth.
After six weeks of age, the obesity risk allele score was not associated with any further increase in length/height, but it was associated with a more rapid weight gain between birth and age 11 years. BMI is derived from height and weight measurements, and the association between the obesity risk allele score and BMI was weak between birth and age three-and-a-half years, but after that age the association with BMI increased rapidly. By age nine, children with a higher obesity risk allele score tended to be heavier and taller, with more fat on their bodies.
What Do These Findings Mean?
The combined obesity allele risk score is associated with higher rates of weight gain and adult obesity, and so the authors conclude that weight gain and growth even in the first few weeks after birth may be the beginning of a pathway of greater adult obesity risk.
A study that tracks a population over time can find associations but it cannot show cause and effect. In addition, only a relatively small proportion (1.7%) of the variation in BMI at nine years of age is explained by the obesity risk allele score.
The authors' method of finding associations between childhood events and adult outcomes via genetic markers of risk of disease as an adult has a significant advantage: the authors did not have to follow the children themselves to adulthood, so their findings are more likely to be relevant to current populations. Despite this, this research does not yield advice for parents how to reduce their children's obesity risk. It does suggest that “failure to thrive” in the first six weeks of life is not simply due to a lack of provision of food by the baby's caregiver but that genetic factors also contribute to early weight gain and growth.
The study looked at the combined obesity risk allele score and the authors did not attempt to identify which individual alleles have greater or weaker associations with weight gain and overweight or obesity. This would require further research based on far larger numbers of babies and children. The findings may also not be relevant to children in other types of setting because of the effects of different nutrition and lifestyles.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000284.
Further information is available on the ALSPAC study
The UK National Health Service and other partners provide guidance on establishing a healthy lifestyle for children and families in their Change4Life programme
The International Obesity Taskforce is a global network of expertise and the advocacy arm of the International Association for the Study of Obesity. It works with the World Health Organization, other NGOs, and stakeholders and provides information on overweight and obesity
The Centers for Disease Control and Prevention (CDC) in the US provide guidance and tips on maintaining a healthy weight, including BMI calculators in both metric and Imperial measurements for both adults and children. They also provide BMI growth charts for boys and girls showing how healthy ranges vary for each sex at with age
The Royal College of Paediatrics and Child Health provides growth charts for weight and length/height from birth to age 4 years that are based on WHO 2006 growth standards and have been adapted for use in the UK
The CDC Web site provides information on overweight and obesity in adults and children, including definitions, causes, and data
The CDC also provide information on the role of genes in causing obesity.
The World Health Organization publishes a fact sheet on obesity, overweight and weight management, including links to childhood overweight and obesity
Wikipedia includes an article on childhood obesity (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1000284
PMCID: PMC2876048  PMID: 20520848
5.  Risk of childhood undernutrition related to small-for-gestational age and preterm birth in low- and middle-income countries 
Background Low- and middle-income countries continue to experience a large burden of stunting; 148 million children were estimated to be stunted, around 30–40% of all children in 2011. In many of these countries, foetal growth restriction (FGR) is common, as is subsequent growth faltering in the first 2 years. Although there is agreement that stunting involves both prenatal and postnatal growth failure, the extent to which FGR contributes to stunting and other indicators of nutritional status is uncertain.
Methods Using extant longitudinal birth cohorts (n = 19) with data on birthweight, gestational age and child anthropometry (12–60 months), we estimated study-specific and pooled risk estimates of stunting, wasting and underweight by small-for-gestational age (SGA) and preterm birth.
Results We grouped children according to four combinations of SGA and gestational age: adequate size-for-gestational age (AGA) and preterm; SGA and term; SGA and preterm; and AGA and term (the reference group). Relative to AGA and term, the OR (95% confidence interval) for stunting associated with AGA and preterm, SGA and term, and SGA and preterm was 1.93 (1.71, 2.18), 2.43 (2.22, 2.66) and 4.51 (3.42, 5.93), respectively. A similar magnitude of risk was also observed for wasting and underweight. Low birthweight was associated with 2.5–3.5-fold higher odds of wasting, stunting and underweight. The population attributable risk for overall SGA for outcomes of childhood stunting and wasting was 20% and 30%, respectively.
Conclusions This analysis estimates that childhood undernutrition may have its origins in the foetal period, suggesting a need to intervene early, ideally during pregnancy, with interventions known to reduce FGR and preterm birth.
doi:10.1093/ije/dyt109
PMCID: PMC3816349  PMID: 23920141
Foetal growth restriction; preterm birth; stunting; wasting; childhood
6.  Prenatal Cocaine Exposure and Small-for-Gestational-Age Status: Effects on Growth at 6 Years of age 
Neurotoxicology and teratology  2011;33(5):575-581.
OBJECTIVE
To evaluate the impact of prenatal cocaine exposure and small-for-gestational-age (SGA) status on childhood growth.
STUDY DESIGN
Cocaine exposure was defined by history or meconium metabolites. Hierarchical linear modeling was used to examine cocaine exposure and SGA status on growth, while controlling for exposure to other drugs and alcohol use.
RESULTS
At birth cocaine-exposed infants (n=364) had significantly lower growth parameters compared to non-exposed children (n=771). At 6 years, weight was similar between exposed and unexposed children. SGA infants continued to be growth impaired. There was a significant interaction between prenatal cocaine exposure and SGA status at 6 years. The negative effects of cocaine on weight and height were greater among non-SGA than SGA children (432 vs. 280 gm, and 0.7 and 0.5 cm, respectively) while negative effects of SGA status on weight and height were larger in non-cocaine exposed compared to the exposed children (2.3 kg vs.1.6 kg and 2.2 and 1.0 cm).
CONCLUSIONS
Children exposed to prenatal cocaine were similar in weight to non-exposed children at 6 years of age. Cocaine had an unexplained greater detrimental effect on non-SGA than SGA children. SGA status at birth has an independent detrimental effect on childhood growth.
doi:10.1016/j.ntt.2011.04.003
PMCID: PMC3183411  PMID: 21849244
Prenatal cocaine exposure; small for gestational age; childhood growth
7.  The relationship between maternal body mass index and tobacco use on small for gestational age infants 
American journal of perinatology  2011;29(3):153-158.
Objective
To estimate the association between pre-pregnancy body mass index (BMI) and small for gestational age (SGA) neonates, and to determine if there is a synergistic effect of tobacco use on SGA across all BMI strata.
