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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
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.
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
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
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
PMCID: PMC3995658  PMID: 24755550
2.  Maternal and fetal variation in genes of cholesterol metabolism is associated with preterm delivery 
To examine the contribution of variants in fetal and maternal cholesterol metabolism genes in preterm delivery (PTD).
Study Design
A total of 40 single-nucleotide polymorphisms (SNPs) in 16 genes related to cholesterol metabolism were examined for 414 preterm infants (gestational ages 22 to 36 weeks; comprising 305 singletons and 109 twins) and at least 1 parent. Fetal effects were assessed using the transmission disequilibrium test (TDT) for each SNP, followed by a log linear model-based approach to utilize families with missing parental genotypes for those SNPs showing significance under TDT. Genetic variant effects were examined for a role in PTD, gestational age and birth weight. Maternal effects were estimated using a log linear model-based approach.
Among singleton gestations, suggestive association (P<0.01 without adjusting for multiple comparisons) was found between birth weight and fetal DHCR7 gene/SNP combinations (rs1630498, P=0.002 and rs2002064, P=0.003). Among all gestations, suggestive associations were found between PTD and fetal HMGCR (rs2303152, P=0.002) and APOA1 (rs 5070, P=0.004). The result for HMGCR was further supported by the log linear model-based test in the single births (P=0.007) and in all births (P=0.006). New associations (APOE and ABCA1) were observed when birth weight was normalized for gestational age suggesting independent effects of variants on birth weight separate from effects on PTD. Testing for maternally mediated genetic effects has identified suggestive association between ABCA1 (rs4149313, P=0.004) and decreased gestational age.
Variants in maternal and fetal genes for cholesterol metabolism were associated with PTD and decreased birth weight or gestational age in this study. Genetic markers may serve as one mechanism to identify high-risk mothers and fetuses for targeted nutritional treatment and/or prevention of low birth weight or PTD.
PMCID: PMC2706423  PMID: 17855807
prematurity; cholesterol; preterm delivery; birth weight
3.  A nearly continuous measure of birth weight for gestational age using a United States national reference 
BMC Pediatrics  2003;3:6.
Fully understanding the determinants and sequelae of fetal growth requires a continuous measure of birth weight adjusted for gestational age. Published United States reference data, however, provide estimates only of the median and lowest and highest 5th and 10th percentiles for birth weight at each gestational age. The purpose of our analysis was to create more continuous reference measures of birth weight for gestational age for use in epidemiologic analyses.
We used data from the most recent nationwide United States Natality datasets to generate multiple reference percentiles of birth weight at each completed week of gestation from 22 through 44 weeks. Gestational age was determined from last menstrual period. We analyzed data from 6,690,717 singleton infants with recorded birth weight and sex born to United States resident mothers in 1999 and 2000.
Birth weight rose with greater gestational age, with increasing slopes during the third trimester and a leveling off beyond 40 weeks. Boys had higher birth weights than girls, later born children higher weights than firstborns, and infants born to non-Hispanic white mothers higher birth weights than those born to non-Hispanic black mothers. These results correspond well with previously published estimates reporting limited percentiles.
Our method provides comprehensive reference values of birth weight at 22 through 44 completed weeks of gestation, derived from broadly based nationwide data. Other approaches require assumptions of normality or of a functional relationship between gestational age and birth weight, which may not be appropriate. These data should prove useful for researchers investigating the predictors and outcomes of altered fetal growth.
PMCID: PMC169185  PMID: 12848901
MeSH Headings: Birth weight; fetal weight; gestational age; premature birth; ultrasonography
4.  smoothHR: An R Package for Pointwise Nonparametric Estimation of Hazard Ratio Curves of Continuous Predictors 
The Cox proportional hazards regression model has become the traditional choice for modeling survival data in medical studies. To introduce flexibility into the Cox model, several smoothing methods may be applied, and approaches based on splines are the most frequently considered in this context. To better understand the effects that each continuous covariate has on the outcome, results can be expressed in terms of splines-based hazard ratio (HR) curves, taking a specific covariate value as reference. Despite the potential advantages of using spline smoothing methods in survival analysis, there is currently no analytical method in the R software to choose the optimal degrees of freedom in multivariable Cox models (with two or more nonlinear covariate effects). This paper describes an R package, called smoothHR, that allows the computation of pointwise estimates of the HRs—and their corresponding confidence limits—of continuous predictors introduced nonlinearly. In addition the package provides functions for choosing automatically the degrees of freedom in multivariable Cox models. The package is available from the R homepage. We illustrate the use of the key functions of the smoothHR package using data from a study on breast cancer and data on acute coronary syndrome, from Galicia, Spain.
PMCID: PMC3876718  PMID: 24454541
Fetal hypoxemia has been proposed to be one of the mechanisms of preterm labor (PTL) and delivery. This may have clinical implications since it may alter: 1) the method/frequency of fetal surveillance; and 2) the indications and duration of tocolysis to an already compromised fetus. The aim of this study was to examine whether there is a difference in the fetal blood gas analysis [pH, PaO2 and base excess (BE)] and in the prevalence of fetal acidemia and hypoxia between: 1) patients in PTL who delivered within 72 hours vs. those who delivered more than 72 hours after cordocentesis; and 2) patients with Fetal Inflammatory Response Syndrome (FIRS) vs. those without this condition.
Patients admitted with PTL underwent amniocentesis and cordocentesis. Ninety women with singleton pregnancies and PTL were classified according to 1) those who delivered within 72 hours (n = 30) and after 72 hours of the cordocentesis (n = 60); and 2) with and without FIRS. FIRS was defined as a fetal plasma concentration of IL-6 >11 pg/mL. Fetal blood gases were determined. Acidemia and hypoxemia were defined as fetal pH and PaO2 below the 5th percentile for gestational age, respectively. For comparisons between the two study groups, ΔpH and ΔPaO2 were calculated by adjusting for gestational age (Δ = observed value-mean for gestational age). Non-parametric statistics were employed.
