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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.  Maternal HIV infection associated with small-for-gestational age infants but not preterm births: evidence from rural South Africa 
Human Reproduction (Oxford, England)  2012;27(6):1846-1856.
BACKGROUND
 Human immunodeficiency virus (HIV) is prevalent in many countries where small-for-gestational age (SGA) and premature delivery are also common. However, the associations between maternal HIV, preterm delivery and SGA infants remain unclear. We estimate the prevalence of SGA and preterm (<37 weeks) births, their associations with antenatal maternal HIV infection and their contribution to infant mortality, in a high HIV prevalent, rural area in South Africa.
METHODS
Data were collected, in a non-randomized intervention cohort study, on all women attending antenatal clinics (2001–2004), before the availability of antiretroviral treatment. Newborns were weighed and gestational age was determined (based on last menstrual period plus midwife assessment antenatally). Poisson regression with robust variance assessed risk factors for preterm and SGA birth, while Cox regression assessed infant mortality and associated factors.
RESULTS
Of 2368 live born singletons, 16.6% were SGA and 21.4% were preterm. HIV-infected women (n= 1189) more commonly had SGA infants than uninfected women (18.1 versus 15.1%; P = 0.051), but percentages preterm were similar (21.8 versus 20.9%; P = 0.621). After adjustment for water source, delivery place, parity and maternal height, the SGA risk in HIV-infected women was higher [adjusted relative risk (aRR) 1.28, 95% confidence interval (CI): 1.06–1.53], but the association between maternal HIV infection and preterm delivery remained weak and not significant (aRR: 1.07, 95% CI: 0.91–1.26). In multivariable analyses, mortality under 1 year of age was significantly higher in SGA and severely SGA than in appropriate-for-gestational-age infants [adjusted hazard ratio (aHR): 2.12, 95% CI: 1.18–3.81 and 2.77, 95% CI: 1.56–4.91], but no difference in infant mortality was observed between the preterm and term infants (aHR: 1.18 95% CI: 0.79–1.79 for 34–36 weeks and 1.31, 95% CI: 0.58–2.94 for <34 weeks).
CONCLUSIONS
Maternal HIV infection increases the risk of SGA, but not preterm births, in this cohort.
doi:10.1093/humrep/des090
PMCID: PMC3357196  PMID: 22442245
HIV; SGA; preterm; Africa; low birthweight
3.  Small for gestational age births among South Indian women: temporal trend and risk factors from 1996 to 2010 
Background
The birth weight and gestational age at birth are two important variables that define neonatal morbidity and mortality. In developed countries, chronic maternal diseases like hypertension, diabetes mellitus, renal disease or collagen vascular disease is the most common cause of intrauterine growth restriction (IUGR). Maternal nutrition, pregnancy induced hypertension, chronic maternal infections, and other infections such as cytomegalovirus, parvovirus, rubella and malaria are the other causes of IUGR. The present study examines the secular trend of Small for Gestational Age (SGA) over 15 years and risk factors for SGA from a referral hospital in India.
Methods
Data from 1996 to 2010 was obtained from the labour room register. A rotational sampling scheme was used i.e. 12 months of the year were divided into 4 quarters. Taking into consideration all deliveries that met the inclusion criteria, babies whose birth weights were less than 10th percentile of the cut off values specific for gestational ages, were categorized as SGA. Only deliveries of live births that occurred between 22 and 42 weeks of pregnancy were considered in this study. Besides bivariate analyses, multivariable logistic regression analysis was done. Nagelkerke R2 statistics and Hosmer and Lemeshow chi-square statistics were used as goodness of fit statistics.
Results
Based on the data from 36,674 deliveries, the incidence of SGA was 11.4% in 1996 and 8.4% in 2010. Women who had multiple pregnancies had the higher odds of having SGA babies, 2.8 (2.3-3.3) times. The women with hypertensive disease had 1.8 (1.5-1.9) times higher odds of having SGA. Underweight women had 1.7 (1.3 - 2.1) times and anaemic mothers had 1.29 (1.01 - 1.6) times higher odds. The mothers who had cardiac disease were 1.4 (1.01 - 2.0) times at higher odds for SGA. In teenage pregnancies, the odds of SGA was 1.3 (1.1 - 1.5) times higher than mothers in the age group 20 to 35 years.
Conclusions
There is a significant reduction in the incidence of SGA by 26% over 15 years. The women with the above modifiable risk factors need to be identified early and provided with health education on optimal birth weight.
doi:10.1186/s12884-015-0440-4
PMCID: PMC4324804  PMID: 25645738
Small for Gestational Age; Birth weight; Risk factors; Incidence; Trend; Obstetric variables
4.  CXCL10/IP-10 
OBJECTIVE
Interferon (IFN)-γ inducible protein, CXCL10/IP-10, is a member of the CXC chemokine family with pro-inflammatory and anti-angiogenic properties. This chemokine has been proposed to be a key link between inflammation and angiogenesis. The aim of this study was to determine whether preeclampsia and delivery of a small for gestational age (SGA) neonate are associated with changes in maternal serum concentration of CXCL10/IP-10.
STUDY DESIGN
This cross-sectional study included patients in the following groups: (1) non pregnant women (N=49); (2) women with normal pregnancies (N=89); (3) patients with preeclampsia (N=100); and (4) patients who delivered an SGA neonate (N=78). SGA was defined as birth weight below the 10th percentile. Maternal serum concentrations of CXCL10/IP-10 were measured by sensitive immunoassay. Non-parametric statistics were used for analysis.
RESULTS
(1) Patients with normal pregnancies had a significantly higher median serum concentration of CXCL10/IP-10 than non-pregnant women (median: 116.1 pg/mL, range: 40.7-1314.3 vs. median: 90.3 pg/mL, range: 49.2-214.7, respectively; p=0.002); (2) no significant correlation was found between maternal serum concentration of CXCL10/IP-10 and gestational age (between 19 and 38 weeks); (3) there were no differences in median serum CXCL10/IP-10 concentrations between patients who delivered an SGA neonate and those with normal pregnancies (median: 122.4 pg/mL, range: 37.3-693.5 vs. median: 116.1 pg/mL, range: 40.7-1314.3, respectively; p>0.05); (4) patients with preeclampsia had a higher median serum concentration of CXCL10/IP-10 than normal pregnant women (median: 156.4 pg/mL, range: 47.4-645.9 vs. median: 116.1 pg/mL, range: 40.7-1314.3, respectively; p<0.05); (5) patients with preeclampsia had a higher median concentration of CXCL10/IP-10 than those who delivered an SGA neonate (median: 156.4 pg/mL, range: 47.4-645.9 vs. median: 122.4 pg/mL, range: 37.3-693.5, respectively; p<0.05).