Study Design
Retrospective cohort study of 65,104 patients seen for second-trimester ultrasound. BMI was categorized into underweight, normal weight, overweight, and obese. SGA was defined as birth weight <10th percentile and <5th percentile. Univariable and multivariable logistic regression analyses were used to evaluate the association between BMI and SGA. Stratified analyses and tests for effect modification were performed to evaluate for a potential synergistic effect between tobacco use and abnormal pre-pregnancy BMI on SGA.
Results
After controlling for potential confounders, underweight BMI was significantly associated with an increased risk for SGA <10th percentile (aOR 1.8, 95% CI 1.5–2.1) while overweight (aOR 0.7, 95% CI 0.7–0.8) and obese BMI (aOR 0.6, 95% CI 0.5–0.7) were associated with a decreased risk of SGA. There was no effect modification of tobacco use on the risk of SGA across all BMI categories.
Conclusion
While both tobacco and underweight BMI are independently associated with SGA, there was no evidence of synergism. Continued emphasis on both smoking cessation and maintenance of normal pre-pregnancy BMI remain paramount to decreasing the incidence of SGA.
doi:10.1055/s-0031-1284224
PMCID: PMC3629943  PMID: 21786218
body mass index; tobacco; small for gestational age; underweight
8.  Prepregnancy body mass index, smoking during pregnancy, and infant birth weight 
Annals of epidemiology  2011;21(6):413-420.
Purpose
Smoking during pregnancy is strongly associated with increased risk of small for gestational age (SGA) and low birth weight, while elevated prepregnancy body mass index (BMI) is associated with a decreased risk of SGA and higher birth weight. We investigated the combined effect of prenatal smoking and prepregnancy BMI on risk of SGA and on birth weight.
Methods
A total of 34,928 singleton, term pregnancies in residents of New York City between 1995 and 2003 were evaluated in multivariable regression models of birth weight and risk of SGA.
Results
Increasing prepregnancy BMI reduced the risk of SGA and increased birth weight. The effect of prenatal smoking on birth weight and SGA diminished in women as their prepregnancy BMI increased, such that prenatal smoking did not significantly impact the risk of SGA among women who were overweight or obese prior to pregnancy. Prenatal smoking decreased mean birth weight by 187 grams (95% confidence interval (CI): -337, -37) among underweight women, by 129 grams (95% CI: -170, -87) among normal weight women, by 46 grams (95% CI: -113, +20) among overweight women, and by 75 grams (95% CI: -162, +11) among obese women.
Conclusions
This study suggests that the effect of smoking during pregnancy on SGA and birth weight is present in underweight and normal weight women but markedly reduced among obese and overweight women.
doi:10.1016/j.annepidem.2010.11.012
PMCID: PMC3090467  PMID: 21421328
birth weight; body mass index; cigarette smoking; fetal growth retardation; infant; small for gestational age
9.  Catch-up growth up to ten years of age in children born very preterm or with very low birth weight 
BMC Pediatrics  2005;5:26.
Background
Improved survival due to advances in neonatal care has brought issues such as postnatal growth and development more to the focus of our attention. Most studies report stunting in children born very preterm and/or small for gestational age. In this article we study the growth pattern of these children and aim to identify factors associated with postnatal catch-up growth.
Methods
1338 children born with a gestational age <32 weeks and/or a birth weight of <1500 grams were followed during a Dutch nationwide prospective study (POPS). Subgroups were classified as appropriate for gestational age and <32 weeks (AGA) or small for gestational age (<32 wks SGA and ≥32 wks SGA). Data were collected at different intervals from birth until 10 years for the 962 survivors and compared to reference values. The correlation between several factors and growth was analysed.
Results
At 10 years the AGA children had attained normal height, whereas the SGA group demonstrated stunting, even after correction for target height (AGA: 0.0 SDS; SGA <32 wks: -0.29SDS and ≥32 wks: -0.13SDS). Catch-up growth was especially seen in the SGA children with a fast initial weight gain. BMI was approximately 1 SD below the population reference mean.
Conclusion
At 10 years of age, children born very preterm AGA show no stunting. However, many children born SGA, especially the very preterm, show persistent stunting. Early weight gain seems an important prognostic factor in predicting childhood growth.
doi:10.1186/1471-2431-5-26
PMCID: PMC1199602  PMID: 16033642
10.  An Episode of Preterm Labor is a Risk Factor for the Birth of an SGA Neonate 
Objective
Patients presenting with an episode of preterm labor that subsides in response to tocolysis and who subsequently deliver at term are considered to have false preterm labor. However, the episode of “preterm labor” may represent the uterine response (i.e., uterine contractions) to an insult that was not severe enough to trigger preterm parturition but which may put the fetus at risk for additional pregnancy complications including growth restriction. The objective of this study was to compare the frequency of small for gestational age (SGA) neonates among patients with an episode of increased uterine contractility who delivered at term and those who delivered preterm.
Study design
This retrospective cohort study included 849 patients. Inclusion criteria were: 1) regular uterine contractions that required hospitalization; 2) intact membranes; 3) gestational age between 20 and 36 weeks. SGA was defined as a birth weight <10th percentile for gestational age. Placental pathology was reviewed and the results were used to classify patients into an inflammatory cluster, vascular cluster or both. Contingency tables, Mann-Whitney U test, and multivariate logistic regression were used for statistical analyses. A p-value of <0.05 was considered significant.
Results
1) The prevalence of SGA neonates in the study population was 16.1% (124/772); 2) patients who delivered at term had a significantly higher frequency of SGA neonates than those who delivered preterm [21.5% (64/298) vs. 12.7% (60/474); p=0.001]; 2) the results of placental pathology were available in 63.7% (492/772) of patients. Patients who delivered at term had a higher frequency of fetal or maternal vascular lesions without histologic evidence of inflammation than those who delivered preterm [29.1 % (43/148) vs. 18.9% (65/344); p=0.01]; and 3) term delivery after an episode of regular preterm uterine contractions was associated with an odds ratio of 2.22 (95% CI: 1.28-3.85) to deliver an SGA neonate after controlling for confounding variables. A sub-analysis limited to patients who received tocolysis showed similar results.