No differences in the median Δ pH (−0.026 vs. −0.016), ΔPaO2 (0.25 mmHg vs. 5.9 mmHg) or BE (−2.4 mEq/L vs. −2.6 mEq/L) were found between patients with PTL who delivered within 72 hours and those who delivered 72 hours after the cordocentesis (p>0.05 for all comparisons). Fetal plasma IL-6 concentration was determined in 63% (57/90) of fetuses and the prevalence of FIRS was 28% (16/57). There was no difference in fetal pH, PaO2 and BE between fetuses with and without FIRS (p>0.05 for all comparisons). Moreover, there was no difference in the rate of fetal acidemia between fetuses with and without FIRS (6.3% vs. 9.8%; p>0.05) and fetal hypoxia between fetuses with or without FIRS (12.5% vs. 19.5%; p>0.05).
Our data do not support a role for acute fetal hypoxemia and metabolic acidemia in the etiology of preterm labor and delivery.
PMCID: PMC3383905  PMID: 21988103
Base excess; cordocentesis; fetal blood gases; hypoxia; intra-amniotic infection; pregnancy; PaO2
6.  Preeclampsia as a Risk Factor for Diabetes: A Population-Based Cohort Study 
PLoS Medicine  2013;10(4):e1001425.
Denice Feig and colleagues assess the association between gestational diabetes, gestational hypertension, and preeclampsia and the development of future diabetes in a database analysis of pregnant women in Ontario, Canada.
Women with preeclampsia (PEC) and gestational hypertension (GH) exhibit insulin resistance during pregnancy, independent of obesity and glucose intolerance. Our aim was to determine whether women with PEC or GH during pregnancy have an increased risk of developing diabetes after pregnancy, and whether the presence of PEC/GH in addition to gestational diabetes (GDM) increases the risk of future (postpartum) diabetes.
Methods and Findings
We performed a population-based, retrospective cohort study for 1,010,068 pregnant women who delivered in Ontario, Canada between April 1994 and March 2008. Women were categorized as having PEC alone (n = 22,933), GH alone (n = 27,605), GDM alone (n = 30,852), GDM+PEC (n = 1,476), GDM+GH (n = 2,100), or none of these conditions (n = 925,102). Our main outcome was a new diagnosis of diabetes postpartum in the following years, up until March 2011, based on new records in the Ontario Diabetes Database. The incidence rate of diabetes per 1,000 person-years was 6.47 for women with PEC and 5.26 for GH compared with 2.81 in women with neither of these conditions. In the multivariable analysis, both PEC alone (hazard ratio [HR] = 2.08; 95% CI 1.97–2.19) and GH alone (HR = 1.95; 95% CI 1.83–2.07) were risk factors for subsequent diabetes. Women with GDM alone were at elevated risk of developing diabetes postpartum (HR = 12.77; 95% CI 12.44–13.10); however, the co–presence of PEC or GH in addition to GDM further elevated this risk (HR = 15.75; 95% CI 14.52–17.07, and HR = 18.49; 95% CI 17.12–19.96, respectively). Data on obesity were not available.
Women with PEC/GH have a 2-fold increased risk of developing diabetes when followed up to 16.5 years after pregnancy, even in the absence of GDM. The presence of PEC/GH in the setting of GDM also raised the risk of diabetes significantly beyond that seen with GDM alone. A history of PEC/GH during pregnancy should alert clinicians to the need for preventative counseling and more vigilant screening for diabetes.
Please see later in the article for the Editors' Summary
Editors' Summary
Diabetes is a chronic disease that occurs either when the pancreas does not produce enough insulin (a hormone that regulates blood sugar), known as type 1 diabetes, or when the body cannot effectively use the insulin it produces—type 2 diabetes. Raised blood sugar, is a common effect of uncontrolled diabetes and over time leads to serious complications and even death. Worryingly, the global burden of type 2 diabetes is increasing worldwide, and the World Health Organization estimates that 90% of the 347 million people with diabetes currently have type 2 diabetes. Previous studies have shown that type 2 diabetes can be prevented or delayed in high risk groups by a range of lifestyle and treatment interventions and so it is important to identify potential high risk groups to screen for type 2 diabetes.
Why Was This Study Done?
Gestational diabetes (a form of diabetes that is related to pregnancy) is a major risk factor for developing type 2 diabetes. Therefore, diabetes prevention strategies should target women with gestational diabetes. Likewise, other common disorders of pregnancy possibly associated with insulin resistance, such as preeclampsia (a condition in which affected women have high blood pressure, fluid retention, and protein in their urine) and gestational hypertension (high blood pressure associated with pregnancy), may lead to the future development of type 2 diabetes. So women with these conditions may also benefit from diabetes prevention strategies. Therefore, in this large database study from Ontario, Canada, the researchers examined whether pregnant women with preeclampsia or gestational hypertension had an increased risk of developing diabetes in the years following pregnancy even if they did not have gestational diabetes.
What Did the Researchers Do and Find?
The researchers used a comprehensive Canadian health database to identify all women age 15 to 50 years of age who delivered in an Ontario hospital between April 1994 and March 2008. They then identified women who had preeclampsia, gestational hypertension, or gestational diabetes through hospital records and outpatient information. The researchers then used records from the Ontario Diabetes Database to record whether these women went on to develop diabetes in the period from 180 days after delivery until March 2011.
Using these methods, the researchers identified 1,010,068 pregnant women suitable for analysis, of whom 22,933 had only preeclampsia, 27,605 had only gestational hypertension, and 30,852 had only gestational diabetes: 2,100 women had both gestational diabetes and gestational hypertension and 1,476 women had gestational diabetes and preeclampsia. Overall, 35,077 women developed diabetes (3.5%) in the follow-up period (median of 8.5 years) at a median age of 37 years. In a modeling analysis, the researchers found that women with gestational diabetes had a 15-fold increased rate of developing diabetes compared to women without gestational diabetes, gestational hypertension, and preeclampsia, while women with gestational diabetes plus either preeclampsia or gestational hypertension had a 20- to 21-fold increased rate. These results were slightly reduced after adjusting for age, income quintile, hypertension prior to pregnancy, and co-morbidity, giving a hazard ratio (HR) of 1.95 for gestational hypertension alone, an HR of 2.08 for preeclampsia alone, an HR of 12.77 for gestational diabetes alone, an HR of 18.49 for gestational diabetes plus gestational hypertension and finally, an HR of 15.75 for gestational diabetes plus preeclampsia.