CONCLUSIONS
Patients with preeclampsia have significantly higher serum concentrations of CXCL10/IP-10 than both normal pregnant women and mothers who have SGA neonates. These results are likely to reflect an anti-angiogenic state as well as an enhanced systemic inflammatory response in patients with preeclampsia. Alternatively, since preeclampsia and SGA share several mechanisms of disease, it is possible that a higher concentration of this chemokine may contribute to the clinical presentation of preeclampsia in patients with a similar intrauterine insult.
doi:10.1080/14767050701483298
PMCID: PMC2396489  PMID: 17943641
Pregnancy; CXCL10; IP-10; chemokine; chemotactic cytokine; small for gestational age; SGA; angiogenesis
5.  Maternal Influenza Immunization and Reduced Likelihood of Prematurity and Small for Gestational Age Births: A Retrospective Cohort Study 
PLoS Medicine  2011;8(5):e1000441.
In an analysis of surveillance data from the state of Georgia (US), Saad Omer and colleagues show an association between receipt of influenza vaccination among pregnant women and reduced risk of premature births.
Background
Infections during pregnancy have the potential to adversely impact birth outcomes. We evaluated the association between receipt of inactivated influenza vaccine during pregnancy and prematurity and small for gestational age (SGA) births.
Methods and Findings
We conducted a cohort analysis of surveillance data from the Georgia (United States) Pregnancy Risk Assessment Monitoring System. Among 4,326 live births between 1 June 2004 and 30 September 2006, maternal influenza vaccine information was available for 4,168 (96.3%). The primary intervention evaluated in this study was receipt of influenza vaccine during any trimester of pregnancy. The main outcome measures were prematurity (gestational age at birth <37 wk) and SGA (birth weight <10th percentile for gestational age). Infants who were born during the putative influenza season (1 October–31 May) and whose mothers were vaccinated against influenza during pregnancy were less likely to be premature compared to infants of unvaccinated mothers born in the same period (adjusted odds ratio [OR] = 0.60; 95% CI, 0.38–0.94). The magnitude of association between maternal influenza vaccine receipt and reduced likelihood of prematurity increased during the period of at least local influenza activity (adjusted OR = 0.44; 95% CI, 0.26–0.73) and was greatest during the widespread influenza activity period (adjusted OR = 0.28; 95% CI, 0.11–0.74). Compared with newborns of unvaccinated women, newborns of vaccinated mothers had 69% lower odds of being SGA (adjusted OR = 0.31; 95% CI, 0.13–0.75) during the period of widespread influenza activity. The adjusted and unadjusted ORs were not significant for the pre-influenza activity period.
Conclusions
This study demonstrates an association between immunization with the inactivated influenza vaccine during pregnancy and reduced likelihood of prematurity during local, regional, and widespread influenza activity periods. However, no associations were found for the pre-influenza activity period. Moreover, during the period of widespread influenza activity there was an association between maternal receipt of influenza vaccine and reduced likelihood of SGA birth.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Maternal infections during pregnancy can have harmful effects on both mother and baby. For example, influenza is associated with increased morbidity and mortality among pregnant women compared to women who are not pregnant or who acquire influenza infection after delivery. And some respiratory infections, especially those that can cause maternal pneumonia such as influenza virus, are known to be associated with the baby being small—below the 10th percentile—for gestational age and with an increased risk of preterm birth—birth before 37 weeks of gestation. Previous studies have shown that inactivated influenza vaccination during pregnancy provides protection against influenza virus for both mother and baby. As there has been an increase in the rate of preterm birth the United States from 9.5% in 1981 to 12.8% in 2006, the impact of maternal influenza immunization on birth outcomes has important public health implications and is of particular interest during influenza pandemics.
Why Was This Study Done?
Given that maternal vaccination can protect babies from influenza virus, it is plausible that influenza vaccination in pregnancy could mitigate adverse birth outcomes such as prematurity and the baby being small for gestational age. The researchers of this study set out to evaluate this hypothesis by investigating whether there was an association between women receiving inactivated influenza vaccine during pregnancy and positive birth outcomes for their babies in the population of the state of Georgia, in the United States.
What Did the Researchers Do and Find?
The researchers conducted a retrospective cohort analysis of a large surveillance dataset (the Georgia Pregnancy Risk Assessment Monitoring System) to analyze the relationship between receipt of inactivated influenza vaccine during any trimester of pregnancy by mothers of infants born between June 1, 2004, and September 30, 2006, and their baby being premature or small for gestational age. The study period encompassed the 2004–2005 and 2005–2006 influenza seasons—the two most recent seasons for which the data were available. The researchers did a stratified analysis for the overall study period, and various periods during it, and also weighted their analysis to adjust for possible oversampling. They used logistic regression to evaluate the association of maternal influenza vaccine and (a) prematurity and (b) small for gestational age, and also used linear regression to evaluate the statistical significance of differences between vaccinated and unvaccinated women for mean gestational age at first antenatal visit and mean birth weight.
During the study period, 4,168 mother–baby pairs were included in the analysis. Local influenza activity was detected during 27 weeks (22.1%), and 578 women (14.9% [weighted]) had received the influenza vaccine during pregnancy, giving a vaccination coverage of 19.2% (weighted) among mothers of infants born during the assumed influenza season. In the study sample, 1,547 babies (10.6% [weighted]) were born premature, and 1,186 babies (11.2% [weighted]) were small for gestational age. Infants who were born during the assumed influenza season (October–May) and whose mothers were vaccinated against influenza during pregnancy were less likely to be premature than infants of unvaccinated mothers born in the same period, with an adjusted odds ratio of 0.60. The effect of maternal influenza vaccine on reducing prematurity was the highest for infants born during the period of widespread influenza activity, with 72% lower odds of prematurity in infants of vaccinated mothers than infants of unvaccinated mothers. Compared with newborns of unvaccinated women, babies of vaccinated mothers also had 69% lower odds of being small for gestational age during the period of widespread influenza activity, but the adjusted and unadjusted odd ratios were not significant for the pre-influenza activity period.
What Do These Findings Mean?