Conclusions
1) patients with an episode of increased uterine contractility that subsided and delivered at term are at risk for delivering an SGA neonate; 2) this suggests that an episode of false preterm labor is not a benign condition; and 3) we propose that insults to the feto-placental unit may be resolved by either irreversible preterm parturition or restricting fetal growth.
doi:10.1016/j.ajog.2007.03.023
PMCID: PMC2041912  PMID: 17547901
increased uterine contractility; intact membranes; small for gestational age; placental pathology; vascular cluster; inflammatory cluster; term delivery
11.  Contribution of prepregnancy body mass index and gestational weight gain to adverse neonatal outcomes: population attributable fractions for Canada 
Background
Low or high prepregnancy body mass index (BMI) and inadequate or excess gestational weight gain (GWG) are associated with adverse neonatal outcomes. This study estimates the contribution of these risk factors to preterm births (PTBs), small-for-gestational age (SGA) and large-for-gestational age (LGA) births in Canada compared to the contribution of prenatal smoking, a recognized perinatal risk factor.
Methods
We analyzed data from the Canadian Maternity Experiences Survey. A sample of 5,930 women who had a singleton live birth in 2005-2006 was weighted to a nationally representative population of 71,200 women. From adjusted odds ratios, we calculated population attributable fractions to estimate the contribution of BMI, GWG and prenatal smoking to PTB, SGA and LGA infants overall and across four obstetric groups.
Results
Overall, 6% of women were underweight (<18.5 kg/m2) and 34.4% were overweight or obese (≥25.0 kg/m2). More than half (59.4%) gained above the recommended weight for their BMI, 18.6% gained less than the recommended weight and 10.4% smoked prenatally. Excess GWG contributed more to adverse outcomes than BMI, contributing to 18.2% of PTB and 15.9% of LGA. Although the distribution of BMI and GWG was similar across obstetric groups, their impact was greater among primigravid women and multigravid women without a previous PTB or pregnancy loss. The contributions of BMI and GWG to PTB and SGA exceeded that of prenatal smoking.
Conclusions
Maternal weight, and GWG in particular, contributes significantly to the occurrence of adverse neonatal outcomes in Canada. Indeed, this contribution exceeds that of prenatal smoking for PTB and SGA, highlighting its public health importance.
doi:10.1186/s12884-015-0452-0
PMCID: PMC4326407  PMID: 25652811
Population attributable fraction; Maternal weight; Preterm birth; Small-for-gestational age; Large-for-gestational age
12.  Pregnancy Weight Gain and Childhood Body Weight: A Within-Family Comparison 
PLoS Medicine  2013;10(10):e1001521.
David Ludwig and colleagues examine the within-family relationship between pregnancy weight gain and the offspring's childhood weight gain, thereby reducing the influence of genes and environment.
Please see later in the article for the Editors' Summary
Background
Excessive pregnancy weight gain is associated with obesity in the offspring, but this relationship may be confounded by genetic and other shared influences. We aimed to examine the association of pregnancy weight gain with body mass index (BMI) in the offspring, using a within-family design to minimize confounding.
Methods and Findings
In this population-based cohort study, we matched records of all live births in Arkansas with state-mandated data on childhood BMI collected in public schools (from August 18, 2003 to June 2, 2011). The cohort included 42,133 women who had more than one singleton pregnancy and their 91,045 offspring. We examined how differences in weight gain that occurred during two or more pregnancies for each woman predicted her children's BMI and odds ratio (OR) of being overweight or obese (BMI≥85th percentile) at a mean age of 11.9 years, using a within-family design. For every additional kg of pregnancy weight gain, childhood BMI increased by 0.0220 (95% CI 0.0134–0.0306, p<0.0001) and the OR of overweight/obesity increased by 1.007 (CI 1.003–1.012, p = 0.0008). Variations in pregnancy weight gain accounted for a 0.43 kg/m2 difference in childhood BMI. After adjustment for birth weight, the association of pregnancy weight gain with childhood BMI was attenuated but remained statistically significant (0.0143 kg/m2 per kg of pregnancy weight gain, CI 0.0057–0.0229, p = 0.0007).
Conclusions
High pregnancy weight gain is associated with increased body weight of the offspring in childhood, and this effect is only partially mediated through higher birth weight. Translation of these findings to public health obesity prevention requires additional study.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Childhood obesity has become a worldwide epidemic. For example, in the United States, the number of obese children has more than doubled in the past 30 years. 7% of American children aged 6–11 years were obese in 1980, compared to nearly 18% in 2010. Because of the rising levels of obesity, the current generation of children may have a shorter life span than their parents for the first time in 200 years.
Childhood obesity has both immediate and long-term effects on health. The initial problems are usually psychological. Obese children often experience discrimination, leading to low self-esteem and depression. Their physical health also suffers. They are more likely to be at risk of cardiovascular disease from high cholesterol and high blood pressure. They may also develop pre-diabetes or diabetes type II. In the long-term, obese children tend to become obese adults, putting them at risk of premature death from stroke, heart disease, or cancer.
There are many factors that lead to childhood obesity and they often act in combination. A major risk factor, especially for younger children, is having at least one obese parent. The challenge lies in unravelling the complex links between the genetic and environmental factors that are likely to be involved.
Why Was This Study Done?
Several studies have shown that a child's weight is influenced by his/her mother's weight before pregnancy and her weight gain during pregnancy. An obese mother, or a mother who puts on more pregnancy weight than average, is more likely to have an obese child.
One explanation for the effects of pregnancy weight gain is that the mother's overeating directly affects the baby's development. It may change the baby's brain and metabolism in such a way as to increase the child's long-term risk of obesity. Animal studies have confirmed that the offspring of overfed rats show these kinds of physiological changes. However, another possible explanation is that mother and baby share a similar genetic make-up and environment so that a child becomes obese from inheriting genetic risk factors, and growing up in a household where being overweight is the norm.
The studies in humans that have been carried out to date have not been able to distinguish between these explanations. Some have given conflicting results. The aim of this study was therefore to look for evidence of links between pregnancy weight gain and children's weight, using an approach that would separate the impact of genetic and environmental factors from a direct effect on the developing baby.
What Did the Researchers Do and Find?
The researchers examined data from the population of the US state of Arkansas recorded between 2003 and 2011. They looked at the health records of over 42,000 women who had given birth to more than one child during this period. This gave them information about how much weight the women had gained during each of their pregnancies. The researchers also looked at the school records of the children, over 91,000 in total, which included the children's body mass index (BMI, which factors in both height and weight). They analyzed the data to see if there was a link between the mothers' pregnancy weight gain and the child's BMI at around 12 years of age. Most importantly, they looked at these links within families, comparing children born to the same mother. The rationale for this approach was that these children would share a similar genetic make-up and would have grown up in similar environments. By taking genetics and environment into account in this manner, any remaining evidence of an impact of pregnancy weight gain on the children's BMI would have to be explained by other factors.