These Findings Mean?
These findings suggest that both preeclampsia and gestational hypertension without gestational diabetes are associated with a 2-fold increased incidence of diabetes in the years following pregnancy after controlling for several important variables. When combined with gestational diabetes, these conditions were associated with a further elevation in diabetes incidence additional to the 13-fold increased incidence resulting from gestational diabetes alone. A limitation of this study was the lack of information on obesity and body mass index, factors which are also associated with increased risk of developing diabetes. Nevertheless, these findings highlight a possible new risk factor for diabetes, and suggest that clinicians should be aware of the need for preventative measures and vigilant screening for diabetes in women with a history of preeclampsia or gestational hypertension.
Additional Information
Please access these Web sites via the online version of this summary at
NHS Choices has information about preeclampsia, gestational diabetes, and gestational hypertension
Living with diabetes is a useful resource for patients with diabetes
The Preeclampsia Foundation has more information about preeclampsia
PMCID: PMC3627640  PMID: 23610560
7.  Individually customised fetal weight charts derived from ultrasound measurements: the Generation R Study 
European Journal of Epidemiology  2011;26(12):919-926.
Maternal and fetal characteristics are important determinants of fetal growth potential, and should ideally be taken into consideration when evaluating fetal growth variation. We developed a model for individually customised growth charts for estimated fetal weight, which takes into account physiological maternal and fetal characteristics known at the start of pregnancy. We used fetal ultrasound data of 8,162 pregnant women participating in the Generation R Study, a prospective, population-based cohort study from early pregnancy onwards. A repeated measurements regression model was constructed, using backward selection procedures for identifying relevant maternal and fetal characteristics. The final model for estimating expected fetal weight included gestational age, fetal sex, parity, ethnicity, maternal age, height and weight. Using this model, we developed individually customised growth charts, and their corresponding standard deviations, for fetal weight from 18 weeks onwards. Of the total of 495 fetuses who were classified as small size for gestational age (<10th percentile) when fetal weight was evaluated using the normal population growth chart, 80 (16%) were in the normal range when individually customised growth charts were used. 550 fetuses were classified as small size for gestational age using individually customised growth charts, and 135 of them (25%) were classified as normal if the unadjusted reference chart was used. In conclusion, this is the first study using ultrasound measurements in a large population-based study to fit a model to construct individually customised growth charts, taking into account physiological maternal and fetal characteristics. These charts might be useful for use in epidemiological studies and in clinical practice.
Electronic supplementary material
The online version of this article (doi:10.1007/s10654-011-9629-7) contains supplementary material, which is available to authorized users.
PMCID: PMC3253277  PMID: 22083366
Customised fetal growth curves; Ultrasound; Fetal weight; Biometry; Ethnicity; Maternal anthropometrics
8.  First trimester screening for trisomy 21 in gestational week 8-10 by ADAM12-S as a maternal serum marker 
A disintegrin and metalloprotease 12 (ADAM12-S) has previously been reported to be significantly reduced in maternal serum from women with fetal aneuploidy early in the first trimester and to significantly improve the quality of risk assessment for fetal trisomy 21 in prenatal screening. The aim of this study was to determine whether ADAM12-S is a useful serum marker for fetal trisomy 21 using the mixture model.
In this case control study ADAM12-S was measured by KRYPTOR ADAM12-S immunoassay in maternal serum from gestational weeks 8 to 11 in 46 samples of fetal trisomy 21 and in 645 controls. Comparison of sensitivity and specificity of first trimester screening for fetal trisomy 21 with or without ADAM12-S included in the risk assessment using the mixture model.
The concentration of ADAM12-S increased from week 8 to 11 and was negatively correlated with maternal weight. Log MoM ADAM12-S was positively correlated with log MoM PAPP-A (r = 0.39, P < 0.001), and with log MoM free beta hCG (r = 0.21, P < 0.001). The median ADAM12-S MoM in cases of fetal trisomy 21 in gestational week 8 was 0.66 increasing to approx. 0.9 MoM in week 9 and 10. The use of ADAM12-S along with biochemical markers from the combined test (PAPP-A, free beta hCG) with or without nuchal translucency measurement did not affect the detection rate or false positive rate of fetal aneuploidy as compared to routine screening using PAPP-A and free β-hCG with or without nuchal translucency.
The data show moderately decreased levels of ADAM12-S in cases of fetal aneuploidy in gestational weeks 8-11. However, including ADAM12-S in the routine risk does not improve the performance of first trimester screening for fetal trisomy 21.
PMCID: PMC2984461  PMID: 21034452
9.  Maternal Exposure to Bisphenol-A and Fetal Growth Restriction: A Case-Referent Study 
We conducted a case-referent study of the effect of exposure to bisphenol-A on fetal growth in utero in full-term, live-born singletons in Alberta, Canada. Newborns <10 percentile of expected weight for gestational age and sex were individually matched on sex, maternal smoking and maternal age to referents with weight appropriate to gestational age. Exposure of the fetus to bisphenol-A was estimated from maternal serum collected at 15–16 weeks of gestation. We pooled sera across subjects for exposure assessment, stratified on case-referent status and sex. Individual 1:1 matching was maintained in assembling 69 case and 69 referent pools created from 550 case-referent pairs. Matched pools had an equal number of aliquots from individual women. We used an analytical strategy conditioning on matched set and total pool-level values of covariates to estimate individual-level effects. Pools of cases and referents had identical geometric mean bisphenol-A concentrations (0.5 ng/mL) and similar geometric standard deviations (2.3–2.5). Mean difference in concentration between matched pools was 0 ng/mL, standard deviation: 1 ng/mL. Stratification by sex and control for confounding did not suggest bisphenol-A increased fetal growth restriction. Our analysis does not provide evidence to support the hypothesis that bisphenol-A contributes to fetal growth restriction in full-term singletons.
