Small For Gestational Age Cases Research Articles

Placental exosomes profile in maternal and fetal circulation in intrauterine growth restriction - Liquid biopsies to monitoring fetal growth

IntroductionPlacenta-derived exosomes may represent an additional pathway by which the placenta communicates with the maternal system to induce maternal vascular adaptations to pregnancy and it may be affected during Fetal growth restriction (FGR). The objective of this study was to quantify the concentration of total and placenta-derived exosomes in maternal and fetal circulation in small fetuses classified as FGR or small for gestational age (SGA). MethodsProspective cohort study in singleton term gestations including 10 normally grown fetuses and 20 small fetuses, sub-classified into SGA and FGR accordingly to birth weight (BW) percentile and fetoplacental Doppler. Exosomes were isolated from maternal and fetal plasma and characterized by morphology, enrichment of exosomal proteins, and size distribution by electron microscopy, western blot, and nanoparticle tracking analysis, respectively. Total and specific placenta-derived exosomes were determined using quantum dots coupled with CD63+ve and placental-type alkaline phosphatase (PLAP)+ve antibodies, respectively. ResultsMaternal concentrations of CD63+ve and PLAP+ve exosomes were similar between the groups (all p > 0.05). However, there was a significant positive correlation between the ratio of placental-derived to total exosomes (PLAP+ve ratio) and BW percentile, [rho = 0.77 (95% CI: 0.57 to 0.89); p = 0.0001]. The contribution of placental exosomes to the total exosome concentration in maternal and fetal circulation showed a significant decrease among cases, with lower PLAP+ve ratios in FGR compared to controls and SGA cases. DiscussionQuantification of placental exosomes in maternal plasma reflects fetal growth and it may be a useful indicator of placental function.

446: Fetal growth surveillance in at-risk pregnancies: How soon is too soon?

To identify the optimal gestational age to initiate fetal growth surveillance in at-risk fetuses who are normally grown at 18-22 weeks. We reviewed deliveries at our institution from January 1, 2013 to March 31, 2017. We included all pregnancies with indicated fetal growth surveillance whose first ultrasound (US) occurred before 22 weeks gestation and who were normally grown at 18-22 weeks. Fetuses with multiple gestations, anomalies precluding measurement of biometric parameters, or discordant gestational age documentation were excluded. Estimated fetal weights (EFWs) were calculated and percentiles assigned using the Hadlock formula and curve. Fetal growth restriction (FGR) was defined as EFW <10th percentile, and small-for-gestational age (SGA) was defined as birth weight <10th percentile according to a recent, sex-specific, nationwide U.S. cohort (Olsen et al, Pediatrics 2010). The primary outcome was the proportion of true positives from new FGR cases first identified at various gestational age ranges (24-276, 28-316, 32-356, ≥36 weeks). We identified 1226 pregnancies who underwent a total of 3854 US exams, with a mean of 3.14 exams per patient. There were 136 SGA neonates (11.1%), 49 of which (36.0%) were correctly identified antenatally by serial US. The gestational age range 32-356 weeks performed best, accounting for 51.0% of all correctly identified SGA cases and just 30.7% of all false positives. The period at which US performed worst worst was 24-276 weeks, which accounted for just 16.3% of all true positives and 32.0% of all false positives. Only 15.6% of fetuses with FGR first identified at 24-276 weeks ultimately required preterm delivery, versus 25.0% of fetuses diagnosed at 32-356 weeks (p<0.001). Cases of FGR first identified at 24-276 weeks had a true positive-false positive ratio that was double the ratio for cases diagnosed at 28-316 weeks and more than triple of ratio for cases diagnosed at 32-356 weeks. Among a cohort of fetuses at risk for FGR, ultrasounds performed at 24-276 weeks led to unnecessary additional surveillance while correctly identifying SGA at a low rate. When making a plan for a fetus at risk of growth restriction, waiting to initiate surveillance until 28-32 weeks could prevent unnecessary testing.

Cord Blood Biomarkers of Cardiac Dysfunction and Damage in Term Growth-Restricted Fetuses Classified by Severity Criteria