The results showed that the amount of weight each mother gained in pregnancy predicted her children's BMI and the likelihood of her children being overweight or obese. For every additional kg the mother gained during pregnancy, the children's BMI increased by 0.022. The children of mothers who put on the most weight had a BMI that was on average 0.43 higher than the children whose mothers had put on the least weight.
The study leaves some questions unanswered, including whether the mother's weight before pregnancy makes a difference to their children's BMI. The researchers were not able to obtain these measurements, nor the weight of the fathers. There may have also been other factors that weren't measured that might explain the links that were found.
What Do These Findings Mean?
This study shows that mothers who gain excessive weight during pregnancy increase the risk of their child becoming obese. This appears to be partly due to a direct effect on the developing baby.
These results represent a significant public health concern, even though the impact on an individual basis is relatively small. They could contribute to several hundred thousand cases of childhood obesity worldwide. Importantly, they also suggest that some cases could be prevented by measures to limit excessive weight gain during pregnancy. Such an approach could prove effective, as most mothers will not want to damage their child's health, and might therefore be highly motivated to change their behavior. However, because inadequate weight gain during pregnancy can also adversely affect the developing fetus, it will be essential for women to receive clear information about what constitutes optimal weight gain during pregnancy.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001521.
The US Centers for Disease Control and Prevention provide Childhood Obesity Facts
The UK National Health Service article “How much weight will I put on during my pregnancy?” provides information on pregnancy and weight gain and links to related resources
doi:10.1371/journal.pmed.1001521
PMCID: PMC3794857  PMID: 24130460
13.  Combination Antiretroviral Use and Preterm Birth 
The Journal of Infectious Diseases  2012;207(4):612-621.
Background. Use of antiretroviral drugs (ARVs) during pregnancy has been associated with higher risk of preterm birth.
Methods. The Pediatric HIV/AIDS Cohort Study network's Surveillance Monitoring for ART Toxicities study is a US-based cohort of human immunodeficiency virus (HIV)–exposed uninfected children. We evaluated maternal ARV use during pregnancy and the risk of any type of preterm birth (ie, birth before 37 completed weeks of gestation), the risk of spontaneous preterm birth (ie, preterm birth that occurred after preterm labor or membrane rupture, without other complications), and the risk of small for gestational age (SGA; ie, a birth weight of <10th percentile for gestational age). Multivariable logistic regression models were used to evaluate the association of ARVs and timing of exposure, while adjusting for maternal characteristics.
Results. Among 1869 singleton births, 18.6% were preterm, 10.2% were spontaneous preterm, and 7.3% were SGA. A total of 89% used 3-drug combination ARV regimens during pregnancy. In adjusted models, the odds of preterm birth and spontaneous preterm birth were significantly greater among mothers who used protease inhibitors during the first trimester (adjusted odds ratios, 1.55 and 1.59, respectively) but not among mothers who used nonnucleoside reverse-transcriptase inhibitor or triple-nucleoside regimens during the first trimester. Combination ARV exposure starting later in pregnancy was not associated with increased risk. No associations were observed between SGA and exposure to combination ARV regimens.
Conclusions. Protease inhibitor use early in pregnancy may be associated with increased risk for prematurity.
doi:10.1093/infdis/jis728
PMCID: PMC3549601  PMID: 23204173
preterm birth; antiretrovirals; pregnancy; small for gestational age
14.  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
15.  Maternal Prepregnancy Body Mass Index and Gestational Weight Gain on Pregnancy Outcomes 
PLoS ONE  2013;8(12):e82310.
Objective
The aim of the present study was to evaluate the single and joint associations of maternal prepregnancy body mass index (BMI) and gestational weight gain (GWG) with pregnancy outcomes in Tianjin, China.
Methods
Between June 2009 and May 2011, health care records of 33,973 pregnant women were collected and their children were measured for birth weight and birth length. The independent and joint associations of prepregnancy BMI and GWG based on the Institute of Medicine (IOM) guidelines with the risks of pregnancy and neonatal outcomes were examined by using Logistic Regression.
Results
After adjustment for all confounding factors, maternal prepregnancy BMI was positively associated with risks of gestational diabetes mellitus (GDM), pregnancy-induced hypertension, caesarean delivery, preterm delivery, large-for-gestational age infant (LGA), and macrosomia, and inversely associated with risks of small-for-gestational age infant (SGA) and low birth weight. Maternal excessive GWG was associated with increased risks of pregnancy-induced hypertension, caesarean delivery, LGA, and macrosomia, and decreased risks of preterm delivery, SGA, and low birth weight. Maternal inadequate GWG was associated with increased risks of preterm delivery and SGA, and decreased risks of LGA and macrosomia, compared with maternal adequate GWG. Women with both prepregnancy obesity and excessive GWG had 2.2–5.9 folds higher risks of GDM, pregnancy-induced hypertension, caesarean delivery, LGA, and macrosomia compared with women with normal prepregnancy BMI and adequate GWG.
Conclusions
Maternal prepregnancy obesity and excessive GWG were associated with greater risks of pregnancy-induced hypertension, caesarean delivery, and greater infant size at birth. Health care providers should inform women to start the pregnancy with a BMI in the normal weight category and limit their GWG to the range specified for their prepregnancy BMI.
doi:10.1371/journal.pone.0082310
PMCID: PMC3869661  PMID: 24376527
16.  Female Survivors of Childhood Cancer: Preterm Birth and Low Birth Weight Among Their Children 
Background
Improved survival after childhood cancer raises concerns over the possible long-term reproductive health effects of cancer therapies. We investigated whether children of female childhood cancer survivors are at elevated risk of being born preterm or exhibiting restricted fetal growth and evaluated the associations of different cancer treatments on these outcomes.
Methods
Using data from the Childhood Cancer Survivor Study, a large multicenter cohort of childhood cancer survivors, we studied the singleton live births of female cohort members from 1968 to 2002. Included were 2201 children of 1264 survivors and 1175 children of a comparison group of 601 female siblings. Data from medical records were used to determine cumulative prepregnancy exposures to chemotherapy and radiotherapy. Logistic regression was used to estimate odds ratios (ORs) for the association between quantitative therapy exposures and preterm (<37 weeks) birth, low birth weight (<2.5 kg), and small-for-gestational-age (SGA) (lowest 10th percentile) births. All statistical tests were two-sided.