PMCID: PMC3881152  PMID: 24336026
BPA; endocrine disruption; small for gestation age; birth weight; epidemiology
10.  New birth weight reference standards customised to birth order and sex of babies from South India 
The foetal growth standards for Indian children which are available today suffer due to methodological problems. These are, for example, not adhering to the WHO recommendation to base gestational age on the number of completed weeks and secondly, not excluding mothers with risk factors. This study has addressed both the above issues and in addition provides birthweight reference ranges with regard to sex of the baby and maternal parity.
Data from the labour room register from 1996 to 2010 was obtained. A rotational sampling scheme was used i.e. the 12 months of the year were divided into 4 quadrants. All deliveries in January were considered to represent the first quadrant. Similarly all deliveries in April, July and October were considered to represent 2nd, 3rd and 4th quadrants. In each successive year different months were included in each quadrant. Only those mothers aged 20–39 years and delivered between 24 to 42 weeks gestational age were considered. Those mothers with obstetric risk factors were excluded. The reference standards were fitted using the Generalized Additive Models for Location Scale and Shape (GAMLSS) method for Box – Cox t distribution with cubic spline smoothing.
There were 41,055 deliveries considered. When women with risk factors were excluded 19,501 deliveries could be included in the final analysis. The male babies of term firstborn were found to be 45 g heavier than female babies. The mean birthweights were 2934 g and 2889.5 g respectively. Similarly, among the preterm babies, the first born male babies weighed 152 g more than the female babies. The mean birthweights were 1996 g and 1844 g respectively.
In the case of later born babies, the term male babies weighed 116grams more than the females. The mean birth weights were 3085 grams and 2969 grams respectively. When considering later born preterm babies, the males outweighed the female babies by 111 grams. The mean birthweights were 2089 grams and 1978 grams respectively. There was a substantial agreement range from k=.883, (p<.01) to k=.943, (p<.01) between adjusted and unadjusted percentile classification for the subgroups of male and female babies and first born and later born ones.
Birth weight charts were adjusted for maternal height using regression methods. The birth weight charts for the first born and later born babies were regrouped into 4 categories, including male and female sexes of the babies. Reference ranges were acquired both for term and preterm babies.
With economic reforms, one expects improvement in birthweights. The mean (sd) birthweights of the year 1996 was 2846 (562) as compared to year 2010 (15 years later) which was 2907 (571). There was only a difference of 61 grams in the mean birthweights over one and a half decade.
New standards are presented from a large number of deliveries over 15 years, customised to the maternal height, from a south Indian tertiary hospital. Reference ranges are made available separately for first born or later born babies, for male and female sexes and for term and preterm babies.
PMCID: PMC3583685  PMID: 23409828
Reference; Foetal growth; Birth weight; Gestational age; Preterm; Modelling; Box–Cox t; Cubic spline smoothing
11.  Optimal fetal growth for the Caucasian singleton and assessment of appropriateness of fetal growth: an analysis of a total population perinatal database 
BMC Pediatrics  2005;5:13.
The appropriateness of an individual's intra uterine growth is now considered an important determinant of both short and long term outcomes, yet currently used measures have several shortcomings. This study demonstrates a method of assessing appropriateness of intrauterine growth based on the estimation of each individual's optimal newborn dimensions from routinely available perinatal data. Appropriateness of growth can then be inferred from the ratio of the value of the observed dimension to that of the optimal dimension.
Fractional polynomial regression models including terms for non-pathological determinants of fetal size (gestational duration, fetal gender and maternal height, age and parity) were used to predict birth weight, birth length and head circumference from a population without any major risk factors for sub-optimal intra-uterine growth. This population was selected from a total population of all singleton, Caucasian births in Western Australia 1998–2002. Births were excluded if the pregnancy was exposed to factors known to influence fetal growth pathologically. The values predicted by these models were treated as the optimal values, given infant gender, gestational age, maternal height, parity, and age.
The selected sample (N = 62,746) comprised 60.5% of the total Caucasian singleton birth cohort. Equations are presented that predict optimal birth weight, birth length and head circumference given gestational duration, fetal gender, maternal height, age and parity. The best fitting models explained 40.5% of variance for birth weight, 32.2% for birth length, and 25.2% for head circumference at birth.
Proportion of optimal birth weight (length or head circumference) provides a method of assessing appropriateness of intrauterine growth that is less dependent on the health of the reference population or the quality of their morphometric data than is percentile position on a birth weight distribution.
PMCID: PMC1174874  PMID: 15910694
12.  Application of Smoothing Methods for Determining of the Effecting Factors on the Survival Rate of Gastric Cancer Patients 
Smoothing methods are widely used to analyze epidemiologic data, particularly in the area of environmental health where non-linear relationships are not uncommon. This study focused on three different smoothing methods in Cox models: penalized splines, restricted cubic splines and fractional polynomials.
The aim of this study was to assess the effects of prognostic factors on survival of patients with gastric cancer using the smoothing methods in Cox model and Cox proportional hazards. Also, all models were compared to each other in order to find the best one.
Materials and Methods
We retrospectively studied 216 patients with gastric cancer who were registered in one referral cancer registry center in Tehran, Iran. Age at diagnosis, sex, presence of metastasis, tumor size, histology type, lymph node metastasis, and pathologic stages were entered in to analysis using the Cox proportional hazards model and smoothing methods in Cox model. The SPSS version 18.0 and R version 2.14.1 were used for data analysis. These models compared with Akaike information criterion.
In this study, The 5 year survival rate was 30%. The Cox proportional hazards, penalized spline and fractional polynomial models let to similar results and Akaike information criterion showed a better performance for these three models comparing to the restricted cubic spline. Also, P-value and likelihood ratio test in restricted cubic spline was greater than other models. Note that the best model is indicated by the lowest Akaike information criterion.