These results show that there was an association between maternal immunization with the inactivated influenza vaccine during pregnancy and reduced likelihood of prematurity during local, regional, and widespread influenza activity periods. In addition, during the period of widespread influenza activity there was an negative association between maternal receipt of influenza vaccine and small for gestational age birth.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000441.
More information about influenza vaccination during pregnancy is available from the World Health Organization and the UK National Health Service
More information about the Georgia Pregnancy Risk Assessment Monitoring System is also available
doi:10.1371/journal.pmed.1000441
PMCID: PMC3104979  PMID: 21655318
6.  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
7.  Clinical Prediction in Early Pregnancy of Infants Small for Gestational Age by Customised Birthweight Centiles: Findings from a Healthy Nulliparous Cohort 
PLoS ONE  2013;8(8):e70917.
Objective
Small for gestational age (SGA) infants comprise up to 50% of all stillbirths and a minority are detected before birth. We aimed to develop and validate early pregnancy predictive models for SGA infants.
Methods
5628 participants from SCOPE, a prospective study of nulliparous pregnant women, were interviewed at 15±1 weeks’ gestation. Fetal anthropometry, uterine and umbilical Doppler studies were performed at 20±1 weeks’. The cohort was divided into training (n = 3735) and validation datasets (n = 1871). All-SGA (birthweight <10th customised centile), Normotensive-SGA (SGA with normotensive mother) and Hypertensive-SGA (SGA with mother who developed hypertension) were the primary outcomes. Multivariable analysis was performed using stepwise logistic regression firstly using clinical variables and then with clinical and ultrasound variables. Receiver operator curves were constructed and areas under the curve (AUC) calculated.
Results
633 infants (11.3%) in the whole cohort were SGA; 465 (8.3%) Normotensive-SGA and 165 (3.0%) Hypertensive-SGA. In the training dataset risk factors for All-SGA at 15±1 weeks’ included: family history of coronary heart disease, maternal birthweight <3000 g and 3000 g to 3499 g compared with ≥3500 g, >12 months to conceive, university student, cigarette smoking, proteinuria, daily vigorous exercise and diastolic blood pressure ≥80. Recreational walking ≥4 times weekly, rhesus negative blood group and increasing random glucose were protective. AUC for clinical risk factors was 0.63. Fetal abdominal or head circumference z scores <10th centile and increasing uterine artery Doppler resistance at 20±1 weeks’ were associated with increased risk. Addition of these parameters increased the AUC to 0.69. Clinical predictors of Normotensive and Hypertensive-SGA were sub-groups of All-SGA predictors and were quite different. The combined clinical and ultrasound AUC for Normotensive and Hypertensive-SGA were 0.69 and 0.82 respectively.
Conclusion
Predictors for SGA of relevance to clinical practice were identified. The identity and predictive potential differed in normotensive women and those who developed hypertension.
doi:10.1371/journal.pone.0070917
PMCID: PMC3733741  PMID: 23940665
8.  Maternal Vitamin D Status and Small-for-Gestational-Age Offspring in Women at High Risk for Preeclampsia 
Obstetrics and gynecology  2014;123(1):40-48.
Objective
To examine the association between second-trimester maternal serum 25-hydroxyvitamin D (25[OH]D) concentrations and risk of small for gestational age (SGA) in singleton, live births.
Methods
We assayed serum samples at 12 to 26 weeks of gestation for 25(OH)D in a sample of participants in a multicenter clinical trial of low-dose aspirin for the prevention of preeclampsia in high-risk women (n=792). Multivariable log-binomial regression models were used to assess the association between 25(OH)D and risk of SGA (birth weight less than the 10th percentile of gestational age) after adjustment for confounders including maternal prepregnancy obesity, race, treatment allocation, and risk group.
Results
Thirteen percent of infants were SGA at birth. Mean (SD) 25(OH)D concentrations were lower in women who delivered SGA (57.9 [29.9] nmol/L0 vs. non-SGA infants (64.8 [29.3] nmol/L, P=0.028). In adjusted models, 25(OH)D concentrations of 50-74 nmol/L and ≥75 nmol/L compared with <30 nmol/L were associated with 43% (95% confidence interval [CI] 0.33-0.99) and 54% (95% CI 0.24-0.87) reductions in risk of SGA, respectively. Race and maternal obesity each modified this association. White women with 25(OH)D ≥50 vs. <50 nmol/L had a 68% reduction in SGA risk (adjusted risk ratio [RR] 0.32, 95% CI 0.17-0.63) and nonobese women 25(OH)D ≥50 vs. <50 nmol/L had a 50% reduction in SGA risk (adjusted RR 0.50, 95% CI 0.31-0.82). There was no association between 25(OH)D and risk of SGA in black or obese mothers.
Conclusion
Maternal vitamin D status in the second trimester is associated with risk of SGA among all women, and in the subgroups of white and nonobese women.
doi:10.1097/AOG.0000000000000049
PMCID: PMC3914014  PMID: 24463662
9.  Does Lack of Multinutrient Supplementation During Early Pregnancy Increase Vulnerability to Alcohol-Related Preterm or Small-for-Gestational-Age Births? 
Maternal and Child Health Journal  2010;15(8):1324-1332.
The objective of this study was to assess whether women who do not take multinutrient supplements during early pregnancy are more susceptible to the effects of low-to-moderate alcohol consumption on preterm birth and small-for-gestational-age birth (SGA) compared to women who do take multinutrients. This analysis included 800 singleton live births to mothers from a cohort of pregnant women recruited for a population-based cohort study conducted in the Kaiser Permanente Medical Care Program in Northern California. Participants were recruited in their first trimester of pregnancy and information about their alcohol use and supplement intake during pregnancy was collected. Preterm birth (n = 53, 7%) was defined as a delivery prior to 37 completed weeks of gestation and SGA birth (n = 124, 16%) was defined as birth weight less than the 10th percentile for the infant’s gestational age and sex compared to US singleton live births. A twofold increase in the odds of SGA birth attributed to low-to-moderate alcohol intake was found among multinutrient supplement non-users (95% CI: 1.1, 5.3). Yet, among multinutrient supplement users, there was no increased risk of an SGA birth for women who drank low-to-moderately compared to women who abstained (aOR: 0.97, 95% CI: 0.6, 1.6). Similar results emerged for preterm birth. Our findings provide marginal evidence that multinutrient supplementation during early pregnancy may modify the risk of SGA births and preterm birth associated with alcohol consumption during pregnancy and may have important implications for pregnant women and women of child-bearing age. However, future research needs to be conducted.
doi:10.1007/s10995-010-0690-8
PMCID: PMC3195813  PMID: 20949322
Low-to-moderate alcohol use; Multinutrient supplement use; Preterm birth; SGA birth; Multivitamin use
10.  Placental growth hormone is increased in the maternal and fetal serum of patients with preeclampsia 
Objectives
Placental growth hormone (PGH) is a pregnancy-specific protein produced by syncytiotrophoblast and extravillous cytotrophoblast. No other cells have been reported to synthesize PGH. Maternal PGH Serum concentration increases with advancing gestational age, while quickly decreasing after delivery of the placenta. The biological properties of PGH include somatogenic, lactogenic, and lipolytic functions. The purpose of this study was to determine whether the maternal serum concentrations of PGH change in women with preeclampsia (PE), women with PE who deliver a small-for-gestational age neonate (PE+SGA), and those with SGA alone.