Results
Survivors’ children were more likely to be born preterm than the siblings’ children (21.1% versus 12.6%; OR = 1.9, 95% confidence interval [CI] = 1.4 to 2.4; P<.001). Compared with the children of survivors who did not receive any radiotherapy, the children of survivors treated with high-dose radiotherapy to the uterus (>500 cGy) had increased risks of being born preterm (50.0% versus 19.6%; OR = 3.5, 95% CI = 1.5 to 8.0; P = .003), low birth weight (36.2% versus 7.6%; OR = 6.8, 95% CI = 2.1 to 22.2; P = .001), and SGA (18.2% versus 7.8%; OR = 4.0, 95% CI = 1.6 to 9.8; P = .003). Increased risks were also apparent at lower uterine radiotherapy doses (starting at 50 cGy for preterm birth and at 250 cGy for low birth weight).
Conclusions
Late effects of treatment for female childhood cancer patients may include restricted fetal growth and early births among their offspring, with risks concentrated among women who receive pelvic irradiation.
doi:10.1093/jnci/djj394
PMCID: PMC2730161  PMID: 17047194
17.  Neonatal Mortality Risk Associated with Preterm Birth in East Africa, Adjusted by Weight for Gestational Age: Individual Participant Level Meta-Analysis 
PLoS Medicine  2012;9(8):e1001292.
In an analysis of four datasets from East Africa, Tanya Marchant and colleagues investigate the neonatal mortality risk associated with preterm birth and how this changes with weight for gestational age.
Background
Low birth weight and prematurity are amongst the strongest predictors of neonatal death. However, the extent to which they act independently is poorly understood. Our objective was to estimate the neonatal mortality risk associated with preterm birth when stratified by weight for gestational age in the high mortality setting of East Africa.
Methods and Findings
Members and collaborators of the Malaria and the MARCH Centers, at the London School of Hygiene & Tropical Medicine, were contacted and protocols reviewed for East African studies that measured (1) birth weight, (2) gestational age at birth using antenatal ultrasound or neonatal assessment, and (3) neonatal mortality. Ten datasets were identified and four met the inclusion criteria. The four datasets (from Uganda, Kenya, and two from Tanzania) contained 5,727 births recorded between 1999–2010. 4,843 births had complete outcome data and were included in an individual participant level meta-analysis. 99% of 445 low birth weight (<2,500 g) babies were either preterm (<37 weeks gestation) or small for gestational age (below tenth percentile of weight for gestational age). 52% of 87 neonatal deaths occurred in preterm or small for gestational age babies. Babies born <34 weeks gestation had the highest odds of death compared to term babies (odds ratio [OR] 58.7 [95% CI 28.4–121.4]), with little difference when stratified by weight for gestational age. Babies born 34–36 weeks gestation with appropriate weight for gestational age had just three times the likelihood of neonatal death compared to babies born term, (OR 3.2 [95% CI 1.0–10.7]), but the likelihood for babies born 34–36 weeks who were also small for gestational age was 20 times higher (OR 19.8 [95% CI 8.3–47.4]). Only 1% of babies were born moderately premature and small for gestational age, but this group suffered 8% of deaths. Individual level data on newborns are scarce in East Africa; potential biases arising due to the non-systematic selection of the individual studies, or due to the methods applied for estimating gestational age, are discussed.
Conclusions
Moderately preterm babies who are also small for gestational age experience a considerably increased likelihood of neonatal death in East Africa.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Worldwide, every year around 3.3 million babies die within their first month of life and the proportion of under-five child deaths that are now in the neonatal period (the first 28 days of life) has increased in all regions of the world and is currently estimated at 41%. Of these deaths, over 90% occur in low- and middle-income countries, and a third of all neonatal deaths occur in sub-Saharan Africa. Low birth weight (defined as <2,500 g) is one of the biggest risk factors associated with neonatal deaths but it is the causes of low birth weight, rather than the low weight itself that is thought to lead to neonatal deaths. The two main causes of low birth weight are preterm birth (delivery before 37 weeks gestation) and/or restricted growth in the womb (intra-uterine growth retardation), resulting in babies who are small for their dates (defined as being in the lowest 10% of weight expected for gestational age with reference to a US population).
Why Was This Study Done?
Despite growing international attention focused on neonatal mortality in recent years, the relative importance of low birth weight, small for gestational age, and preterm birth in causing newborn deaths remains unclear. So in this study, the researchers investigated these relationships by calculating the risk of neonatal mortality associated with preterm birth after adjusting for weight for gestational age by conducting a meta-analysis (synthesis of the data) using information from studies reporting neonatal mortality conducted in sub-Saharan Africa.
What Did the Researchers Do and Find?
The researchers identified potential African datasets and selected four out of a possible ten to include in their analysis as these studies included three essential birth outcomes: birth weight; gestational age measured using antenatal ultrasound, or neonatal assessment on the day of birth; and neonatal mortality. These four studies were conducted in Kenya, Tanzania, and Uganda, all in East Africa. The researchers analysed each study separately but also conducted a pooled statistical analysis on all four studies. To give a more detailed analysis, the researchers categorized babies into six groups taking into account whether the babies were moderately preterm (born at 34–36 weeks) or very preterm (born before 34 weeks) and whether their weight was appropriate for their gestational age.
The researchers included a total of 4,843 live births in their analysis and found that overall, 9.2% of babies were low birth weight, 4.0% were preterm, and 20.4% were small for gestational age. Amongst low birth weight babies, 26.1% were preterm, 85.0% were small for gestational age, and 98.8% were either preterm or small for gestational age. In their detailed analysis, the researchers found that the odds (chance) of death in the first 28 days of life were seven times higher for babies born low birth weight compared to those with normal birth weight, with low birth weight infants experiencing a neonatal mortality rate of 80.9/1,000 live births. The odds of death were twice as high for babies born small for gestational age compared to those born appropriate for gestational age, giving a neonatal mortality rate of 29.3/1,000 live births. Furthermore, compared to those born at term, the odds of death were over six times higher for babies born moderately preterm and almost 60 times higher for babies born very preterm with almost half of all very preterm babies dying in the first 28 days of life, giving a neonatal mortality rate 473.6/1,000 live births. However, moderately preterm babies who were small for gestational age had a much greater odds of death than moderately preterm babies who were of the appropriate weight for their gestational age.
What Do These Findings Mean?