Objective: To assess cardiovascular function and damage in term small-for-gestational-age (SGA) and intrauterine growth-restricted (IUGR) fetuses by echocardiography and biomarkers in cord blood. Methods: This was a cohort study including 60 normal fetuses and 47 term small fetuses subclassified as small for gestational age (SGA) with estimated fetal weight (EFW) between the 3rd and 9th centiles and normal fetoplacental Doppler (n = 14) or intrauterine growth restriction (IUGR, n = 33) if EFW <3rd centile or EFW <10th centile together with cerebroplacental ratio <5th and/or mean uterine artery pulsatility index >95th centile. Fetal echocardiography included left myocardial performance index (MPI) and annular plane systolic excursion. Fetal B-type natriuretic peptide (BNP), troponin-I, heart-type fatty acid-binding proteins (H-FABP), and homocysteine concentrations were measured in cord blood collected at delivery. Results: Both SGA and IUGR cases presented echocardiographic signs of systolic and diastolic dysfunction with increased MPI (mean controls 0.43 [SD 0.12], SGA 0.47 [0.03], and IUGR 0.57 [0.08], p < 0.01) and decreased mitral annular plane systolic excursion (controls 6.0 mm [1.0], SGA 5.5 mm [0.6], and IUGR 4.9 mm [0.8], p = 0 01). IUGR fetuses presented increased levels of cord blood BNP (controls 17.2 pg/mL [11.5], SGA 22.4 pg/mL [10.7], and IUGR 31.2 pg/mL [26.8], p < 0.01). Troponin I was increased in both SGA and IUGR cases (controls 0.004 ng/mL [0.007], SGA 0.012 ng/mL [0.02], and IUGR 0.018 ng/mL [0.05], p < 0.01). H-FABP and homocysteine showed similar values among groups. Conclusions: Cardiac dysfunction and cell damage is a common feature of term SGA and IUGR fetuses despite of the severity criteria for perinatal outcome. Further research is needed to evaluate the potential long-term consequences on their cardiovascular system.

Prediction of fetal growth restriction using estimated fetal weight vs a combined screening model in the third trimester

To compare the performance of third-trimester screening, based on estimated fetal weight centile (EFWc) vs a combined model including maternal baseline characteristics, fetoplacental ultrasound and maternal biochemical markers, for the prediction of small-for-gestational-age (SGA) neonates and late-onset fetal growth restriction (FGR). This was a nested case-control study within a prospective cohort of 1590 singleton gestations undergoing third-trimester (32 + 0 to 36 + 6 weeks' gestation) evaluation. Maternal baseline characteristics, mean arterial pressure, fetoplacental ultrasound and circulating biochemical markers (placental growth factor (PlGF), lipocalin-2, unconjugated estriol and inhibin A) were assessed in all women who subsequently delivered a SGA neonate (n = 175), defined as birth weight < 10th centile according to customized standards, and in a control group (n = 875). Among SGA cases, those with birth weight < 3rd centile and/or abnormal uterine artery pulsatility index (UtA-PI) and/or abnormal cerebroplacental ratio (CPR) were classified as FGR. Logistic regression predictive models were developed for SGA and FGR, and their performance was compared with that obtained using EFWc alone. In SGA cases, EFWc, CPR Z-score and maternal serum concentrations of unconjugated estriol and PlGF were significantly lower, while mean UtA-PI Z-score and lipocalin-2 and inhibin A concentrations were significantly higher, compared with controls. Using EFWc alone, 52% (area under receiver-operating characteristics curve (AUC), 0.82 (95% CI, 0.77-0.85)) of SGA and 64% (AUC, 0.86 (95% CI, 0.81-0.91)) of FGR cases were predicted at a 10% false-positive rate. A combined screening model including a-priori risk (maternal characteristics), EFWc, UtA-PI, PlGF and estriol (with lipocalin-2 for SGA) achieved a detection rate of 61% (AUC, 0.86 (95% CI, 0.83-0.89)) for SGA cases and 77% (AUC, 0.92 (95% CI, 0.88-0.95)) for FGR. The combined model for the prediction of SGA and FGR performed significantly better than did using EFWc alone (P < 0.001 and P = 0.002, respectively). A multivariable integrative model of maternal characteristics, fetoplacental ultrasound and maternal biochemical markers modestly improved the detection of SGA and FGR cases at 32-36 weeks' gestation when compared with screening based on EFWc alone. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

EP14.35: The influence of fetal gender on the antenatal detection of small‐for‐gestational‐age fetuses

To evaluate the influence of fetal gender on the antenatal detection of small for gestational age (SGA) fetuses. This is a prospective observational cohort of women attending for pregnancy care at the John Radcliffe Hospital, Oxford, UK. 2062 unselected singleton pregnancies had ultrasound fetal biometry at 20 and 36 weeks; umbilical and middle cerebral artery Doppler at 36 weeks; and birthweight and gender assessed at birth. The abdominal circumference (AC) growth velocity was defined as the z-score difference between 20 and 36 weeks adjusted for the interval in days and the lowest decile derived from local data was used. Fetal SGA was defined as EFW < 10th centile; and SGA at birth was defined as birthweight < 10th centile adjusted for gender. Comparisons between categorical variables were performed using the chi-squared test. Quantitative variables were assessed for normality and comparisons were performed using the student t-test. Amongst 199 cases of fetal SGA there were more female (57.8%) than male (42.2%) fetuses (OR 1.443; p=0.017). AC growth velocity in the lowest decile was less common in girls (OR 0.390; p=0.002). There were no significant differences in CPR < 5th centile (OR 0.759; p=0.488) or EFW< 3rd centile (OR 0.64; p=0.159) between female and male fetuses. Overall detection rate of SGA at birth was 46%. The detection rate of SGA at birth for boys and girls was 41% and 51% respectively (p=0.1925); the positive predictive value of EFW < 10th centile for boys and girls was 50% and 40% respectively (p=0.1937). The use of a universal EFW centile threshold leads to over representation of female fetuses as fetal SGA. Female fetal SGA are less likely to have a clinically significant reduction of AC velocity than males and therefore may be at less risk. Antenatal adjustment for fetal gender could improve the detection of fetuses at risk.