Study Design
This cross-sectional study included maternal serum from normal pregnant women (n=61), patients with severe PE (n=48), PE+SGA (n=30), and SGA alone (n=41). Fetal cord blood from uncomplicated pregnancies (n=16) and PE (n=16) was also analyzed. PGH concentrations were measured by ELISA. Non-parametric statistics were used for analysis.
Results
(1) Women with severe PE had a median serum concentration of PGH higher than normal pregnant women (PE: median: 23,076 pg/mL (3473-94 256) vs. normal pregnancy: median: 12 157 pg/mL (2617-34 016); p < 0.05), pregnant women who delivered an SGA neonate (SGA: median 10 206 pg/mL (1816-34 705); p < 0.05], as well as pregnant patients with PE and SGA (PE + SGA: median: 11 027 pg/mL (1232-61 702); p <0.05); (2) No significant differences were observed in the median maternal serum concentration of PGH among pregnant women with PE and SGA, SGA alone, and normal pregnancy (p > 0.05); (3) Compared to those of the control group, the median umbilical serum concentration of PGH was significantly higher in newborns of preeclamptic women (PE: median 356.1 pg/mL (72.6-20 946), normal pregnancy: median 128.5 pg/mL (21.6-255.9); p < 0.01]; (4) PGH was detected in all samples of cord blood.
Conclusion
(1) PE is associated with higher median concentrations of PGH in both the maternal and fetal circulation compared to normal pregnancy. (2) Patients with PE+SGA had lower maternal serum concentrations of PGH than preeclamptic patients without SGA. (3) Contrary to previous findings, PGH was detectable in the fetal circulation. The observations reported herein are novel and suggest that PGH may play a role in the mechanisms of disease in preeclampsia and fetal growth restriction.
doi:10.1080/14767050701463571
PMCID: PMC2276338  PMID: 17701665
Pregnancy; placental growth hormone; preeclampsia; small for gestational age; fetal growth
11.  Smoking Ban and Small-For-Gestational Age Births in Ireland 
PLoS ONE  2013;8(3):e57441.
Background
Ireland introduced a comprehensive workplace smoke-free legislation in March, 2004. Smoking-related adverse birth outcomes have both health care and societal cost implications. The main aim of this study was to determine the impact of the Irish smoke-free legislation on small-for-gestationa- age (SGA) births.
Methods and Findings
We developed a population-based birthweight (BW) percentile curve based on a recent study to compute SGA (BW <5th percentile) and very SGA (vSGA - BW<3rd percentile) for each gestational week. Monthly births born between January 1999 and December 2008 were analyzed linking with monthly maternal smoking rates from a large referral maternity university hospital. We ran individual control and CUSUM charts, with bootstrap simulations, to pinpoint the breakpoint for the impact of ban implementation ( = April 2004). Monthly SGA rates (%) before and after April 2004 was considered pre and post ban period births, respectively. Autocorrelation was tested using Durbin Watson (DW) statistic. Mixed models using a random intercept and a fixed effect were employed using SAS (v 9.2). A total of 588,997 singleton live-births born between January 1999 and December 2008 were analyzed. vSGA and SGA monthly rates declined from an average of 4.7% to 4.3% and from 6.9% to 6.6% before and after April 2004, respectively. No auto-correlation was detected (DW = ∼2). Adjusted mixed models indicated a significant decline in both vSGA and SGA rates immediately after the ban [(−5.3%; 95% CI −5.43% to −5.17%, p<0.0001) and (−0.45%; 95% CI: −0.7% to −0.19%, p<0.0007)], respectively. Significant gradual effects continued post the ban periods for vSGA and SGA rates, namely, −0.6% (p<0.0001) and −0.02% (p<0.0001), respectively.
Conclusions
A significant reduction in small-for-gestational birth rates both immediately and sustained over the post-ban period, reinforces the mounting evidence of the positive health effect of a successful comprehensive smoke-free legislation in a vulnerable population group as pregnant women.
doi:10.1371/journal.pone.0057441
PMCID: PMC3608631  PMID: 23555561
12.  Could alterations in maternal plasma visfatin concentration participate in the phenotypes definition of preeclampsia and SGA? 
Objective
Women with preeclampsia and those who delivered a small-for-gestational-age (SGA) neonate share several mechanisms of disease, including chronic uteroplacental ischemia and failure of physiologic transformation of the spiral arteries. However, the clinical manifestation of these obstetrical syndromes is remarkably different. It has been proposed that an altered maternal metabolic state, as well as a unique circulating cytokines milieu, predispose women to develop either preeclampsia or SGA. Compelling evidence suggests that adipose tissue orchestrates both metabolic pathways and immunological responses via the production of adipokines. Visfatin is a novel adipocytokine with metabolic and immunomodulating properties. The objective of this study was to determine whether preeclampsia and SGA are associated with alterations in maternal circulating visfatin concentrations.
Methods
This cross-secitonal study included pregnant women in the following groups: (1) normal pregnancy (n = 158); (2) patients with preeclampsia (n = 43) of which 32 had an AGA and 11 had an SGA neonate; (3) patients without preeclampsia who delivered an SGA neonate (n = 55). Maternal plasma visfatin concentrations were measured by ELISA. Nonparametric tests and multiple linear regression analysis were used.