These findings from East Africa show that babies born either small for gestational age or preterm contributed 52% of neonatal deaths. The detailed analysis suggests that babies born preterm are at the greatest risk of death, but size for gestational age also plays an important role especially in moderately preterm babies. The results from this study emphasize the pressing need to find ways to prevent preterm delivery and intra-uterine growth retardation and also illustrate the importance of measuring and reporting outcomes of individual babies.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001292.
A recent PLOS Medicine study by Oestergaard et al. has the latest global figures on neonatal mortality
UNICEF provides information on neonatal mortality
The World Health Organization (WHO) provides factsheets on the causes of neonatal mortality, including preterm birth
doi:10.1371/journal.pmed.1001292
PMCID: PMC3419185  PMID: 22904691
18.  Earlier Mother's Age at Menarche Predicts Rapid Infancy Growth and Childhood Obesity 
PLoS Medicine  2007;4(4):e132.
Background
Early menarche tends to be preceded by rapid infancy weight gain and is associated with increased childhood and adult obesity risk. As age at menarche is a heritable trait, we hypothesised that age at menarche in the mother may in turn predict her children's early growth and obesity risk.
Methods and Findings
We tested associations between mother's age at menarche, mother's adult body size and obesity risk, and her children's growth and obesity risk in 6,009 children from the UK population-based Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort who had growth and fat mass at age 9 y measured by dual-energy X-ray absorptiometry. A subgroup of 914 children also had detailed infancy and childhood growth data. In the mothers, earlier menarche was associated with shorter adult height (by 0.64 cm/y), increased weight (0.92 kg/y), and body mass index (BMI, 0.51 kg/m2/y; all p < 0.001). In contrast, in her children, earlier mother's menarche predicted taller height at 9 y (by 0.41 cm/y) and greater weight (0.80 kg/y), BMI (0.29 kg/m2/y), and fat mass index (0.22 kg/m2/year; all p < 0.001). Children in the earliest mother's menarche quintile (≤11 y) were more obese than the oldest quintile (≥15 y) (OR, 2.15, 95% CI 1.46 to 3.17; p < 0.001, adjusted for mother's education and BMI). In the subgroup, children in the earliest quintile showed faster gains in weight (p < 0.001) and height (p < 0.001) only from birth to 2 y, but not from 2 to 9 y (p = 0.3–0.8).
Conclusions
Earlier age at menarche may be a transgenerational marker of a faster growth tempo, characterised by rapid weight gain and growth, particularly during infancy, and leading to taller childhood stature, but likely earlier maturation and therefore shorter adult stature. This growth pattern confers increased childhood and adult obesity risks.
Earlier age at menarche may be a transgenerational marker of faster growth, particularly during infancy, leading to taller childhood stature but earlier maturation and hence shorter adult stature.
Editors' Summary
Background.
Childhood obesity is a rapidly growing problem. Twenty-five years ago, overweight children were rare. Now, 155 million of the world's children are overweight and 30–45 million are obese. Overweight and obese children—those having a higher than average body mass index (BMI; weight divided by height squared) for their age and sex—are at increased risk of becoming obese adults. Such people are more likely to develop heart disease, diabetes, and other health problems than lean people. Many factors are involved in the burgeoning size of children. Parental obesity, for example, predisposes children to being overweight. In part, this is because parents influence the eating habits of their offspring and the amount of exercise they do. In addition, though, children inherit genetic factors from their parents that make them more likely to put on weight.
Why Was This Study Done?
To prevent childhood obesity, health care professionals need ways to predict which infants are likely to become obese so that they can give parents advice on controlling their children's weight. In girls, early menarche (the start of menstruation) is associated with an increased risk of childhood and adult obesity and tends to be preceded by rapid weight gain in the first two years of life. Because age at menarche is inherited, the researchers in this study have investigated whether mothers' age at menarche predicts rapid growth in infancy and childhood obesity in their offspring using data from the Avon Longitudinal Study of Parents and Children (ALSPAC). In 1991–1992, this study recruited nearly 14,000 children born in Bristol, UK. Since then, the children have been regularly examined to investigate how their environment and genetic inheritance interact to affect their health.
What Did the Researchers Do and Find?
The researchers measured the growth and fat mass of 6,009 children from ALSPAC at 9 years of age. For 914 of these children, the researchers had detailed data on their growth during infancy and early childhood. They then looked for any associations between the mother's age at menarche (as recalled during pregnancy), mother's adult body size, and the children's growth and obesity risk. In the mothers, earlier menarche was associated with shorter adult height and increased weight and BMI. In the children, those whose mothers had earlier menarche were taller and heavier than those whose mothers had a later menarche. They also had a higher BMI and more body fat. The children whose mothers had their first period before they were 11 were twice as likely to be obese as those whose mothers did not menstruate until they were 15 or older. Finally, for the children with detailed early growth data, those whose mothers had the earliest menarche had faster weight and height gains in the first two years of life (but not in the next seven years) than those whose mothers had the latest menarche.
What Do These Findings Mean?
These findings indicate that earlier mother's menarche predicts a faster growth tempo (the speed at which an individual reaches their adult height) in their offspring, which is characterized by rapid weight and height gain during infancy. This faster growth tempo leads to taller childhood stature, earlier sexual maturity, and—because age at puberty determines adult height—shorter adult stature. An inherited growth pattern like this, the researchers write, confers an increased risk of childhood and adult obesity. As with all studies that look for associations between different measurements, these findings will be affected by the accuracy of the measurements—for example, how well the mothers recalled their age at menarche. Furthermore, because puberty, particularly in girls, is associated with an increase in body fat, a high BMI at age nine might indicate imminent puberty rather than a risk of long-standing obesity—further follow-up studies will clarify this point. Nevertheless, the current findings provide a new factor—earlier mother's menarche—that could help health care professionals identify which infants require early growth monitoring to avoid later obesity.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040132.
The Avon Longitudinal Study of Parents and Children has a description of the study and results to date
The US Centers for Disease Control and Prevention provides information on overweight and obesity (in English and Spanish)
US Department of Health and Human Services's program, Smallstep Kids, is an interactive site for children about healthy eating (in English and Spanish)
The International Obesity Taskforce has information on obesity and its prevention
The World Heart Federation's Global Prevention Alliance provides details of international efforts to halt the obesity epidemic and its associated chronic diseases
The Child Growth Foundation has information on childhood growth and its measurement
doi:10.1371/journal.pmed.0040132
PMCID: PMC1876410  PMID: 17455989
19.  Reduced genetic influence on childhood obesity in small for gestational age children 
BMC Medical Genetics  2013;14:10.