The long-term neurodevelopmental outcomes of infants born full-term with low birth weight.

Tosun A, Gürbüz-Özgür B, Aksu H, Kaynak-Türkmen M. The long-term neurodevelopmental outcomes of infants born full-term with low birth weight. Turk J Pediatr 2017; 59: 169-176. In this study, it was aimed to evaluate the neurological developments of pre-school or school-aged children together with their school successes, intelligence quotient and symptom severity of attention deficit hyperactivity disorder who were born at the 37th gestational week and above with birth weights below tenth percentile, which is called small for gestational age (SGA). A total of 74 patients with SGA and 75 healthy children were evaluated. The patients were evaluated by child neurologist and child psychiatrist. Wechsler Intelligence Scale for Children-Revised, Ankara Developmental Screening Inventory, and The Turgay DSM-IV-Based Child and Adolescent Disruptive Behavioral Disorders Screening and Rating Scale (T-DSM-IV-S) were applied according to their age groups. SGA cases had been breastfed for shorter durations (p: 0.004), had walked later (p < 0.001), talked later (p < 0.001), and had encountered more vision disorders (p: 0.009) than the control group. SGA cases were determined to encounter febrile convulsions more frequently (p: 0.007). SGA cases were determined to exhibit lower school success (p < 0.001), were diagnosed with attention deficit hyperactivity disorder more frequently (p < 0.001), and their mental developments were delayed (p < 0.001). In cases with SGA, inattention (p: 0.004) and conduct disorder (p: 0.029) subscales and the total scale scores (p: 0.022) of T-DSM-IV-S were significantly lower when compared to the control group. We consider that being SGA may have a negative impact on child`s behavior, attention and academic achievement in long-term.

Short-term outcome of periviable small-for-gestational-age babies: is our counseling up to date?

There are limited data for counseling on and management of periviable small-for-gestational-age (SGA) fetuses. We therefore aimed to investigate the short-term outcome of periviable SGA fetuses in relation to the likely underlying cause. This was a retrospective study of data from three London tertiary fetal medicine centers obtained between 2000 and 2015. We included viable singleton pregnancies with a severely small fetus, defined as those with an abdominal circumference ≤ 3rd percentile, identified between 22 + 0 and 25 + 6 weeks' gestation. Data obtained included fetal biometry, presence of placental anomalies, uterine and fetal Doppler and neonatal outcome. We excluded cases with structural abnormalities, proven or suspected abnormal karyotype or genetic syndromes. Cases were classified according to the suspected underlying cause of the small fetal size into one of the following categories: uteroplacental insufficiency, evidence of placental damage with normal uterine artery Doppler, viral infection, or unclassied. There were 245 cases included in the study. Of these, at diagnosis of SGA, 201 (82%) were categorized as uteroplacental cause, 13 (5%) as suspected placental cause, one (0.4%) as suspected viral cause and 30 (12%) could not be assigned to any of these categories. Overall, 101 (41%) cases survived the neonatal period; 89 (36%) underwent in-utero fetal demise, 22 (9%) died neonatally and 33 (14%) pregnancies were terminated. The diagnosis-to-delivery interval was 8.1 weeks in those that survived and 4.5 weeks in those that died neonatally. Almost 90% of periviable SGA cases are associated with uteroplacental insufficiency or intraplacental damage. Survival is related to gestational age at delivery, with outcomes better than might be assumed at diagnosis and some pregnancies reaching term. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Organ weights and ratios for postmortem identification of fetal growth restriction: utility and confounding factors.