Results
(1) Women who delivered an SGA neonate had a higher median maternal plasma visfatin concentration than those with a normal pregnancy (20.0 ng/ml, interquartile range: 17.2-24.6 vs. 15.2 ng/ml, 12.1-19.2, respectively; P < 0.001) than those with preeclampsia (14.5 ng/ml, 12.5-18.7; P < 0.001); (2) the median maternal plasma visfatin concentration did not differ significantly between patients with preeclampsia and those with a normal pregnancy (P = 0.8); (3) among patients with preeclampsia, there was no significant difference in the median maternal plasma visfatin concentration between those with or without an SGA neonate (P = 0.5); (4) in a linear regression model, delivery of an SGA neonate and pregestational body mass index were independently associated with increased visfatin concentration after adjustment for confounding factors (maternal age, smoking, gestational age at blood collection and the presence of preeclampsia or SGA).
Conclusion
(1) Patients with SGA, but not those with preeclampsia, had a higher maternal plasma visfatin concentration than those with a normal pregnancy; (2) this finding suggests differential involvement of visfatin in SGA and preeclampsia; (3) we propose that changes in circulating maternal visfatin concentration may be implicated in the phenotypic definitions and distinction of preeclampsia and SGA.
doi:10.3109/14767050903301017
PMCID: PMC3554253  PMID: 19900033
Adipokine; pregnancy; fetal growth; metabolism; obesity
13.  Parental occupation and risk of small-for-gestational-age births: a nationwide epidemiological study in Sweden 
Human Reproduction (Oxford, England)  2010;25(4):1044-1050.
BACKGROUND
Although evidence suggests that some occupations may be a risk factor for small-for-gestational age (SGA) birth, associations between a wide range of maternal and paternal occupations and risk of SGA births remain unclear. Our objective was to analyze the risk of SGA births by parental occupation, including the entire Swedish population of mothers (≥20 years) and fathers.
METHODS
We linked nationwide data (1990–2004) on singletons born to employed mothers to nationwide data on maternal and paternal occupation and other individual-level variables. Information on parental occupations was obtained from the 1990 census. Approximately 95% of SGA births (calculated using normative data) were defined on the basis of ultrasound. Odds ratios of SGA birth were calculated with 95% confidence intervals. Women and men were analyzed separately.
RESULTS
There were 816 310 first singleton live births during the study period, of which 29 603 were SGA events. Families with low incomes had an increased risk of SGA births. After accounting for maternal age at the infant's birth, period of birth, family income, region of residence, marital status and smoking habits, several maternal occupational groups (including ‘mechanics and iron and metalware workers’ and ‘packers, loaders and warehouse workers’) had a significantly higher risk of SGA birth than the reference group (all women in the study population). Among paternal occupational groups, only waiters had an increased risk of SGA birth.
CONCLUSIONS
This large-scale follow-up study shows that maternal occupation affects risk of SGA birth, whereas paternal occupation does not seem to have an impact on SGA birth. Further studies are required to examine the specific agents in those maternal occupations that are associated with an increased risk of SGA birth.
doi:10.1093/humrep/deq004
PMCID: PMC2839909  PMID: 20133322
family income; follow-up study; occupational exposure; small for gestational age
14.  High‐altitude ancestry protects against hypoxia‐associated reductions in fetal growth 
Objective
The chronic hypoxia of high‐altitude (⩾2500 m) residence has been shown to decrease birth weight in all populations studied to date. However, multigenerational high‐altitude populations appear protected relative to newcomer groups. This study aimed to determine whether such protection exists independently of other factors known to influence fetal growth and whether admixed populations (ie, people having both high‐ and low‐altitude ancestry) show an intermediate level of protection.
Design
3551 medical records from consecutive deliveries to Andean, European or Mestizo (ie, admixed) women at low, intermediate or high altitudes in Bolivia were evaluated for maternal characteristics influencing fetal growth as measured by birth weight and the frequency of small for gestational age births (SGA or ⩽10th percentile birth weight for gestational age and sex). Two‐way analysis of variance and χ2 tests were used to compare maternal and infant characteristics. The effects of ancestry or altitude on SGA and birth weight were assessed using logistic or linear regression models, respectively.
Results
Altitude decreased birth weight and increased SGA in all ancestry groups. Andean infants weighed more and were less often SGA than Mestizo or European infants at high altitude (13%, 16% and 33% respectively, p<0.01). After accounting for the influences of maternal hypertensive complications of pregnancy, parity, body weight, and number of prenatal visits, European relative to Andean ancestry increased the frequency of SGA at high altitude nearly fivefold.
Conclusions
Andean relative to European ancestry protects against altitude‐associated reductions in fetal growth. The intermediate protection seen in the admixed (Mestizo) group is consistent with the influence of genetic or other Andean‐specific protective characteristics.
doi:10.1136/adc.2006.109579
PMCID: PMC2675361  PMID: 17329275
genetic adaptation; hypoxia; intrauterine growth restriction; preeclampsia; uteroplacental blood flow
15.  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
16.  Birth weight- and fetal weight-growth restriction: impact on neurodevelopment 
Early human development  2012;88(9):765-771.
Background
The newborn classified as growth-restricted on birth weight curves, but not on fetal weight curves, is classified prenatally as small for gestational age (SGA), but postnatally as appropriate for gestational age (AGA).
Aims
To see (1) to what extent the neurodevelopmental outcomes at 24 months corrected age differed among three groups of infants (those identified as SGA based on birth weight curves (B-SGA), those identified as SGA based on fetal weight curves only (F-SGA), and the referent group of infants considered AGA, (2) if girls and boys were equally affected by growth restriction, and (3) to what extent neurosensory limitations influenced what we found.
Study design
Observational cohort of births before the 28 week of gestation. Outcome measures: Mental Development Index (MDI) and Psychomotor Development Index (PDI) of the Bayley Scales of Infant Development II.
Results
B-SGA, but not F-SGA girls were at an increased risk of a PDI < 70 (OR=2.8; 95% CI: 1.5, 5.3) compared to AGA girls. B-SGA and F-SGA boys were not at greater risk of low developmental indices than AGA boys. Neurosensory limitations diminished associations among girls of B-SGA with low MDI, and among boys B-SGA and F-SGA with PDI < 70.
Conclusions
Only girls with the most severe growth restriction were at increased risk of neurodevelopmental impairment at 24 months corrected age in the total sample. Neurosensory limitations appear to interfere with assessing growth restriction effects in both girls and boys born preterm.
doi:10.1016/j.earlhumdev.2012.04.004
PMCID: PMC3694609  PMID: 22732241
17.  Association between Soluble (Pro)Renin Receptor Concentration in Cord Blood and Small for Gestational Age Birth: A Cross-Sectional Study 
PLoS ONE  2013;8(3):e60036.