Background
Children born small-for-gestational-age (SGA) are at increased risk of developing obesity and metabolic diseases later in life, a risk which is magnified if followed by accelerated postnatal growth. We investigated whether common gene variants associated with adult obesity were associated with increased postnatal growth, as measured by BMI z-score, in children born SGA and appropriate for gestational age (AGA) in the Auckland Birthweight Collaborative.
Methods
A total of 37 candidate SNPs were genotyped on 547 European children (228 SGA and 319 AGA). Repeated measures of BMI (z-score) were used for assessing obesity status, and results were corrected for multiple testing using the false discovery rate.
Results
SGA children had a lower BMI z-score than non-SGA children at assessment age 3.5, 7 and 11 years. We confirmed 27 variants within 14 obesity risk genes to be individually associated with increasing early childhood BMI, predominantly in those born AGA.
Conclusions
Genetic risk variants are less important in influencing early childhood BMI in those born SGA than in those born AGA, suggesting that non-genetic or environmental factors may be more important in influencing childhood BMI in those born SGA.
doi:10.1186/1471-2350-14-10
PMCID: PMC3556300  PMID: 23339409
BMI; Childhood obesity; AGA children; SGA children
20.  Inter-pregnancy weight change impacts placental weight and is associated with the risk of adverse pregnancy outcomes in the second pregnancy 
Background
The inter-pregnancy period is considered a teachable moment when women are receptive to weight- management guidance aimed at optimising pregnancy outcome in subsequent pregnancies. In population based studies inter-pregnancy weight change is associated with several adverse pregnancy outcomes but the impact on placental size is unknown.
Methods
The association between inter-pregnancy weight change and the primary risk of adverse pregnancy outcomes in the second pregnancy was investigated in 12,740 women with first two consecutive deliveries at a single hospital using logistic regression.
Results
Compared with women who were weight stable, weight loss (>1BMI unit) between pregnancies was associated with an increased risk of spontaneous preterm delivery, low placental weight and small for gestational age (SGA) birth, while weight gain (>3BMI units) increased the risk of pre-eclampsia, gestational hypertension, emergency caesarean section, placental oversize and large for gestational age (LGA) birth at the second pregnancy. The relationship between weight gain and pre-eclampsia risk was evident in women who were overweight at first pregnancy only (BMI ≥25 units), while that between weight loss and preterm delivery was confined to women with a healthy weight at first pregnancy (BMI <25 units). In contrast, the association between weight loss and SGA was independent of first pregnancy BMI. A higher percentage of women who were obese at first pregnancy were likely to experience a large weight gain (P < 0.01) or weight loss (P < 0.001) between consecutive pregnancies compared with the normal BMI reference group.
Conclusion
Inter-pregnancy weight change in either direction increases the risk of a number of contrasting pregnancy complications, including extremes of placental weight. The placenta may lie on the causal pathway between BMI change and the risk of LGA or SGA birth.
doi:10.1186/1471-2393-14-40
PMCID: PMC3900734  PMID: 24450357
Inter-pregnancy weight change; Placenta; Pregnancy complications; Birth weight; Parity; Maternal body mass index
21.  Outcomes of Small for Gestational Age Infants < 27 Weeks’ Gestation 
The Journal of pediatrics  2013;163(1):55-60.e1-3.
Objective
To determine whether small for gestational age (SGA) infants <27 weeks gestation is associated with mortality, morbidity, growth and neurodevelopmental impairment at 18–22 months’ corrected age (CA).
Study design
This was a retrospective cohort study from National Institute of Child Health and Human Development Neonatal Research Network’s Generic Database and Follow-up Studies. Infants born at <27 weeks’ gestation from January 2006 to July 2008 were included. SGA was defined as birth weight <10th percentile for gestational age by the Olsen growth curves. Infants with birth weight ≥10th percentile for gestational age were classified as non-SGA. Maternal and infant characteristics, neonatal outcomes and neurodevelopmental data were compared between the groups. Neurodevelopmental impairment was defined as any of the following: cognitive score <70 on BSID III, moderate or severe cerebral palsy, bilateral hearing loss (+/− amplification) or blindness (vision <20/200). Logistic regression analysis evaluated the association between SGA status and death or neurodevelopmental impairment.
Results
There were 385 SGA and 2586 non-SGA infants. Compared with the non-SGA group, mothers of SGA infants were more likely to have higher level of education, prenatal care, cesarean delivery, pregnancy-induced hypertension and antenatal corticosteroid exposure. SGA infants were more likely to have postnatal growth failure, a higher mortality and to have received prolonged mechanical ventilation and postnatal steroids. SGA status was associated with higher odds of death or neurodevelopmental impairment [OR 3.91 (95% CI: 2.91–5.25), P<0.001].
Conclusion
SGA status among infants <27 weeks’ gestation was associated with an increased risk for postnatal steroid use, mortality, growth failure and neurodevelopmental impairment at 18–22 months’ CA.
doi:10.1016/j.jpeds.2012.12.097
PMCID: PMC3947828  PMID: 23415614
extremely preterm infants; neurodevelopmental follow-up
22.  Mortality risk in preterm and small-for-gestational-age infants in low-income and middle-income countries: a pooled country analysis 
Lancet  2013;382(9890):417-425.
Summary
Background
Babies with low birthweight (<2500 g) are at increased risk of early mortality. However, low birthweight includes babies born preterm and with fetal growth restriction, and not all these infants have a birthweight less than 2500 g. We estimated the neonatal and infant mortality associated with these two characteristics in low-income and middle-income countries.
Methods
For this pooled analysis, we searched all available studies and identified 20 cohorts (providing data for 2 015 019 livebirths) from Asia, Africa, and Latin America that recorded data for birthweight, gestational age, and vital statistics through 28 days of life. Study dates ranged from 1982 through to 2010. We calculated relative risks (RR) and risk differences (RD) for mortality associated with preterm birth (<32 weeks, 32 weeks to <34 weeks, 34 weeks to <37 weeks), small-for-gestational-age (SGA; babies with birthweight in the lowest third percentile and between the third and tenth percentile of a US reference population), and preterm and SGA combinations.
Findings
Pooled overall RRs for preterm were 6·82 (95% CI 3·56–13·07) for neonatal mortality and 2·50 (1·48–4·22) for post-neonatal mortality. Pooled RRs for babies who were SGA (with birthweight in the lowest tenth percentile of the reference population) were 1·83 (95% CI 1·34–2·50) for neonatal mortality and 1·90 (1·32–2·73) for post-neonatal mortality. The neonatal mortality risk of babies who were both preterm and SGA was higher than that of babies with either characteristic alone (15·42; 9·11–26·12).