The postmortem fetal brain:liver weight ratio is commonly used as a marker of nutrition for diagnosis of fetal growth restriction (FGR). However, there are limited data regarding the effects of intrauterine retention, fetal maceration and postmortem interval on organ weights and their ratios at autopsy. Our aims were to examine the relationships between gestational-age-adjusted and sex-adjusted fetal organ weights at autopsy, cause of intrauterine death and effects of intrauterine retention, and to determine whether the brain:liver weight ratio is a reliable marker of FGR in intrauterine death. As part of a larger study examining autopsy findings in intrauterine death, data from two specialist centers in London were collated in a specially designed database. Autopsy and clinical information for > 1000 intrauterine deaths between 2005 and 2013 were extracted. Adjusted (delta) organ weights were calculated by plotting against gestational age female and male brain, liver, thymus, heart, combined kidney, combined lung, spleen and combined adrenal gland weights. Polynomial regression was used to determine best fit and to calculate expected (50th centile) organ weights and deviations from expected. We compared adjusted organ weights and body:organ weight ratios in fetuses which were small-for-gestational age (SGA) at autopsy (birth weight < 10th centile for normal live births) vs those in fetuses which were not, and in macerated vs non-macerated fetuses. The majority of fetal organs (brain, liver, heart, thymus, lungs, kidneys and thyroid) in SGA fetuses were significantly lighter than those in non-SGA fetuses. Body:organ weight ratios for thymus, liver and spleen were significantly greater in SGA fetuses, indicating these organs to be disproportionately small. The majority of organs were significantly lighter in macerated compared with non-macerated fetuses and body:organ weight ratios for most organs (liver, thymus, lung, pancreas, adrenal gland, kidney, heart) were significantly greater in macerated compared with non-macerated fetuses. When SGA cases with demonstrable placental histological abnormalities were compared with other SGA cases, there was a significant difference in the brain:liver weight ratio (median, 6 vs 3.5). Changes after intrauterine death lead to loss of fetal weight, with preferential weight loss of visceral organs such as the liver. Maceration therefore affects the brain:liver weight ratio and adjustment should be made for such changes during interpretation of ratios. Fetal organ weights may be affected significantly by mechanism of death and postmortem changes. The fetal brain:liver weight ratio may provide useful information regarding intrauterine growth status at time of death, provided that adjustment is made for effects of intrauterine retention and that appropriate cut-off values are used. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Effects of intrauterine retention and postmortem interval on body weight following intrauterine death: implications for assessment of fetal growth restriction at autopsy.

According to the classification system used, 15-60% of stillbirths remain unexplained, despite undergoing recommended autopsy examination, with variable attribution of fetal growth restriction (FGR) as a cause of death. Distinguishing small-for-gestational age (SGA) from pathological FGR is a challenge at postmortem examination. This study uses data from a large, well-characterized series of intrauterine death autopsies to investigate the effects of secondary changes such as fetal maceration, intrauterine retention and postmortem interval on body weight. Autopsy findings from intrauterine death investigations (2005-2013 inclusive, from Great Ormond Street Hospital and St George's Hospital, London) were collated into a research database. Growth charts published by the World Health Organization were used to determine normal expected weight centiles for fetuses born ≥ 24 weeks' gestation, and the effects of intrauterine retention (maceration) and postmortem interval were calculated. There were 1064 intrauterine deaths, including 533 stillbirths ≥ 24 weeks' gestation with a recorded birth weight. Of these, 192 (36%) had an unadjusted birth weight below the 10th centile and were defined as SGA. The majority (86%) of stillborn SGA fetuses demonstrated some degree of maceration, indicating a significant period of intrauterine retention after death. A significantly greater proportion of macerated fetuses were present in the SGA population compared with the non-SGA population (P = 0.01). There was a significant relationship between increasing intrauterine retention interval and both more severe maceration and reduction in birth weight (P < 0.0001 for both), with an average artifactual reduction in birth weight of around -0.8 SD of expected weight. There was an average 12% reduction in fetal weight between delivery and autopsy and, as postmortem interval increased, fetal weight loss increased (P = 0.0001). Based on birth weight alone, 36% of stillbirths are classified as SGA. However, fetuses lose weight in utero with increasing intrauterine retention and continue to lose weight between delivery and autopsy, resulting in erroneous overestimation of FGR. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Classifying neonatal growth outcomes: use of birth weight, placental evaluation and individualized growth assessment

Objective: To compare neonatal growth outcomes determined by birth weight (BW), placental assessment (Plac Assess) and individualized growth assessment (IGA). Methods: This retrospective analysis was carried out in 45 selected pregnancies at risk for fetal growth restriction. Serial fetal biometry was carried out in the 2nd and 3rd trimester. First and second trimester placental biomarkers, 2nd trimester uterine artery (Ut A) velocimetry and postnatal placental pathology were evaluated as indicators of placental insufficiency. At delivery, weight (WT), head circumference (HC) and crown–heel length (CHL) were measured. BWs were categorized as large-for-gestational-age (LGA), appropriate-for-gestational-age (AGA) and small-for-gestational age (SGA) (<10th, 10th–90th and >90th percentiles). In these categories, neonatal growth outcomes were classified as growth restricted (GR), normal (NORMAL) or macrosomic (MACRO) based on BW plus Plac Assess (Ut A velocimetry, biomarkers, pathology) or IGA [growth potential realization index profile (WT, HC and CHL)]. Results: There were 6 LGA, 14 AGA and 25 SGA neonates in this sample. All 14 AGA neonates were considered NORMAL by both IGA and BW + Plac Assess. All six LGA neonates were classified as MACRO by BW + Plac Assess but only four by IGA (the remaining two were NORMAL and high NORMAL). The 25 SGA cases could be divided into five subgroups based on IGA and BW + Plac Assess. The largest subgroup (56%) was GR and the next largest (24%) was NORMAL by both classification methods. In the remaining 20%, there was some evidence of GR but IGA and BW + Plac Assess were not in complete agreement. Conclusions: Agreement was good for all three methods in the LGA and AGA groups. The SGA group was heterogeneous but agreement between IGA and BW + Plac Assess was 89%. These results, using more sophisticated growth assessment methods, confirm placental insufficiency as a primary cause of growth restriction. Most normal and GR SGA neonates can be identified with conventional anatomical measurements if IGA is used.