Objective
The (pro)renin receptor [(P)RR] has been recognized as a multifunctional receptor. The purpose of this study was to assess the association between plasma soluble (P)RR [s(P)RR] concentration in human cord blood (i.e., neonatal blood at birth) and small for gestational age (SGA) birth.
Methods
Participants were women with a singleton pregnancy who delivered at the National Center for Child Health and Development between January 2010 and December 2011. Inclusion criteria were availability of maternal pre-pregnancy and paternal body mass index, and the absence of structural anomalies in neonates. s(P)RR concentration in cord blood was measured in 621 neonates. The 621 pairs of mothers and neonates were categorized into four groups based on quartiles of s(P)RR concentrations in cord blood. SGA was defined as a birth weight below the 10th percentile for gestational age. Logistic regression analysis was performed to assess the association between cord plasma s(P)RR concentration (quartiles) and incidence of SGA births.
Results
Among 621 neonates, 55 (8.9%) were diagnosed as SGA (SGA group) and 566 (91.1%) were not (non-SGA group). Average s(P)RR concentration in cord blood was 66.1±12.6 ng/ml (mean±standard deviation). There were 155 pairs in the first plasma s(P)RR concentration quartile (Q1: <58.2 ng/ml), 153 pairs in the second quartile (Q2: 58.2–65.1 ng/ml), 157 pairs in the third quartile (Q3: 65.1–73.1 ng/ml) and 156 pairs in the fourth quartile (Q4: >73.1 ng/ml). The distribution of SGA births was 18 (11.6%) in Q1, 14 (9.2%) in Q2, 16 (10.2%) in Q3 and 7 (4.5%) in Q4, respectively. The odds ratio of SGA births was 0.24 (95% confidence interval: 0.08–0.71) for the fourth quartile compared to the first quartile in multivariate models. The P-value for trend was also significant (P = 0.020).
Conclusion
High s(P)RR concentration is associated with a lower SGA birth likelihood.
doi:10.1371/journal.pone.0060036
PMCID: PMC3605421  PMID: 23555874
18.  Risk Factors and Adverse Perinatal Outcomes among Term and Preterm Infants Born Small-for-Gestational-Age: Secondary Analyses of the WHO Multi-Country Survey on Maternal and Newborn Health 
PLoS ONE  2014;9(8):e105155.
Background
Small for gestational age (SGA) is not only a major indicator of perinatal mortality and morbidity, but also the morbidity risks in later in life. We aim to estimate the association between the birth of SGA infants and the risk factors and adverse perinatal outcomes among twenty-nine countries in Africa, Latin America, the Middle East and Asia in 359 health facilities in 2010–11.
Methods
We analysed facility-based, cross-sectional data from the WHO Multi-country Survey on Maternal and Newborn Health. We constructed multilevel logistic regression models with random effects for facilities and countries to estimate the risk factors for SGA infants using country-specific birthweight reference standards in preterm and term delivery, and SGA’s association with adverse perinatal outcomes. We compared the risks and adverse perinatal outcomes with appropriate for gestational age (AGA) infants categorized by preterm and term delivery.
Results
A total of 295,829 singleton infants delivered were analysed. The overall prevalence of SGA was highest in Cambodia (18.8%), Nepal (17.9%), the Occupied Palestinian Territory (16.1%), and Japan (16.0%), while the lowest was observed in Afghanistan (4.8%), Uganda (6.6%) and Thailand (9.7%). The risk of preterm SGA infants was significantly higher among nulliparous mothers and mothers with chronic hypertension and preeclampsia/eclampsia (aOR: 2.89; 95% CI: 2.55–3.28) compared with AGA infants. Higher risks of term SGA were observed among sociodemographic factors and women with preeclampsia/eclampsia, anaemia and other medical conditions. Multiparity (> = 3) (AOR: 0.88; 95% CI: 0.83–0.92) was a protective factor for term SGA. The risk of perinatal mortality was significantly higher in preterm SGA deliveries in low to high HDI countries.
Conclusion
Preterm SGA is associated with medical conditions related to preeclampsia, but not with sociodemographic status. Term SGA is associated with sociodemographic status and various medical conditions.
doi:10.1371/journal.pone.0105155
PMCID: PMC4132094  PMID: 25119107
19.  Socio-demographic characteristics of women sustaining injuries during pregnancy: a study from the Danish National Birth Cohort 
BMJ Open  2012;2(4):e000826.
Objectives
To describe adverse birth outcomes associated with hospital-treated injuries that took place among women in the Danish National Birth Cohort.
Design
Longitudinal cohort study.
Setting
Denmark.
Participants
90 452 women and their offspring selected from the Danish National Birth Cohort.
Primary and secondary outcome measures
To determine if injured women were more likely to deliver an infant preterm, with low birth weight, stillborn or have a spontaneous abortion, the authors estimated HRs. ORs were generated to assess APGAR scores and infants born small for gestational age (SGA). Models were adjusted for maternal smoking and drinking during pregnancy, household socioeconomic status, eclampsia/pre-eclampsia or gestational diabetes status during pregnancy and maternal age at birth; estimates for preterm birth were also adjusted for prior history of preterm birth.
Results
In the cohort of 90 452 pregnant women, 3561 (3.9%) received medical treatment for an injury during pregnancy. Injured pregnant women were more likely to deliver infants that were stillborn or have pregnancies terminated by spontaneous abortion. The authors did not detect an adverse effect between injuries sustained during pregnancy and delivery of preterm, low birth weight or SGA infants, or infants with an APGAR score of <7.
Conclusions
The study shows that injuries occurring among women from an unselected population may not have an adverse effect on birth weight, gestational age, APGAR score or SGA status but may adversely affect the risk of stillbirth and spontaneous abortions in some situations.
Article summary
Article focus
We describe adverse birth outcomes associated with injuries that took place among pregnant women in the Danish National Birth Cohort and include in our assessment injury severity, cause and mechanism.
Key messages
Injured pregnant women were more likely to deliver infants that were stillborn or have pregnancies that were terminated by spontaneous abortion. We did not detect an adverse effect between injuries sustained during pregnancy and delivery of preterm, low birth weight or SGA infants, or infants with an APGAR score of <7.
Women sustaining head or neck injuries were more likely to deliver an infant SGA and have a stillbirth, though these results were not statistically significant.