Interpretation
Many babies in low-income and middle-income countries are SGA. Preterm birth affects a smaller number of neonates than does SGA, but is associated with a higher mortality risk. The mortality risks associated with both characteristics extend beyond the neonatal period. Differentiation of the burden and risk of babies born preterm and SGA rather than with low birthweight could guide prevention and management strategies to speed progress towards Millennium Development Goal 4—the reduction of child mortality.
Funding
Bill & Melinda Gates Foundation.
doi:10.1016/S0140-6736(13)60993-9
PMCID: PMC3796350  PMID: 23746775
23.  Effects of gestation and birth weight on the growth and development of very low birthweight small for gestational age infants: a matched group comparison 
AIMS—To investigate the effects of small for gestational age (SGA) in very low birthweight (VLBW) infants on growth and development until the fifth year of life.
METHODS—VLBW (< 1500 g) infants, selected from a prospective study, were classified as SGA (n = 115) on the basis of birth weight below the 10th percentile for gestational age and were compared with two groups of appropriate for gestational age (AGA) infants matched according to birth weight (AGA-BW; n = 115) or gestation at birth (AGA-GA; n = 115). Prenatal, perinatal, and postnatal risk factors were recorded, and duration and intensity of treatment were computed from daily assessments. Body weight, length, and head circumference were measured at birth, five and 20 months (corrected for prematurity), and at 56 months. General development was assessed at five and 20 months with the Griffiths scale of babies abilities, and cognitive development at 56 months with the Columbia mental maturity scales, a vocabulary (AWST) and language comprehension test (LSVTA).
RESULTS—Significant group differences were found in complications (pregnancy, birth, and neonatal), parity, and multiple birth rate. The AGA-GA group showed most satisfactory growth up to 56 months, with both the AGA-BW and SGA groups lagging behind. The AGA-GA group also scored significantly more highly on all developmental and cognitive tests than the other groups. Developmental test results were similar for the SGA and AGA-BW groups at five and 20 months, but AGA-BW infants (lowest gestation) had lower scores on performance intelligence quotient and language comprehension at 56 months than the SGA group. When prenatal and neonatal complications, parity, and multiple birth were accounted for, group differences in growth remained, but differences in cognitive outcome disappeared after five months.
CONCLUSIONS—Being underweight and with a short gestation (SGA and VLBW) leads to poor weight gain and head growth in infancy but does not result in poorer growth than in infants of the same birth weight but shorter gestation (AGA-BW) in the long term. SGA is related to early developmental delay and later language problems; however, neonatal complications may have a larger detrimental effect on long term cognitive development of VLBW infants than whether they are born SGA or AGA.


doi:10.1136/fn.82.3.F208
PMCID: PMC1721075  PMID: 10794788
24.  Interactions between Smoking and Weight in Pregnancies Complicated by Preeclampsia and Small-for-Gestational-Age Birth 
American Journal of Epidemiology  2008;168(4):427-433.
Cigarette smoking protects against preeclampsia but increases the risk of small-for-gestational-age birth (SGA). Regarding body weight, the converse is true: obesity elevates rates of preeclampsia but reduces rates of SGA. The authors assessed the combined effects of smoking and weight among US women developing preeclampsia or SGA, studying 7,757 healthy, primigravid women with singleton pregnancies in 1959–1965. Smoking (never, light, heavy), stratified by prepregnancy body mass index (BMI (weight (kg)/height (m)2); underweight, overweight, obese), was examined in relation to preeclampsia and SGA. Among underweight (BMI <18.5) and normal-weight (BMI 18.5–24.9) women, smoking decreased the risk of preeclampsia (for heavy smoking, light smoking, nonsmoking, test for trend p = 0.002 for underweight and p = 0.009 for normal weight) after adjustment for age, race, and socioeconomic status. However, among overweight/obese women (BMI ≥25), this trend was not apparent (p = 0.4). Among both underweight and overweight women, smoking significantly increased SGA risk (trend p < 0.001 for underweight and p = 0.02 for overweight/obese). Obesity eliminated the inverse association between smoking and preeclampsia but did not substantially alter the positive association between smoking and SGA. A possible unifying biologic explanation is discussed in this paper.
doi:10.1093/aje/kwn140
PMCID: PMC2562690  PMID: 18558661
body weight; infant, small for gestational age; overweight; pre-eclampsia; pregnancy; smoking
25.  Latin American Consensus: Children Born Small for Gestational Age 
BMC Pediatrics  2011;11:66.
Background
Children born small for gestational age (SGA) experience higher rates of morbidity and mortality than those born appropriate for gestational age. In Latin America, identification and optimal management of children born SGA is a critical issue. Leading experts in pediatric endocrinology throughout Latin America established working groups in order to discuss key challenges regarding the evaluation and management of children born SGA and ultimately develop a consensus statement.
Discussion
SGA is defined as a birth weight and/or birth length greater than 2 standard deviations (SD) below the population reference mean for gestational age. SGA refers to body size and implies length-weight reference data in a geographical population whose ethnicity is known and specific to this group. Ideally, each country/region within Latin America should establish its own standards and make relevant updates. SGA children should be evaluated with standardized measures by trained personnel every 3 months during year 1 and every 6 months during year 2. Those without catch-up growth within the first 6 months of life need further evaluation, as do children whose weight is ≤ -2 SD at age 2 years. Growth hormone treatment can begin in SGA children > 2 years with short stature (< -2.0 SD) and a growth velocity < 25th percentile for their age, and should continue until final height (a growth velocity below 2 cm/year or a bone age of > 14 years for girls and > 16 years for boys) is reached. Blood glucose, thyroid function, HbA1c, and insulin-like growth factor-1 (IGF-1) should be monitored once a year. Monitoring insulin changes from baseline and surrogates of insulin sensitivity is essential. Reduced fetal growth followed by excessive postnatal catch-up in height, and particularly in weight, should be closely monitored. In both sexes, gonadal function should be monitored especially during puberty.
Summary
Children born SGA should be carefully followed by a multidisciplinary group that includes perinatologists, pediatricians, nutritionists, and pediatric endocrinologists since 10% to 15% will continue to have weight and height deficiency through development and may benefit from growth hormone treatment. Standards/guidelines should be developed on a country/region basis throughout Latin America.
doi:10.1186/1471-2431-11-66
PMCID: PMC3163535  PMID: 21771322

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