Role of early second‐trimester uterine artery Doppler screening to predict small‐for‐gestational‐age babies in nulliparous women Environmental and urinary markers of prenatal exposure to drinking water disinfection by-products, fetal growth, and duration of gestation in the PELAGIE birth cohort (Brittany, France, 2002-2006). Perinatal morbidity and mortality in early-onset fetal growth restriction: cohort outcomes of the trial of randomized umbilical and fetal flow in Europe (TRUFFLE). Maternal homocysteine in pregnancy and offspring birthweight: epidemiological associations and Mendelian randomization analysis. High prevalence of polycystic ovary syndrome in women born small for gestational age. Ultrasound screening for fetal growth restriction at 36 vs 32 weeks' gestation: a randomized trial (ROUTE). International standards for fetal growth based on serial ultrasound measurements: the Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project The performance of tests of publication bias and other sample size effects in systematic reviews of diagnostic test accuracy was assessed. Vitamin D status is associated with uteroplacental dysfunction indicated by pre-eclampsia and small-for-gestational-age birth in a large prospective pregnancy cohort in Ireland with low vitamin D status. Small-for-gestational-age infants among uncomplicated pregnancies at term: a secondary analysis of 9 Maternal-Fetal Medicine Units Network studies. Association Between Vitamin D Supplementation During Pregnancy and Offspring Growth, Morbidity, and Mortality Maternal serum 25-hydroxyvitamin D and measures of newborn and placental weight in a U.S. multicenter cohort study.
BACKGROUND : Trophoblastic invasion of the uterine spiral arteries substantially increases compliance to accommo date increased blood flow to the placenta . Failure of this process impedes uterine artery blood flow , and this may be detected by uterine artery Doppler flow studies . However , the clinical utility of uterine artery Doppler flow studies in the prediction of adverse pregnancy outcomes in a general population remains largely unknown . OBJECTIVE : We sought to determine the utility of early second‐trimester uterine artery Doppler studies as a predictor of small‐for‐gestational‐age neonates . STUDY DESIGN : Nulliparous women with a viable singleton pregnancy were recruited during their first trimester into an observational prospect i ve cohort study at 8 institutions across the United States . Participants were seen at 3 study visits during pregnancy and again at delivery . Three indices of uterine artery Doppler flow ( resistance index , pulsatility index , and diastolic notching ) were measured in the right and left uterine arteries between 16 weeks 0 days ' and 22 weeks 6 days ' gestation . Test characteristics for varying thresholds in the prediction of small for gestational age ( defined as birthweight < 5th percentile for gestational age [ Alex and er growth curve ] ) were evaluated . RESULTS : Uterine artery Doppler indices , birthweight , and gestational age at birth were available for 8024 women .  Birthweight < 5th percentile for gestational age occurred in 358 ( 4.5 % ) births . Typical thresholds for the uterine artery Doppler indices were all associated with birthweight < 5th percentile for gestational age ( P < .0001 for each ) , but the positive predictive values for these cutoffs were all < 15 % and areas under receiver operating characteristic curves ranged from 0.50‐0.60 . Across the continuous scales for these measures , the areas under receiver operating characteristic curves ranged from 0.56‐0.62 . Incorporating maternal age , early pregnancy body mass index , race/ethnicity , smoking status prior to pregnancy , chronic hypertension , and pregestational diabetes in the prediction model result ed in only modest improvements in the areas under receiver operating characteristic curves ranging from 0.63‐0.66 . CONCLUSION : In this large prospect i ve cohort , early second‐trimester uterine artery Doppler studies were not a clinical ly useful test for predicting small‐for‐gestational‐age babies Although prenatal exposure to water disinfection by-products does not appear to affect the duration of gestation , its impact on fetal growth remains an open question . The authors studied the associations between prenatal exposure to disinfection