The use of smoothing methods helps us to eliminate non-linear effects but it is more appropriate to use Cox proportional hazards model in medical data because of its’ ease of interpretation and capability of modeling both continuous and discrete covariates. Also, Cox proportional hazards model and smoothing methods analysis identified that age at diagnosis and tumor size were independent prognostic factors for the survival of patients with gastric cancer (P < 0.05). According to these results the early detection of patients at younger age and in primary stages may be important to increase survival.
PMCID: PMC3652506  PMID: 23682331
Proportional Hazards Models; Survival; Stomach Neoplasms
13.  Placental Weight Mediates the Effects of Prenatal Factors on Fetal Growth: the Extent Differs by Preterm Status 
Obesity (Silver Spring, Md.)  2013;21(3):10.1002/oby.20254.
Elevated pre-pregnancy body mass index (BMI), excessive gestational weight gain (GWG), and gestational diabetes (GDM) are known determinants of fetal growth. The role of placental weight is unclear. We aimed to examine the extent to which placental weight mediates the associations of pre-pregnancy BMI, GWG, and GDM with birthweight-for-gestational age, and whether the relationships differ by preterm status. We examined 1035 mother-infant pairs at birth from the Boston Birth Cohort. Data were collected by questionnaire and clinical measures. Placentas were weighed without membranes or umbilical cords. We performed sequential models excluding and including placental weight, stratified by preterm status. We found that 21% of mothers were obese, 42% had excessive GWG, and 5% had GDM. 41% were preterm. Among term births, after adjustment for sex, gestational age, maternal age, race, parity, education, smoking and stress during pregnancy, birthweight-for-gestational age z-score was 0.55 (0.30, 0.80) units higher for pre-pregnancy obesity vs. normal weight. It was 0.34 (0.13, 0.55) higher for excessive vs. adequate GWG, 0.67 (0.24, 1.10) for GDM vs. no DM, with additional adjustment for pre-pregnancy BMI. Adding placental weight to the models attenuated the estimates for pre-pregnancy obesity by 20%, excessive GWG by 32%, and GDM by 21%. Among preterm infants, GDM was associated with 0.67 (0.34, 1.00) higher birthweight-for-gestational age z-score, but pre-pregnancy obesity and excessive GWG were not. Attenuation by placental weight was 36% for GDM. These results suggest that placental weight partially mediates the effects of pre-pregnancy obesity, GDM and excessive GWG on fetal growth among term infants.
PMCID: PMC3418379  PMID: 23592670
pre-pregnancy BMI; gestational weight gain; gestational diabetes; placental weight; fetal growth; birth weight z-score
14.  Second Trimester Estimated Fetal Weight and Fetal Weight Gain Predict Childhood Obesity 
The Journal of pediatrics  2012;161(5):864-870.
To determine the extent to which fetal weight during mid-pregnancy and fetal weight gain from mid-pregnancy to birth predict adiposity and blood pressure (BP) at age 3 years.
Study design
Among 438 children in the Project Viva cohort, we estimated fetal weight at 16–20 (median 18) weeks gestation using ultrasound biometry measures. We analyzed fetal weight gain as change in quartile of weight from the second trimester until birth, and we measured height, weight, subscapular and triceps skinfold thicknesses and BP at age 3.
Mean (SD) estimated weight at 16–20 weeks was 234 (30) grams and birth weight was 3518 (420) grams. In adjusted models, weight estimated during the second trimester and at birth were associated with higher BMI z-scores at age 3 years (0.32 units [95% C.I. 0.04, 0.60] and 0.53 units [95% C.I. 0.24, 0.81] for the highest v. lowest quartile of weight). Infants with more rapid fetal weight gain and those who remained large from mid-pregnancy to birth had higher BMI z-scores (0.85 units [95% C.I. 0.30, 1.39] and 0.63 units [95% C.I. 0.17, 1.09], respectively) at age 3 than infants who remained small during fetal life. We did not find associations between our main predictors and sum or ratio of subscapular and triceps skinfold thicknesses or systolic BP.
More rapid fetal weight gain and persistently high fetal weight during the second half of gestation predicted higher BMI z-score at age 3 years. The rate of fetal weight gain throughout pregnancy may be important for future risk of adiposity in childhood.
PMCID: PMC3962288  PMID: 22682615
childhood blood pressure; cohort
15.  Association of Birth Weight With Asthma-Related Outcomes at Age 2 Years 
Pediatric pulmonology  2006;41(7):643-648.
Summary. Background: Although lower birth weight associated with prematurity raises the risk of asthma in childhood, few prospective studies have examined higher birth weight, and few have separated the two components of birth weight, fetal growth and length of gestation.
Objective. To examine the associations of fetal growth and length of gestation with asthma-related outcomes by age 2 years.
Methods. We studied 1,372 infants and toddlers born after 34 weeks’ gestation in Project Viva, a prospective cohort study of pregnant mothers and their children. The main outcome measures were parent report of (1) any wheezing (or whistling in the chest) from birth to age 2 years, (2) recurrent wheezing during the first 2 years of life, and (3) doctor’s diagnosis of asthma, wheeze or reactive airwaydisease (“asthma”) by age 2. We calculated gestational age from the last menstrual period or ultrasound examination, and determined birth weight for gestational age z-value (“fetal growth”) using US national reference data.
Results. Infants’ mean birth weight was 3,527 (SD, 517; range, 1,559–5,528) grams. By age 2 years, 34% of children had any wheezing, 14% had recurrent wheezing, and 16% had doctor-diagnosed asthma. After adjusting for several parent, child, and household characteristics in logistic regression models, we found that infants with birth weight ≥4,000 g were not more likely to have any wheezing (odds ratio (OR), 0.91; 95% confidence interval (CI): 0.62, 1.34) or doctor-diagnosed asthma (OR, 0.80; 95% CI: 0.49, 1.31) than infants with birth weight 3,500–3,999 g. In models examining length of gestation and fetal growth separately, neither the highest nor the lowest groups of either predictor were associated with the three outcomes. Boys had a higher incidence of asthma-related outcomes than girls, and exposure to passive smoking, parental history of asthma, and exposure to older siblings were all associated with greater risk of recurrent wheeze or asthma-related outcomes at age 2 years.