Strengths and limitations of this study
Previous studies have selected pregnant trauma patients or emergency room patients; our study, however, presents injuries among pregnant women from a general population.
We only have data on late spontaneous abortions, and if injured fetuses are aborted early, we would not detect an association.
doi:10.1136/bmjopen-2012-000826
PMCID: PMC3391365  PMID: 22761281
20.  Correlates and outcomes of preterm birth, low birth weight, and small for gestational age in HIV-exposed uninfected infants 
Background
Preterm birth (PTB), low birth weight (LBW) and small for gestational age (SGA) contribute to neonatal mortality. Maternal HIV-1 infection has been associated with an increased risk of PTB, but mechanisms underlying this association are undefined. We describe correlates and outcomes of PTB, LBW, and SGA in HIV-exposed uninfected infants.
Methods
This was a retrospective analysis of cohort study. Between 1999–2002, pregnant, HIV-infected women were enrolled into an HIV-1 transmission study. Logistic regression was used to identify correlates of PTB, LBW and SGA in HIV-negative, spontaneous singleton deliveries. Associations between birth outcomes and mortality were measured using survival analyses.
Results
In multivariable models, maternal plasma (OR = 2.1, 95% CI = 1.1-3.8) and cervical HIV-1 RNA levels (OR = 1.6, 95% CI = 1.1-2.4), and CD4 < 15% (OR = 2.4, 95% CI = 1.0-5.6) were associated with increased odds of PTB. Abnormal vaginal discharge and cervical polymorphonuclear leukocytes were also associated with PTB. Cervical HIV-1 RNA level (OR = 2.4, 95% CI = 1.5-6.7) was associated with an increased odds of LBW, while increasing parity (OR = 0.46, 95% CI = 0.24-0.88) was associated with reduced odds. Higher maternal body mass index (OR = 0.75, 95% CI = 0.61-0.92) was associated with a reduced odds of SGA, while bacterial vaginosis was associated with >3-fold increased odds (OR = 3.2, 95% CI = 1.4-7.4). PTB, LBW, and SGA were each associated with a >6-fold increased risk of neonatal death, and a >2-fold increased rate of infant mortality within the first year.
Conclusions
Maternal plasma and cervical HIV-1 RNA load, and genital infections may be important risk factors for PTB in HIV-exposed uninfected infants. PTB, LBW, and SGA are associated with increased neonatal and infant mortality in HIV-exposed uninfected infants.
doi:10.1186/1471-2393-14-7
PMCID: PMC3897882  PMID: 24397463
Preterm birth; Low birth weight; Small for gestational age; Pediatric HIV
21.  Hypoglycemia in term newborns with a birth weight below the 10th percentile 
Paediatrics & Child Health  2010;15(5):271-275.
BACKGROUND:
Current recommendations suggest that routine screening for hypoglycemia should be performed in all term newborns with a birth weight (BW) below the 10th percentile. The impact of updated growth curves on the incidence of hypoglycemia in small-for-gestational-age (SGA) newborns has not been evaluated.
OBJECTIVES:
To evaluate the occurrence and severity of hypoglycemia in term newborns with a BW between the 10th and fifth percentile, and below the fifth percentile, using recently updated growth curves.
DESIGN:
A one-year prospective cohort study.
METHODS:
Inclusion criteria were gestational age of 37 weeks or greater and BW below the 10th percentile. Neonatal hypoglycemia was defined as a blood glucose level of less than 2.6 mmol/L measured after 2 h of life. Blood glucose was measured routinely for all SGA infants during the first 36 h of life.
RESULTS:
A total of 187 SGA infants met the study criteria: 85 infants with a BW between the 10th and fifth percentile, and 102 infants with a BW below the fifth percentile. The characteristics of the study cohort were similar between BW groups. Twenty-six per cent of the infants screened had at least one episode of hypoglycemia: 22% of infants in the 10th to fifth percentile group and 28% in the less than fifth percentile group. Hypoglycemia was symptomatic in four infants, all of whom were below the fifth percentile for BW. The mean (± SD) lowest blood glucose level was 2.1±0.4 mmol/L (range 0.6 mmol/L to 2.5 mmol/L) in the 10th to fifth percentile group and 2.0±0.5 mmol/L (range 0.8 mmol/L to 2.5 mmol/L) in the less than fifth percentile group (P=0.05).
CONCLUSION:
The present study demonstrates a high incidence of hypoglycemia among SGA infants with a BW below the 10th percentile using updated growth curves. There was no difference in the incidence of hypoglycemia among SGA infants with a BW below the fifth percentile versus those with a BW between the 10th and fifth percentile.
PMCID: PMC2912629  PMID: 21532790
Full-term infants; Hypoglycemia; SGA
22.  Prior Preterm or Small-for-Gestational-Age Birth Related to Maternal Metabolic Syndrome 
Obstetrics and gynecology  2011;117(2 Pt 1):225-232.
OBJECTIVE
To estimate whether women who deliver small babies due to preterm birth or growth restriction have excess risk for cardiovascular disease and diabetes later in life.
METHODS
Eight years after pregnancy, we estimated the prevalence of metabolic syndrome and its components in a cohort study of women with prior preterm (preterm birth before 37 weeks, n=181) or small for gestational age ([SGA], less than the tenth percentile, n=192) births, compared with women with term births (37 or more weeks, n=306). Women delivered at Magee-Womens Hospital in Pittsburgh, Pennsylvania, and those with preeclampsia or prepregnancy diabetes or hypertension were excluded. Women underwent a structured interview and fasting blood sampling.
RESULTS
Women were, on average, 8 years postpartum and 39 years old at evaluation. Women with a prior preterm birth had higher blood pressure, triglycerides, and LDL-cholesterol compared with those in a term control group. Women with prior SGA births were leaner and more likely to smoke compared with those with term births. Women with prior preterm birth had elevated risk of metabolic syndrome, adjusted for demographic, smoking and body size factors (23% preterm compared with 17% control group; odds ratio [OR] 1.76 [1.06, 2.80]). In women with a prior preterm birth, low HDL (11% preterm compared with 5% control group; OR 2.6 [1.2, 5.2]), hypertriglyceridemia (22% compared with 14%; OR 1.9 [1.2, 2.9]), and elevated glucose (24% compared with 19%; OR 1.5 [1.0, 2.3]) accounted for this excess metabolic syndrome. In women with SGA, the only element of metabolic syndrome that was aberrant was glucose metabolism.