by-products and fetal growth restriction ( FGR ) and preterm birth in the PELAGIE cohort , a French birth cohort comprising 3,421 pregnant women recruited between 2002 and 2006 . Exposure was assessed by estimating levels of  trihalomethanes ( THMs ) in tap water during pregnancy and maternal water use and by measuring maternal urinary levels of trichloroacetic acid ( TCAA ) during early pregnancy in a nested case-control design that compared 174 FGR cases , 114 preterm births , and 399 controls . Higher uptake of THMs ( especially brominated THMs ) was associated with a higher risk of FGR . Women with TCAA detected in their urine ( > 0.01 mg/L ) had a higher risk of FGR than those with TCAA levels below the detection limit ( adjusted odds ratio = 1.8 , 95 % confidence interval : 0.9 , 3.7 ) and had an odds ratio for preterm birth below 1 ( adjusted odds ratio = 0.8 , 95 % confidence interval : 0.3 , 2.6 ) . Results from this prospect i ve study , the first to use a biomarker of disinfection by-product exposure , suggest that prenatal exposure affects fetal growth , but the causal agent or agents remain to be identified OBJECTIVES Few data exist for counseling and perinatal management of women after an antenatal diagnosis of early-onset fetal growth restriction . Yet , the consequences of preterm delivery and its attendant morbidity for both mother and baby are far reaching . The objective of this study was to describe perinatal morbidity and mortality following early-onset fetal growth restriction based on time of antenatal diagnosis and delivery . METHODS We report cohort outcomes for a prospect i ve multicenter r and omized management study of fetal growth restriction ( Trial of R and omized Umbilical and Fetal Flow in Europe ( TRUFFLE ) ) performed in 20 European perinatal centers between 2005 and 2010 . Women with a singleton fetus at 26 - 32 weeks of gestation , with abdominal circumference < 10(th ) percentile and umbilical artery Doppler pulsatility index > 95(th ) percentile , were recruited . The main outcome measure was a composite of fetal or neonatal death or severe morbidity : survival to discharge with severe brain injury , bronchopulmonary dysplasia , proven neonatal sepsis or necrotizing enterocolitis . RESULTS Five-hundred and three of 542 eligible women formed the study group . Mean ± SD gestational age at diagnosis was 29 ± 1.6 weeks and mean ± SD estimated fetal weight was 881 ± 217 g ; 12 ( 2.4 % ) babies died in utero . Gestational age at delivery was 30.7 ± 2.3 weeks , and birth weight was 1013 ± 321 g. Overall , 81 % of deliveries were indicated by fetal condition and 97 % were by Cesarean section . Of 491 liveborn babies , outcomes were available for 490 amongst whom there were 27 ( 5.5 % ) deaths and 118 ( 24 % ) babies suffered severe morbidity . These babies were smaller at birth ( 867 ± 251 g ) and born earlier ( 29.6 ± 2.0 weeks ) . Death and severe morbidity were significantly related to gestational age , both at study entry and delivery and also with the presence of maternal hypertensive morbidity . The median time to delivery was 13 days for women without hypertension , 8 days for those with gestational hypertension , 4 days for pre-eclampsia and 3 days for HELLP syndrome . CONCLUSIONS Fetal outcome in this study was better than expected from contemporary reports : perinatal death was uncommon ( 8 % ) and 70 % survived without severe neonatal morbidity . The intervals to delivery , death and severe morbidity were related to the presence and severity of maternal hypertensive conditions BACKGROUND Disturbed one-carbon ( 1-C ) metabolism in the mother is associated with poor fetal growth but causality of this relationship has not been established . METHODS We studied the association between maternal total homocysteine and offspring birthweight in the Pune Maternal Nutrition Study ( PMNS , Pune , India ) and Parthenon Cohort Study ( Mysore , India ) . We tested for evidence of causality within a Mendelian r and omization framework , using a methylenetetrahydrofolatereductase ( MTHFR ) gene variant rs1801133 ( earlier known as 677C→T ) by instrumental variable and triangulation analysis , separately and using meta- analysis . RESULTS Median ( IQR ) homocysteine concentration and mean ( SD ) birthweight were 8.6 µmol/l ( 6.7,10.8 ) and 2642 g ( 379 ) in the PMNS and 6.0 µmol/l ( 5.1,7.1 ) and 