Conclusion. Although male sex, exposure to smoking, parental history of asthma, and exposure to older siblingswere associated with increased riskof wheezing and asthma-related outcomes in this prospective study of children born after 34 weeks gestation, fetal growth and length of gestation were not.
PMCID: PMC1488724  PMID: 16703577
asthma; birth weight; fetal growth; length of gestation; wheezing
16.  Fetal autonomic brain age scores, segmented heart rate variability analysis, and traditional short term variability 
Disturbances of fetal autonomic brain development can be evaluated from fetal heart rate patterns (HRP) reflecting the activity of the autonomic nervous system. Although HRP analysis from cardiotocographic (CTG) recordings is established for fetal surveillance, temporal resolution is low. Fetal magnetocardiography (MCG), however, provides stable continuous recordings at a higher temporal resolution combined with a more precise heart rate variability (HRV) analysis. A direct comparison of CTG and MCG based HRV analysis is pending. The aims of the present study are: (i) to compare the fetal maturation age predicting value of the MCG based fetal Autonomic Brain Age Score (fABAS) approach with that of CTG based Dawes-Redman methodology; and (ii) to elaborate fABAS methodology by segmentation according to fetal behavioral states and HRP. We investigated MCG recordings from 418 normal fetuses, aged between 21 and 40 weeks of gestation. In linear regression models we obtained an age predicting value of CTG compatible short term variability (STV) of R2 = 0.200 (coefficient of determination) in contrast to MCG/fABAS related multivariate models with R2 = 0.648 in 30 min recordings, R2 = 0.610 in active sleep segments of 10 min, and R2 = 0.626 in quiet sleep segments of 10 min. Additionally segmented analysis under particular exclusion of accelerations (AC) and decelerations (DC) in quiet sleep resulted in a novel multivariate model with R2 = 0.706. According to our results, fMCG based fABAS may provide a promising tool for the estimation of fetal autonomic brain age. Beside other traditional and novel HRV indices as possible indicators of developmental disturbances, the establishment of a fABAS score normogram may represent a specific reference. The present results are intended to contribute to further exploration and validation using independent data sets and multicenter research structures.
PMCID: PMC4243554  PMID: 25505399
prenatal diagnosis; fetal autonomic brain age; magnetocardiography; cardiotocography
17.  Modeling Dose-Dependent Neural Processing Responses Using Mixed Effects Spline Models: with application to a PET study of ethanol 
NeuroImage  2007;40(2):698-711.
For functional neuroimaging studies that involve experimental stimuli measuring dose levels, e.g. of an anesthetic agent, typical statistical techniques include correlation analysis, analysis of variance or polynomial regression models. These standard approaches have limitations: correlation analysis only provides a crude estimate of the linear relationship between dose levels and brain activity; ANOVA is designed to accommodate a few specified dose levels; polynomial regression models have limited capacity to model varying patterns of association between dose levels and measured activity across the brain. These shortcomings prompt the need to develop methods that more effectively capture dose-dependent neural processing responses. We propose a class of mixed effects spline models that analyze the dose-dependent effect using either regression or smoothing splines. Our method offers flexible accommodation of different response patterns across various brain regions, controls for potential confounding factors, and accounts for subject variability in brain function. The estimates from the mixed effects spline model can be readily incorporated into secondary analyses, for instance, targeting spatial classifications of brain regions according to their modeled response profiles. The proposed spline models are also extended to incorporate interaction effects between the dose-dependent response function and other factors. We illustrate our proposed statistical methodology using data from a PET study of the effect of ethanol on brain function. A simulation study is conducted to compare the performance of the proposed mixed effects spline models and a polynomial regression model. Results show that the proposed spline models more accurately capture varying response patterns across voxels, especially at voxels with complex response shapes. Finally, the proposed spline models can be used in more general settings as a flexible modeling tool for investigating the effects of any continuous covariates on neural processing responses.
PMCID: PMC2323024  PMID: 18206392
Regression splines; Smoothing splines; Dose-dependent effect; Mixed effects spline models; Continuous covariates
18.  Particulate matter exposure during pregnancy is associated with birth weight, but not gestational age, 1962-1992: a cohort study 
Environmental Health  2012;11:13.
Exposure to air pollutants is suggested to adversely affect fetal growth, but the evidence remains inconsistent in relation to specific outcomes and exposure windows.
Using birth records from the two major maternity hospitals in Newcastle upon Tyne in northern England between 1961 and 1992, we constructed a database of all births to mothers resident within the city. Weekly black smoke exposure levels from routine data recorded at 20 air pollution monitoring stations were obtained and individual exposures were estimated via a two-stage modeling strategy, incorporating temporally and spatially varying covariates. Regression analyses, including 88,679 births, assessed potential associations between exposure to black smoke and birth weight, gestational age and birth weight standardized for gestational age and sex.
Significant associations were seen between black smoke and both standardized and unstandardized birth weight, but not for gestational age when adjusted for potential confounders. Not all associations were linear. For an increase in whole pregnancy black smoke exposure, from the 1st (7.4 μg/m3) to the 25th (17.2 μg/m3), 50th (33.8 μg/m3), 75th (108.3 μg/m3), and 90th (180.8 μg/m3) percentiles, the adjusted estimated decreases in birth weight were 33 g (SE 1.05), 62 g (1.63), 98 g (2.26) and 109 g (2.44) respectively. A significant interaction was observed between socio-economic deprivation and black smoke on both standardized and unstandardized birth weight with increasing effects of black smoke in reducing birth weight seen with increasing socio-economic disadvantage.
The findings of this study progress the hypothesis that the association between black smoke and birth weight may be mediated through intrauterine growth restriction. The associations between black smoke and birth weight were of the same order of magnitude as those reported for passive smoking. These findings add to the growing evidence of the harmful effects of air pollution on birth outcomes.