CONCLUSION
Eight years after pregnancy, women with prior preterm or SGA births had evidence of metabolic syndrome compared with women with term births. Screening and intervention in these women after pregnancy may delay or prevent disease.
doi:10.1097/AOG.0b013e3182075626
PMCID: PMC3074407  PMID: 21252733
23.  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
24.  Identification of Patients at Risk for Early Onset and/or Severe Preeclampsia With the Use of Uterine Artery Doppler Velocimetry and Placental Growth Factor 
OBJECTIVE:
Preeclampsia has been proposed to be an anti-angiogenic state that may be detected by the determination of the concentrations of the soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and placental growth factor (PlGF) in maternal blood even before the clinical development of the disease. The purpose of this study was to determine the role of the combined use of uterine artery Doppler velocimetry (UADV) and maternal plasma PlGF and sVEGFR-1 concentrations in the second trimester for the identification of patients at risk for severe and/or early onset preeclampsia.
STUDY DESIGN:
A prospective cohort study was designed to examine the relationship between abnormal UADV and plasma concentrations of PlGF and sVEGFR-1 in 3348 pregnant women. Plasma samples were obtained between 22 and 26 weeks of gestation at the time of ultrasound examination. Abnormal UADV was defined as the presence of bilateral uterine artery notches and/or a mean pulsatility index above the 95th percentile for the gestational age. Maternal plasma PlGF and sVEGFR-1 concentrations were determined with the use of sensitive and specific immunoassays. The primary outcome was the development of early onset preeclampsia (≤34 weeks of gestation) and/or severe preeclampsia. Secondary outcomes included preeclampsia, the delivery of a small for gestational age (SGA) neonate without preeclampsia, spontaneous preterm birth at ≤32 and ≤35 weeks of gestation, and a composite of severe neonatal morbidity. Contingency tables, chi-square test, receiver operating characteristic curve, and multivariate logistic regression were used for statistical analyses. A probability value of <.05 was considered significant.
RESULTS:
(1) The prevalence of preeclampsia, severe preeclampsia, and early onset preeclampsia were 3.4% (113/3296), 1.0% (33/3296), and 0.8% (25/3208), respectively. UADV was performed in 95.4% (3146/3296) and maternal plasma PlGF concentrations were determined in 93.5% (3081/3296) of the study population. (2) Abnormal UADV and a maternal plasma PlGF <280 pg/mL were independent risk factors for the occurrence of preeclampsia, severe preeclampsia, early onset preeclampsia, and SGA without preeclampsia. (3) Among patients with abnormal UADV, maternal plasma PlGF concentration contributed significantly in the identification of patients destined to develop early onset preeclampsia (area under the curve, 0.80; P<.001) and severe preeclampsia (area under the curve, 0.77; P<.001). (4) In contrast, maternal plasma sVEGFR-1 concentration was of limited use in the prediction of early onset and/or severe preeclampsia. (5) The combination of abnormal UADV and maternal plasma PlGF of <280 pg/mL was associated with an odds ratio (OR) of 43.8 (95% CI, 18.48-103.89) for the development of early onset preeclampsia, an OR of 37.4 (95% CI, 17.64-79.07) for the development of severe preeclampsia, an OR of 8.6 (95% CI, 5.35-13.74) for the development of preeclampsia, and an OR of 2.7 (95% CI, 1.73-4.26) for the delivery of a SGA neonate in the absence of preeclampsia.
CONCLUSION:
The combination of abnormal UADV and maternal plasma PlGF concentration of <280 pg/mL in the second trimester is associated with a high risk for preeclampsia and early onset and/or severe preeclampsia in a low-risk population. Among those with abnormal UADV, a maternal plasma concentration of PlGF of <280 pg/mL identifies most patients who will experience early onset and/or severe preeclampsia.
doi:10.1016/j.ajog.2006.11.002
PMCID: PMC2190731  PMID: 17403407
gestational hypertension; placental growth factor (PlGF); preeclampsia small for gestational age; soluble vascular endothelial growth factor receptor-1 (sVEGFR-1); uterine artery Doppler velocimetry; vascular endothelial growth factor (VEGF)
25.  Outcomes of small for gestational age micropremies depending on how young or how small they are 
Korean Journal of Pediatrics  2011;54(6):246-252.
Purpose
The outcomes of small for gestational age (SGA) infants especially in extremely low birth weight infants (ELBWIs) are controversial. This study evaluated the mortality and morbidity of ELBWIs, focusing on whether or not they were also SGA.
Methods
The medical records of 415 ELBWIs (birth weight <1,000 g), who were inborn and admitted to the Samsung Medical Center neonatal intensive care unit from January 2000 to December 2008, were reviewed retrospectively. Mortality and morbidities were compared by body size groups: very SGA (VSGA), birth weight ≤3rd percentile; SGA, 3rd to 10th percentile; and appropriate for gestational age (AGA) infants, >10th percentile for gestational age. For gestational subgroup analysis, groups were divided into infants with gestational age ≤24+6 weeks (subgroup I), 25+0 to 26+6 weeks (subgroup II), and ≥27+0 weeks (subgroup III).
Results
Gestational age was 29+2±2+6 weeks in the VSGA infants (n=49), 27+5±2+2 weeks in the SGA infants (n=45), and 25+4±1+4 weeks in AGA infants (n=321). Birth weight was 692±186.6 g, 768±132.9 g, and 780±142.5 g in the VSGA, SGA, and AGA groups, respectively. Cesarean section rate and maternal pregnancy-induced hypertension were more common in the VSGA and SGA than in AGA pregnancies. However, chorioamnionitis was more common in the AGA group. The mortalities of the lowest gestational group (subgroup I), and also of the lower gestational group (subgroup I+II) were significantly higher in the VSGA group than the SGA or AGA groups (P=0.020 and P=0.012, respectively). VSGA and SGA infants showed lower incidence in respiratory distress syndrome, ductal ligation, bronchopulmonary dysplasia, intraventricular hemorrhage than AGA group did. However, by multiple logistic regression analysis of each gestational subgroup, the differences were not significant.
Conclusion
Of ELBWIs, extremely SGA in the lower gestational subgroups, had an impact on mortality, which may provide information useful for prenatal counseling.
doi:10.3345/kjp.2011.54.6.246
PMCID: PMC3174360  PMID: 21949519
Small for gestational age; Extremely low birth weight infants; Mortality; Morbidity

Results 1-25 (1012006)