Prediction of small-for-gestational-age neonates: screening by biophysical and biochemical markers at 19-24 weeks.

To investigate the value of combined screening by maternal characteristics and medical history, fetal biometry and biophysical and biochemical markers at 19-24 weeks' gestation, for prediction of delivery of small-for-gestational-age (SGA) neonates, in the absence of pre-eclampsia (PE), and examine the potential value of such assessment in deciding whether the third-trimester scan should be at 32 and/or 36 weeks' gestation. This was a screening study in 7816 singleton pregnancies, including 389 (5.0%) that delivered SGA neonates with birth weight < 5(th) percentile (SGA < 5(th) ), in the absence of PE. Multivariable logistic regression analysis was used to determine if screening by a combination of maternal factors, fetal biometry, uterine artery pulsatility index (UtA-PI) and maternal serum concentrations of placental growth factor (PlGF) and α-fetoprotein (AFP) had significant contribution in predicting SGA neonates. A model was developed for selecting the gestational age for third-trimester assessment, at 32 and/or 36 weeks, based on the results of screening at 19-24 weeks. Significant independent contributions to the prediction of SGA < 5(th) were provided by maternal factors, fetal biometry, UtA-PI and serum PlGF and AFP. The detection rate (DR) of such combined screening at 19-24 weeks was 100%, 78% and 42% for SGA < 5(th) delivering < 32, at 32-36 and ≥ 37 weeks' gestation, respectively, at a false-positive rate (FPR) of 10%. In a hypothetical model, it was estimated that if the desired objective of prenatal screening is to predict about 80% of the cases of SGA < 5(th) , it would be necessary to select 11% of the population at the 19-24-week assessment to be reassessed at 32 weeks and 44% to be reassessed at 36 weeks; 57% would not require a third-trimester scan. Prenatal prediction of a high proportion of SGA neonates necessitates the undertaking of screening in the third trimester of pregnancy, in addition to assessment in the second trimester, and the timing of such screening, at 32 and/or 36 weeks, should be contingent on the results of the assessment at 19-24 weeks.

Extensive shift in placental transcriptome profile in preeclampsia and placental origin of adverse pregnancy outcomes.

One in five pregnant women suffer from gestational complications, prevalently driven by placental malfunction. Using RNASeq, we analyzed differential placental gene expression in cases of normal gestation, late-onset preeclampsia (LO-PE), gestational diabetes (GD) and pregnancies ending with the birth of small-for-gestational-age (SGA) or large-for-gestational-age (LGA) newborns (n = 8/group). In all groups, the highest expression was detected for small noncoding RNAs and genes specifically implicated in placental function and hormonal regulation. The transcriptome of LO-PE placentas was clearly distinct, showing statistically significant (after FDR) expressional disturbances for hundreds of genes. Taqman RT-qPCR validation of 45 genes in an extended sample (n = 24/group) provided concordant results. A limited number of transcription factors including LRF, SP1 and AP2 were identified as possible drivers of these changes. Notable differences were detected in differential expression signatures of LO-PE subtypes defined by the presence or absence of intrauterine growth restriction (IUGR). LO-PE with IUGR showed higher correlation with SGA and LO-PE without IUGR with LGA placentas. Whereas changes in placental transcriptome in SGA, LGA and GD cases were less prominent, the overall profiles of expressional disturbances overlapped among pregnancy complications providing support to shared placental responses. The dataset represent a rich catalogue for potential biomarkers and therapeutic targets.

Prediction of small-for-gestational-age neonates: screening by fetal biometry at 19-24 weeks.