PMCID: PMC3324390  PMID: 22404858
Black smoke; Particulate matter; Air pollution; Birth weight; Gestational age
19.  Use of linear mixed models for genetic evaluation of gestation length and birth weight allowing for heavy-tailed residual effects 
The distribution of residual effects in linear mixed models in animal breeding applications is typically assumed normal, which makes inferences vulnerable to outlier observations. In order to mute the impact of outliers, one option is to fit models with residuals having a heavy-tailed distribution. Here, a Student's-t model was considered for the distribution of the residuals with the degrees of freedom treated as unknown. Bayesian inference was used to investigate a bivariate Student's-t (BSt) model using Markov chain Monte Carlo methods in a simulation study and analysing field data for gestation length and birth weight permitted to study the practical implications of fitting heavy-tailed distributions for residuals in linear mixed models.
In the simulation study, bivariate residuals were generated using Student's-t distribution with 4 or 12 degrees of freedom, or a normal distribution. Sire models with bivariate Student's-t or normal residuals were fitted to each simulated dataset using a hierarchical Bayesian approach. For the field data, consisting of gestation length and birth weight records on 7,883 Italian Piemontese cattle, a sire-maternal grandsire model including fixed effects of sex-age of dam and uncorrelated random herd-year-season effects were fitted using a hierarchical Bayesian approach. Residuals were defined to follow bivariate normal or Student's-t distributions with unknown degrees of freedom.
Posterior mean estimates of degrees of freedom parameters seemed to be accurate and unbiased in the simulation study. Estimates of sire and herd variances were similar, if not identical, across fitted models. In the field data, there was strong support based on predictive log-likelihood values for the Student's-t error model. Most of the posterior density for degrees of freedom was below 4. Posterior means of direct and maternal heritabilities for birth weight were smaller in the Student's-t model than those in the normal model. Re-rankings of sires were observed between heavy-tailed and normal models.
Reliable estimates of degrees of freedom were obtained in all simulated heavy-tailed and normal datasets. The predictive log-likelihood was able to distinguish the correct model among the models fitted to heavy-tailed datasets. There was no disadvantage of fitting a heavy-tailed model when the true model was normal. Predictive log-likelihood values indicated that heavy-tailed models with low degrees of freedom values fitted gestation length and birth weight data better than a model with normally distributed residuals.
Heavy-tailed and normal models resulted in different estimates of direct and maternal heritabilities, and different sire rankings. Heavy-tailed models may be more appropriate for reliable estimation of genetic parameters from field data.
PMCID: PMC2909158  PMID: 20591149
20.  Reexamining the effects of gestational age, fetal growth, and maternal smoking on neonatal mortality 
Low birth weight (<2,500 g) is a strong predictor of infant mortality. Yet low birth weight, in isolation, is uninformative since it is comprised of two intertwined components: preterm delivery and reduced fetal growth. Through nonparametric logistic regression models, we examine the effects of gestational age, fetal growth, and maternal smoking on neonatal mortality.
We derived data on over 10 million singleton live births delivered at ≥ 24 weeks from the 1998–2000 U.S. natality data files. Nonparametric multivariable logistic regression based on generalized additive models was used to examine neonatal mortality (deaths within the first 28 days) in relation to fetal growth (gestational age-specific standardized birth weight), gestational age, and number of cigarettes smoked per day. All analyses were further adjusted for the confounding effects due to maternal age and gravidity.
The relationship between standardized birth weight and neonatal mortality is nonlinear; mortality is high at low z-score birth weights, drops precipitously with increasing z-score birth weight, and begins to flatten for heavier infants. Gestational age is also strongly associated with mortality, with patterns similar to those of z-score birth weight. Although the direct effect of smoking on neonatal mortality is weak, its effects (on mortality) appear to be largely mediated through reduced fetal growth and, to a lesser extent, through shortened gestation. In fact, the association between smoking and reduced fetal growth gets stronger as pregnancies approach term.
Our study provides important insights regarding the combined effects of fetal growth, gestational age, and smoking on neonatal mortality. The findings suggest that the effect of maternal smoking on neonatal mortality is largely mediated through reduced fetal growth.
PMCID: PMC535930  PMID: 15574192
21.  First trimester fetal growth restriction and cardiovascular risk factors in school age children: population based cohort study 
Objective To examine whether first trimester fetal growth restriction correlates with cardiovascular outcomes in childhood.
Design Population based prospective cohort study.
Setting City of Rotterdam, the Netherlands.
Participants 1184 children with first trimester fetal crown to rump length measurements, whose mothers had a reliable first day of their last menstrual period and a regular menstrual cycle.
Main outcomes measures Body mass index, total and abdominal fat distribution, blood pressure, and blood concentrations of cholesterol, triglycerides, insulin, and C peptide at the median age of 6.0 (90% range 5.7-6.8) years. Clustering of cardiovascular risk factors was defined as having three or more of: high android fat mass; high systolic or diastolic blood pressure; low high density lipoprotein cholesterol or high triglycerides concentrations; and high insulin concentrations.
Results One standard deviation score greater first trimester fetal crown to rump length was associated with a lower total fat mass (−0.30%, 95% confidence interval −0.57% to −0.03%), android fat mass (−0.07%, −0.12% to −0.02%), android/gynoid fat mass ratio (−0.53, −0.89 to −0.17), diastolic blood pressure (−0.43, −0.84 to −0.01, mm Hg), total cholesterol (−0.05, −0.10 to 0, mmol/L), low density lipoprotein cholesterol (−0.04, −0.09 to 0, mmol/L), and risk of clustering of cardiovascular risk factors (relative risk 0.81, 0.66 to 1.00) in childhood. Additional adjustment for gestational age and weight at birth changed these effect estimates only slightly. Childhood body mass index fully explained the associations of first trimester fetal crown to rump length with childhood total fat mass. First trimester fetal growth was not associated with other cardiovascular outcomes. Longitudinal growth analyses showed that compared with school age children without clustering of cardiovascular risk factors, those with clustering had a smaller first trimester fetal crown to rump length and lower second and third trimester estimated fetal weight but higher weight growth from the age of 6 months onwards.