To investigate the value of fetal biometry at 19-24 weeks' gestation in the prediction of delivery of small-for-gestational-age (SGA) neonates, in the absence of pre-eclampsia (PE), and examine the potential value of such assessment in deciding whether the third-trimester scan should be at 32 and/or 36 weeks' gestation. This was a screening study in 88,187 singleton pregnancies, including 5003 (5.7%) that delivered SGA neonates with birth weight < 5(th) percentile (SGA < 5(th)). Multivariable logistic regression analysis was used to determine if screening by a combination of maternal characteristics and medical history and Z-scores of fetal head circumference (HC), abdominal circumference (AC) and femur length (FL) had significant contribution in predicting SGA neonates. A model was developed for selecting the gestational age for third-trimester assessment, at 32 and/or 36 weeks, based on the results of screening at 19-24 weeks. Combined screening by maternal factors and fetal biometry at 19-24 weeks, predicted 76%, 58% and 44% of SGA < 5(th) delivering < 32, 32-36 and ≥ 37 weeks' gestation, respectively, at a false-positive rate (FPR) of 10%. The detection rate (DR) of SGA < 5(th) delivering at 32-36 weeks improved from 58% to 82% with screening at 32 weeks rather than at 19-24 weeks. Similarly, the DR of SGA < 5(th) delivering ≥ 37 weeks improved from 44% with screening at 19-24 weeks to 61% and 76% with screening at 32 and 36 weeks, respectively. In a hypothetical model, it was estimated that if the desired objective of prenatal screening is to predict about 80% of the cases of SGA < 5(th), it would be necessary to select 28% of the population at the 19-24-week assessment to be reassessed at 32 weeks and 41% to be reassessed at 36 weeks; in 59% of pregnancies there would be no need for a third-trimester scan. Prenatal prediction of a high proportion of SGA neonates necessitates the undertaking of screening in the third trimester of pregnancy, in addition to assessment in the second trimester, and the timing of such screening, either at 32 and/or 36 weeks, should be contingent on the results of the assessment at 19-24 weeks.

Maternal zinc deficiency during pregnancy elevates the risks of fetal growth restriction: a population-based birth cohort study.

We investigated the association between maternal zinc level during pregnancy and the risks of low birth weight (LBW) and small for gestational age (SGA) infants in a large population-based birth cohort study. In this study, 3187 pregnant women were recruited. For serum zinc level, 2940 pregnant women were sufficient (≥56 μg/dL) and 247 deficient (<56 μg/dL). Of interest, 7.3% newborns were with LBW among subjects with low zinc level (RR: 3.48; 95% CI: 2.03, 5.96; P < 0.001). Adjusted RR for LBW was 3.41 (95% CI: 1.97, 5.91; P < 0.001) among subjects with low zinc level. Moreover, 15.0% newborns were with SGA among subjects with low zinc level (RR: 1.98; 95% CI: 1.36, 2.88; P < 0.001). Adjusted RR for SGA was 1.93 (95% CI: 1.32, 2.82; P < 0.001) among subjects with low zinc level. A nested case-control study within above cohort showed that maternal serum zinc level was lower in SGA cases as compared with controls. By contrast, maternal serum C-reactive protein, TNF-α and IL-8 levels were significantly higher in SGA cases than that of controls. Moreover, nuclear NF-κB p65 was significantly up-regulated in placentas of SGA cases as compared with controls. Taken together, maternal zinc deficiency during pregnancy elevates the risks of LBW and SGA infants.

First trimester PAPP-A2, PAPP-A and hCGβ in small-for-gestational-age pregnancies.

Pregnancy-associated plasma protein-A2 (PAPP-A2) is a recently discovered protease that cleaves a subset of insulin-like growth factor binding proteins (IGFBP). The molecular function suggests its involvement in the IGF system that is vital for fetal growth and development. Our objectives were to establish first trimester median curves of PAPP-A2, PAPP-A and hCGβ for singleton normal pregnancies and to investigate whether an altered level of one or more of the biomarkers is associated with small-for-gestational-age (SGA) neonates before and after stratification according to maternal hypertension and/or proteinuria. This was a case-control study based on 985 pregnant women delivering normal-weighted neonates and 170 pregnant women delivering SGA neonates. PAPP-A2 was measured by ELISA. PAPP-A and hCGβ were measured by an automatic analyzer. Median curves from 8+1 to 14+0 were established and all concentration values were converted to multiples of the median (MoM) values. Before stratification the SGA cases had unaffected PAPP-A2 MoM and hCGβ MoM levels but lower PAPP-A MoM compared with normal controls. After stratification the SGA normotensive subgroup had lower PAPP-A2 MoM and PAPP-A MoM levels than the normal normotensive subgroup. Severe preeclamptic women delivering SGA neonates had higher PAPP-A2 MoM compared to the normotensive women delivering SGA neonates. Pregnant women delivering SGA neonates did not have altered levels of PAPP-A2 or hCGβ but had lower PAPP-A level in the first trimester compared with pregnant women delivering normal-weighted neonates. Pregnancies complicated with severe preeclampsia and SGA may be associated with high PAPP-A2 level.

Small-for-gestational-age birth and maternal plasma antioxidant levels in mid-gestation: a nested case-control study.

To assess whether maternal plasma antioxidant levels in mid-pregnancy are associated with small-for-gestational-age (SGA) birth. Case-control study nested within a population-based cohort study. Four hospitals in Montreal, Canada. Pregnant women recruited before 24 weeks of gestation, whose pregnancies were not complicated by pre-eclampsia or preterm delivery. Blood samples were obtained at 24-26 weeks and assayed for nutritionally derived antioxidant levels in SGA cases (n = 324) and randomly selected controls with birthweights between the 25th and 75th centiles (n = 672). We performed logistic regression analyses using the standardised z-score of each antioxidant as the main independent variable, after summing highly correlated antioxidants or combining via principle component analysis. We adjusted for risk factors for SGA that were associated with antioxidant levels. SGA, birthweight <10th centile for gestational age and sex. Retinol was positively associated with risk of SGA (adjusted odds ratio [OR] 1.41; 95% confidence interval [95% CI] 1.22-1.63, per SD increase). Carotenoids (log of the sum of β-carotene, lutein/zeaxanthin, α- and β-cryptoxanthin) were negatively associated with SGA (adjusted OR 0.64; 95% CI 0.54-0.78, per SD increase). We found no significant associations between SGA and lycopene or any of the forms of vitamin E assessed, including α-tocopherol, corrected α-tocopherol (per nmol/l of low-density lipoprotein articles), or γ-tocopherol. Elevated retinol may be associated with an increased risk of SGA, whereas elevated carotenoid levels may reduce the risk. A better understanding of the nature of these associations is required, however, before recommending specific nutritional interventions in an attempt to prevent SGA birth.

Impact of growth hormone treatment on children’s height

Background The use of growth hormone (GH) is a routinetreatment for growth hormone deficiency (GHD), small forgestational age (SGA), and Turner syndrome (TS). During thetreatment, height measurement at regular intervals is a vital stepto assess success. To date, there have been no previous studieson GH treatment in Dr. Soetomo Hospital, Surabaya, the referralhospital in East Indonesia.Objective To compare body height between pre- and post-growthhormone treatment in pediatric patients.Method This study was a non-randomized, pre-post clinical trialperformed at Dr. Soetomo Hospital, Surabaya. The prospectivecohort was accessed during January 2008-June 2013. Theinclusion criteria was GH treatment for more than 3 months.Clinical data on GH treatment, including diagnosis, age, heightpre-and post-treatment, height gain, duration of treatment, andparental satisfaction were collected. Two-tailed, paired T-test andPearson’s test were used for statistical analyses.Result Nineteen patients underwent GH treatment during thestudy period, but only twelve patients had complete data and wereincluded in the study. Eight subjects were female. Subjects’ meanage was 11 (range 8-15) years. Nine patients had GHD, 2 hadTS, and 1 had SGA. Mean pre-treatment height was 121.05 cm,while mean post-treatment height was 130.5 cm. Mean durationof treatment was 10.5 (range 3-30) months. Mean height gainwas 0.8 cm/month in GHD and SGA cases, and 0.78 cm/monthfor the TS cases. Eleven parents reported satisfaction with theresults of GH treatment in their children. There is significantdiffrent between pre- and post-treatment (P=0.001). Pearson’scorrelation test (r=0.90) revealed a strong correlation betweengrowth hormone treatment and height gain.Conclusion Growth hormone treatment has impact on heights inGH defficiency, Turner syndrome, and small for gestational age.

CYP17A1 gene polymorphisms and environmental exposure to organochlorine pesticides contribute to the risk of small for gestational age

ObjectivesThe cytochrome P-450c17α enzyme encoded by the cytochrome P-450c17α (CYP17A1) gene plays a role in oestrogen synthesis. Genetic variation in the maternal CYP17A1 gene leads to differences in oestrogen level that affect fetal growth and cause small for gestational age (SGA). Organochlorine pesticides (OCPs) are endocrine disruptors that alter the normal oestrogen–progesterone balance, and are associated with adverse reproductive outcomes. This study was designed to investigate the effect of the gene–environment interaction between maternal CYP17A1 gene polymorphisms and maternal and cord OCP levels on the risk of SGA. Study designMaternal and cord blood samples of 50 term SGA cases (birth weight <10th percentile for gestational age as per Lubchenco's growth chart) and 50 normal pregnancies (controls) were collected. Women with occupational exposure to OCPs, anaemia, hypertension, antiphospholipid antibody syndrome, medical disease, parity of more than four, or a history of smoking, alcohol consumption or chronic drug intake were excluded from both groups. Maternal and cord blood samples were collected at the time of delivery or after delivery, respectively. The OCP levels of the samples were analyzed using a gas chromatography system equipped with an electron capture detector, and polymerase chain reaction–restriction fragment length polymorphism was used for polymorphic analysis of the CYP17A1 gene. ResultsSignificantly (p<0.05) higher levels of α-hexachlorocyclohexane (HCH), β-HCH and γ-HCH were found in maternal and cord blood samples of the SGA cases compared with the controls. The frequency of the A1A2/A2A2 genotype was significantly lower [p=0.041, odds ratio (OR) 0.421, 95% confidence interval (CI) 0.184–0.966] in the SGA cases compared with the controls. When gene–environment interactions between CYP17A1 gene polymorphisms and OCP levels were considered, a significant (p=0.004) association was found between a high level of endosulfan in cord blood and the A1A1 (wild-type) genotype of CYP17A1, leading to an estimated reduction in birth weight of 315g. ConclusionsHigher OCP levels and the A1A1 genotype of CYP17A1 in pregnant women may be considered as important aetiological factors in idiopathic SGA. This study provides evidence that genetic variation and its interaction with environmental exposure may increase the risk of SGA. Further studies are needed with a larger sample size, incorporating other gene polymorphisms and environmental exposures, to strengthen these observations.