Conclusions Impaired first trimester fetal growth is associated with an adverse cardiovascular risk profile in school age children. Early fetal life might be a critical period for cardiovascular health in later life.
PMCID: PMC3901421  PMID: 24458585
22.  A semi-parametric generalization of the Cox proportional hazards regression model: Inference and Applications 
The assumption of proportional hazards (PH) fundamental to the Cox PH model sometimes may not hold in practice. In this paper, we propose a generalization of the Cox PH model in terms of the cumulative hazard function taking a form similar to the Cox PH model, with the extension that the baseline cumulative hazard function is raised to a power function. Our model allows for interaction between covariates and the baseline hazard and it also includes, for the two sample problem, the case of two Weibull distributions and two extreme value distributions differing in both scale and shape parameters. The partial likelihood approach can not be applied here to estimate the model parameters. We use the full likelihood approach via a cubic B-spline approximation for the baseline hazard to estimate the model parameters. A semi-automatic procedure for knot selection based on Akaike’s Information Criterion is developed. We illustrate the applicability of our approach using real-life data.
PMCID: PMC2976538  PMID: 21076652
censored survival data analysis; crossing hazards; Frailty model; maximum likelihood; regression; spline function; Akaike information criterion; Weibull distribution; extreme value distribution
23.  Validating the weight gain of preterm infants between the reference growth curve of the fetus and the term infant 
BMC Pediatrics  2013;13:92.
Current fetal-infant growth references have an obvious growth disjuncture around 40 week gestation overlapping where the fetal and infant growth references are combined. Graphical smoothening of the disjuncture to connect the matching percentile curves has never been validated. This study was designed to compare weight gain patterns of contemporary preterm infants with a fetal-infant growth reference (derived from a meta-analysis) to validate the previous smoothening assumptions and inform the revision of the Fenton chart.
Growth and descriptive data of preterm infants (23 to 31 weeks) from birth through 10 weeks post term age were collected in three cities in Canada and the USA between 2001 and 2010 (n = 977). Preterm infants were grouped by gestational age into 23–25, 26–28, and 29–31 weeks. Comparisons were made between the weight data of the preterm cohort and the fetal-infant growth reference.
Median weight gain curves of the three preterm gestational age groups were almost identical and remained between the 3rd and the 50th percentiles of the fetal-infant-growth-reference from birth through 10 weeks post term. The growth velocity of the preterm infants decreased in a pattern similar to the decreased velocity of the fetus and term infant estimates, from a high of 17–18 g/kg/day between 31–34 weeks to rates of 4–5 g/kg/day by 50 weeks in each gestational age group. The greatest discrepancy in weight gain velocity between the preterm infants and the fetal estimate was between 37 and 40 weeks; preterm infants grew more rapidly than the fetus. The infants in this study regained their birthweight earlier compared to those in the 1999 National Institute of Child Health and Human Development report.
The weight gain velocity of preterm infants through the period of growth data disjuncture between 37 and 50 weeks gestation is consistent with and thus validates the smoothening assumptions made between preterm and post-term growth references.
PMCID: PMC3700759  PMID: 23758808
24.  A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants 
BMC Pediatrics  2013;13:59.
The aim of this study was to revise the 2003 Fenton Preterm Growth Chart, specifically to: a) harmonize the preterm growth chart with the new World Health Organization (WHO) Growth Standard, b) smooth the data between the preterm and WHO estimates, informed by the Preterm Multicentre Growth (PreM Growth) study while maintaining data integrity from 22 to 36 and at 50 weeks, and to c) re-scale the chart x-axis to actual age (rather than completed weeks) to support growth monitoring.
Systematic review, meta-analysis, and growth chart development. We systematically searched published and unpublished literature to find population-based preterm size at birth measurement (weight, length, and/or head circumference) references, from developed countries with: Corrected gestational ages through infant assessment and/or statistical correction; Data percentiles as low as 24 weeks gestational age or lower; Sample with greater than 500 infants less than 30 weeks. Growth curves for males and females were produced using cubic splines to 50 weeks post menstrual age. LMS parameters (skew, median, and standard deviation) were calculated.
Six large population-based surveys of size at preterm birth representing 3,986,456 births (34,639 births < 30 weeks) from countries Germany, United States, Italy, Australia, Scotland, and Canada were combined in meta-analyses. Smooth growth chart curves were developed, while ensuring close agreement with the data between 24 and 36 weeks and at 50 weeks.
The revised sex-specific actual-age growth charts are based on the recommended growth goal for preterm infants, the fetus, followed by the term infant. These preterm growth charts, with the disjunction between these datasets smoothing informed by the international PreM Growth study, may support an improved transition of preterm infant growth monitoring to the WHO growth charts.
PMCID: PMC3637477  PMID: 23601190
Infant, Premature; Infant, very low birth weight; Preterm infant; Growth; Weight; Head circumference; Length; Percentile
25.  Validation of a model for optimal birth weight: a prospective study using serial ultrasounds 
BMC Pediatrics  2012;12:73.
The aim of this study was to validate a model for optimal birth weight derived from neonatal records, and to test the assumption that preterm births may be considered optimally grown if they are not exposed to common factors that perturb fetal growth.
Weights of fetuses were estimated from serial biometric ultrasound scans (N = 2,848) and combined with neonatal weights for a prospective pregnancy cohort (N = 691). Non-Caucasians, fetuses subsequently born preterm and those with diagnosed or suspected determinants of aberrant growth were excluded leaving fetuses assumed to have experienced normal growth. A generalised linear longitudinal growth model for optimal weight was derived, including terms for gestational duration, infant sex, maternal height and birth order. This model was compared to a published model derived solely from birth weights.
Prior to 30 weeks gestation, the published model yielded systematically lower weights than the model derived from both fetal weight and neonatal weight. From 30 weeks gestation the two models were indistinguishable.
The model for optimal birth weight was valid for births that have attained at least 30 weeks gestation. The model derived from both fetal and neonatal weights is recommended prior to this gestation.
PMCID: PMC3464982  PMID: 22703448
Fetal growth; Preterm delivery; Proportion of optimal birth weight

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