Effect of serum IGF-1, IGFBP-3 and HtSDS in rhGH-treated SGA children

Objective To investigate the clinical value of serum insulin-like growth factor-1 (IGF-1),insulin-like growth factor-binding protein-3 (IGFBP-3) and mean height standard deviation score(HtSDS) in recombinant human growth hormone (rhGH)-treated small for gestational age (SGA) children.Methods 32 cases of SGA failed of catch-up growth were subcutaneously injected with rhGH every night before bed at a dose of 0.15-0.20u· kg-1 · d-1.And the variation of serum IGF-1,IGFBP-3,HtSDS,body height and growth velocity (GV) were monitored at 3,6,9 and 12 months of the treatment and compared.Results The GV (cm/years) increased to (12.4 ± 3.2),(11.0 ± 2.3),(10.1 ± 3.5),(9.4 ± 1.8) versus (4.1 ± 0.5) before treatment,suggesting a significant catch-up growth after treatment (F =51.35,P ＜ 0.01).Accordingly,HtSDS increased to (-2.55 ± 0.73),(-2.39 ± 0.65),(-2.21 ± 0.58),(-2.09 ± 0.94) versus (-2.81 ± 0.64),suggesting that height gaps were reduced compared to the normal children of the same age and sex after rhGH treatment (F =4.99,P ＜0.01).The serum levels of IGF-1,IGFBP-3 were significantly increased compared to pre-treatment (F =34.52,14.04,all P ＜ 0.01),especially for serum IGF-1,which maintained at a high level after 3 months of treatment and up to peak after 6 months.However,the ratio of IGF-1/IGFBP-3 showed no increase after treatment (F =1.82,P ＞ 0.05).There was a significant positive correlation between the serum level of IGF-1 and △HtSDS after the rhGH treatment within six months (r3 =0.72,r6 =0.91),while there was no correlation between them after 9 months (r9 =0.26,r12 =0.33).There were no serious adverse events during the rhGH treatment.Conelusion The serum levels of IGF-1,IGFBP-3 were significantly increased after the rhGH treatment,especially for serum IGF-1.There was a significant positive correlation between the serum level of IGF-1 and △HtSDS within six months,but not after 9 months.The rhGH treatment could be a safe and effective strategy for SGA children. Key words: Growth hormone; Infant,low birth weight; Insulin-like growth factor-Ⅰ ; Insulin-like growth factorbinding protein3 ; Body height

Maternal Serum Placental Growth Factor Isoforms 1 and 2 at 11-13, 20-24 and 30-34 Weeks' Gestation in Late-Onset Pre-Eclampsia and Small for Gestational Age Neonates

Objective: To compare the maternal serum concentrations of placental growth factor (PlGF)-1 and PlGF-2 in the first, second and third trimesters in normal pregnancies and in those complicated by pre-eclampsia (PE) or the delivery of small for gestational age (SGA) neonates after 37 weeks. Methods: Serum PlGF-1 and PlGF-2 were measured at 11-13, 20-24 and 30-34 weeks' gestation in 50 cases of PE, 99 cases of SGA and 298 controls. The values of PlGF-1 and PlGF-2 at 11-13 weeks were expressed as multiples of the median (MoM) after adjustment for maternal characteristics. The distributions of PlGF-1 and PlGF-2 in cases and controls at 20-24 and 30-34 weeks were converted to MoM of the values at 11-13 weeks and compared. Results: Serum PlGF-1 and PlGF-2 levels were highly correlated and both increased with gestational age. At 30-34 weeks, the median MoM values for PlGF-1 and PlGF-2 in the late PE (4.2 and 4.3) and late SGA (7.2 and 6.0) groups were significantly lower than in the controls (12.8 and 9.9). Combining the two isoforms did not improve the prediction of late PE and late SGA provided by PlGF-1 alone. Conclusions: The performances of serum PlGF-1 and PlGF-2 in the prediction of late PE and late SGA are similar.