2871 g ( 443 ) in the Parthenon study . Offspring birthweight  was inversely related to maternal homocysteine concentration-PMNS : -22 g/SD [ 95 % confidence interval ( CI ) : ( -50 , 5 ) , adjusted for gestational age and offspring gender ] ; Parthenon : -57 g ( -92 , -21 ) ; meta- analysis : -40 g ( -62 , -17 ) ] . Maternal risk genotype at rs1801133 predicted higher homocysteine concentration [ PMNS : 0.30 SD/allele ( 0.14 , 0.46 ) ; Parthenon : 0.21 SD ( 0.02 , 0.40 ) ; meta- analysis : 0.26 SD ( 0.14 , 0.39 ) ] ; and lower birthweight [ PMNS : -46 g ( -102 , 11 , adjusted for gestational age , offspring gender and rs1801133 genotype ) ; Parthenon : -78 g ( -170 , 15 ) ; meta- analysis : -61 g ( -111 , -10 ) ] . Instrumental variable and triangulation analysis supported a causal association between maternal homocysteine concentration and offspring birthweight . CONCLUSIONS Our findings suggest a causal role for maternal homocysteine ( 1-C metabolism ) in fetal growth . Reducing maternal homocysteine concentrations may improve fetal growth BACKGROUND There is evidence that intrauterine growth restriction , result ing in newborn girls that are small for gestational age ( SGA ) , may be related to the onset of polycystic ovary syndrome ( PCOS ) . Thus , we studied whether women born SGA have a higher prevalence of PCOS than women born appropriate for gestational age ( AGA ) . METHODS This was a prospect i ve birth cohort study of 384 women born at term between June 1 , 1978 , and May 31 , 1979 , in Ribeirão Preto , Brazil . After exclusion , 165 women effectively participated in this study , of whom 43 were SGA and 122 were AGA . The prevalence of PCOS was analysed . At a mean age of 29 years , the women agreed to follow the study protocol , which included :  anamnesis , physical examination , serum tests [ follicle stimulating hormone , luteinizing hormone , total and free testosterone , dehydroepi and rostenedione sulphate , 17-OH-progesterone , fasting insulin , sex steroid-binding globulin ( SHBG ) and fasting glucose ] and pelvic ultrasound . Data regarding gestational age , birthweight , age at menarche and maternal data were obtained from the files of the cohort . The adjusted relative risk ( RR ) values of the SGA , insulin resistance , body mass index , maternal smoking and parity variables were analysed using Poisson regression with robust adjustment of variance for the prediction of PCOS . RESULTS The prevalence of PCOS was higher in the SGA group than in the AGA group [ adjusted RR = 2.44 , 95 % CI ( 1.39 - 4.28 ) ] . Hyper and rogenism was more prevalent in the SGA women than in the AGA women ( P = 0.011 ) . Circulating SHBG was lower in the SGA women than in the AGA women ( P = 0.041 ) , but fasting insulinemia was similar in both groups . CONCLUSIONS The prevalence of PCOS in SGA women was twice as high as in AGA women in our study population OBJECTIVE To compare the utility of routine third-trimester ultrasound examination at 36 weeks ' gestation with that at 32 weeks in detecting  fetal growth restriction ( FGR ) . METHODS This was an open-label parallel r and omized trial ( ROUTE study ) conducted at a single general hospital serving a geographically well-defined catchment area in Barcelona , Spain , between May 2011 and April 2014 . Women with no adverse medical or obstetric history and a singleton pregnancy without fetal abnormalities at routine second-trimester scan were assigned r and omly to undergo a scan at 32 weeks ' gestation ( n = 1272 ) or at 36 weeks ' gestation ( n = 1314 ) . Primary outcome measures were detection rates of FGR ( customized birth weight < 10(th ) centile ) and severe FGR ( customized birth weight < 3(rd ) centile ) . RESULTS There were no significant differences in perinatal outcome between those who underwent a scan at 32 weeks ' gestation and those who underwent a scan at 36 weeks ' gestation . Severe FGR at birth was associated significantly with emergency Cesarean delivery for fetal distress ( odds ratio ( OR ) , 3.4 ( 95 % CI , 1.8 - 6.7 ) ) , neonatal admission ( OR , 2.23 ( 95 % CI , 1.23 - 4.05 ) ) , hypoglycemia ( OR , 9.5 ( 95 % CI , 1.8 - 49.8 ) ) and hyperbilirubinemia ( OR , 9.0 ( 95 % CI , 4.6 - 17.6 ) ) . Despite similar false-positive rates ( FPRs ) ( 6.4 % vs 8.2 % ) , FGR detection rates were superior at 36 vs 32 weeks ' gestation ( sensitivity , 38.8 % vs 22.5 % ; P = 0.006 ) , with positive and negative likelihood ratios of 6.1 vs 2.7 and 0.65 vs 0.84 , respectively . In cases of severe FGR , FPRs for both scans were also similar ( 8.5 % vs 8.7 % ) , but detection rates were superior at 36 vs 32 weeks ' gestation ( 61.4 % vs 32.5 % ; P = 0.008 ) . Positive and negative likelihood ratios were 7.2 vs 3.7 and 0.4 vs 0.74 , respectively . CONCLUSION In low-risk pregnancies , routine ultrasound examination at 36 weeks ' gestation was more effective than that at 32 weeks ' gestation in detecting FGR and related adverse perinatal and neonatal outcomes BACKGROUND In 2006 , WHO produced international growth st and ards for infants and children up to age 5 years on the basis of recommendations from a WHO expert committee . Using the same methods and conceptual approach , the Fetal Growth Longitudinal Study ( FGLS ) , part of the INTERGROWTH-21(st ) Project , aim ed to develop international growth and size st and ards for fetuses . METHODS The multicentre , population -based FGLS assessed fetal growth in geographically defined urban population s in eight countries , in which most of the health and nutritional needs of mothers were met and adequate antenatal care was provided . We used ultrasound to take fetal anthropometric measurements prospect ively from 14 weeks and 0 days of gestation until birth in a cohort of women with adequate health and nutritional status who were at low risk of intrauterine growth restriction . All women had a reliable estimate of gestational age confirmed by ultrasound measurement of fetal crown-rump length in the first trimester . The five primary ultrasound measures of fetal growth -- head circumference , biparietal diameter , occipitofrontal diameter , abdominal circumference , and femur length -- were obtained every 5 weeks ( within 1 week either side ) from 14 weeks to 42 weeks of gestation . The best fitting curves for the five measures were selected using second-degree fractional polynomials and further modelled in a multilevel framework to account for the longitudinal design of the study . FINDINGS We screened 13,108 women commencing antenatal care at less than 14 weeks and 0 days of gestation , of whom 4607 ( 35 % ) were eligible . 4321 ( 94 % ) eligible women had pregnancies without major complications and delivered live singletons without congenital malformations ( the analysis population ) . We documented very low maternal and perinatal mortality and morbidity , confirming that the participants were at low risk of adverse outcomes . For each of the five fetal growth measures , the mean differences between the observed and smoothed centiles for the 3rd , 50th , and 97th centiles , respectively , were small : 2·25 mm ( SD 3·0 ) , 0·02 mm ( 3·0 ) , and -2·69 mm ( 3·2 ) for head circumference ; 0·83 mm ( 0·9 ) , -0·05 mm ( 0·8 ) , and -0·84 mm ( 1·0 ) for biparietal diameter ; 0·63 mm ( 1·2 ) , 0·04 mm ( 1·1 ) , and -1·05 mm ( 1·3 ) for occipitofrontal diameter ; 2·99 mm ( 3·1 ) , 0·25 mm ( 3·2 ) , and -4·22 mm ( 3·7 ) for abdominal circumference ; and 0·62 mm ( 0·8 ) , 0·03 mm ( 0·8 ) , and -0·65 mm ( 0·8 ) for femur length . We calculated the 3rd , 5th 10th , 50th , 90th , 95th and 97th centile curves according to gestational age for these ultrasound measures , representing the international st and ards for fetal growth . INTERPRETATION We recommend these international fetal growth st and ards for the clinical interpretation of routinely taken ultrasound measurements and for comparisons across population s. FUNDING Bill & Melinda Gates Foundation BACKGROUND AND OBJECTIVE Publication bias and other sample size effects are issues for meta-analyses of test accuracy , as for r and omized trials . We investigate limitations of st and ard funnel plots and tests when applied to meta-analyses of test accuracy and look for improved methods . METHODS Type I and type II error rates for existing and alternative tests of sample size effects were estimated and compared in simulated meta-analyses of test accuracy . RESULTS Type I error rates for the Begg , Egger , and Macaskill tests are inflated for typical diagnostic odds ratios ( DOR ) , when disease prevalence differs from 50 % and when thresholds favor sensitivity over specificity or vice versa . Regression and correlation tests based on functions of effective sample size are valid , if occasionally conservative , tests for sample size effects . Empirical evidence suggests that they have adequate power to be useful tests . When DORs are heterogeneous , however , all tests of funnel plot asymmetry have low power . CONCLUSION Existing tests that use st and ard errors of odds ratios are likely to be seriously misleading if applied to meta-analyses of test accuracy . The effective sample size funnel plot and associated regression test of asymmetry should be used to detect publication bias and other sample size related effects BACKGROUND Associations between vitamin D and pregnancy outcomes have been inconsistent . OBJECTIVES We described the distribution of 25-hydroxyvitamin D3 [ 25(OH)D3 ] , 3-epi-25(OH)D3 , and 25(OH)D2 in early pregnancy and investigated associations with pre-eclampsia and small-for-gestational-age ( SGA ) birth , which are indicative of uteroplacental dysfunction . DESIGN The SCOPE ( Screening for Pregnancy Endpoints ) Irel and prospect i ve pregnancy cohort study included 1768 well-characterized low-risk , nulliparous women resident at 52 ° N.  Serum 25(OH)D3 , 3-epi-25(OH)D3 , and 25(OH)D2  were quantified at 15 wk of gestation with the use of a CDC-accredited liquid chromatography-t and em mass spectrometry method . RESULTS The mean ± SD total 25(OH)D concentration was 56.7 ± 25.9 nmol/L , and 17 % and 44 % of women had 25(OH)D concentrations < 30 and < 50 nmol/L , respectively . The prevalence of pre-eclampsia was 3.8 % , and 10.7 % of infants were SGA . There was a lower risk of pre-eclampsia plus SGA combined ( 13.6 % ) at 25(OH)D concentrations > 75 nmol/L ( adjusted OR : 0.64 ; 95 % CI : 0.43 , 0.96 ) . The main predictors of 25(OH)D were the use of vitamin D-containing supplements ( adjusted mean difference : 20.1 nmol/L ; 95 % CI : 18.5 , 22.7 nmol/L ) and summer sampling ( adjusted mean difference : 15.5 nmol/L ; 95 % CI : 13.4 , 17.6 nmol/L ) . Non-Caucasian ethnicity ( adjusted mean difference : -19.3 nmol/L ; 95 % CI : -25.4 , -13.2 nmol/L ) and smoking ( adjusted mean difference : -7.0 nmol/L ; 95 % CI : -10.5 , -3.6 nmol/L ) were negative predictors of 25(OH)D. The mean ± SD concentration of 3-epi-25(OH)D3 , which was detectable in 99.9 % of sample s , was 2.6 ± 1.6 nmol/L. Determinants of 3-epi-25(OH)D3 were 25(OH)D3 ( adjusted mean difference : 0.052 nmol/L ; 95 % CI : 0.050 , 0.053 nmol/L ) and maternal age ( adjusted mean difference : -0.018 nmol/L ; 95 % CI : -0.026 , -0.009 nmol/L ) . The mean ± SD concentration of 25(OH)D2 was 3.1 ± 2.7 nmol/L , which was present in all sample s. No adverse effects of 25(OH)D concentrations > 125 nmol/L were observed . CONCLUSIONS In the first report to our knowledge of CDC-accredited 25(OH)D data and pregnancy outcomes from a large , clinical ly vali date d , prospect i ve cohort study , we observed a protective association of a 25(OH)D concentration > 75 nmol/L and a reduced risk of uteroplacental dysfunction as indicated by a composite outcome of SGA and pre-eclampsia . Well- design ed , adequately powered r and omized controlled trials are required to verify this observation . The SCOPE pregnancy cohort was registered at www.anzctr.org.au as ACTRN12607000551493 BACKGROUND Most small ( birthweight < 10 % ) for-gestational-age cases occur at term , in uncomplicated pregnancies , and are not identified during prenatal visits as having fetal growth restriction . Hence , they do not benefit from antepartum surveillance and timed delivery . There is dismissive and disquieting opinion that small for gestational age among uncomplicated pregnancies is not associated with increased morbidities and , therefore , does not warrant improved detection . Our hypothesis was that among uncomplicated pregnancies at term , small for gestational age have significantly higher morbidity and mortality than appropriate ( birthweight 10 - 89 % ) for gestational age . OBJECTIVE We sought to compare composite neonatal morbidity among uncomplicated term singleton pregnancies with small vs appropriate for gestational age . STUDY DESIGN We culled collected data from 9 completed Maternal-Fetal Medicine Units studies conducted from 1989 through 2004 . All data were collected prospect ively by trained staff . We excluded women who delivered < 37 weeks and those with hypertension or diabetes , multiple gestation , known anomalies , and birthweight of ≥90 % for gestational age . Using multivariable analysis , we compared composite neonatal morbidity , which included stillbirth and neonatal mortality between small and appropriate for gestational age . R and om effect logistic regressions were used to account for study heterogeneity , with adjustment for potential confounders . We calculated adjusted odds ratios and 95 % confidence intervals . RESULTS Of the > 91,000 women enrolled in the studies , 60 % ( n = 50,011 ) met the inclusion criteria . Among the uncomplicated pregnancies , 10.8 % ( n = 5416 ) were small for gestational age . The rate of composite neonatal morbidity of 16 % in small for gestational age and 10 % in appropriate for gestational age persisted ( adjusted odds ratio , 1.75 ; 95 % confidence interval , 1.71 - 1.78 ) . After adjustment for confounders , the following neonatal morbidities were significantly more common among term small than appropriate for gestational age : Apgar < 4 at 5 minutes , respiratory distress syndrome , mechanical ventilation , necrotizing enterocolitis grade 2 or 3 , and neonatal sepsis . Lastly , rate of stillbirths ( 3.5 vs 0.9/1000 births ; adjusted odds ratio , 3.49 ; 95 % confidence interval , 1.83 - 6.67 ) and neonatal mortality ( 1.1 vs 0.4/1000 births ; adjusted odds ratio , 2.56 ; 95 % confidence interval , 1.83 - 3.57 ) were significantly more common with small than appropriate for gestational age . In secondary analyses the composite neonatal morbidity among newborns at < 5 % and at 5 - 9 % was significantly higher than appropriate for gestational age . Lastly , in subgroup analyses of women who delivered at 37.0 - 38.6 weeks or at ≥39.0 weeks , the increased rate of composite neonatal morbidity , stillbirth , and neonatal mortality among small for gestational age persisted . CONCLUSION Among uncomplicated pregnancies at term , small- compared to appropriate-for-gestational-age newborns have a significantly higher likelihood of composite neonatal morbidity , stillbirth , and neonatal mortality . A large multicenter trial is warranted to determine if improved detection of small for gestational age among uncomplicated pregnancies can mitigate morbidities and mortality , without disproportionate interventions and iatrogenic complications Importance Whether vitamin D supplementation during pregnancy is beneficial and safe for offspring is unclear . Objective To systematic ally review studies of the effects of vitamin D supplementation during pregnancy on offspring growth , morbidity  , and mortality . Data Sources Search es of Medline , Embase , and the Cochrane Data base of Systematic Review s were conducted up to October 31 , 2017 . Key search terms were vitamin D , pregnancy , r and omized controlled trials , and offspring outcomes . Study Selection R and omized clinical trials of vitamin D supplementation during pregnancy and offspring outcomes . Data Extraction and Synthesis Two authors independently extracted data , and the quality of the studies was assessed . Summary risk ratio ( RR ) , risk difference ( RD ) or mean difference ( MD ) , and 95 % CI were calculated using fixed-effects or r and om-effects meta- analysis . Main Outcomes and Measures Main outcomes were fetal or neonatal mortality , small for gestational age ( SGA ) , congenital malformation , admission to a neonatal intensive care unit , birth weight , Apgar scores , neonatal 25-hydroxyvitamin D ( 25[OH]D ) and calcium concentrations , gestational age , preterm birth , infant anthropometry , and respiratory morbidity during childhood . Results Twenty-four clinical trials involving 5405 participants met inclusion criteria . Vitamin D supplementation during pregnancy was associated with a lower risk of SGA ( RR , 0.72 ; 95 % CI , 0.52 to 0.99 ; RD , −5.60 % ; 95 % CI , −0.86 % to −10.34 % ) without risk of fetal or neonatal mortality ( RR , 0.72 ; 95 % CI , 0.47 to 1.11 ) or congenital abnormality ( RR , 0.94 ; 95 % CI , 0.61 to 1.43 ) . Neonates with prenatal vitamin D supplementation had higher 25(OH)D levels ( MD , 13.50 ng/mL ; 95 % CI , 10.12 to 16.87 ng/mL ) , calcium levels ( MD , 0.19 mg/dL ; 95 % CI , 0.003 to 0.38 mg/dL ) , and weight at birth ( MD , 75.38 g ; 95 % CI , 22.88 to 127.88 g ) , 3 months ( MD , 0.21 kg ; 95 % CI , 0.13 to 0.28 kg ) , 6 months ( MD , 0.46 kg ; 95 % CI , 0.33 to 0.58 kg ) , 9 months ( MD , 0.50 kg ; 95 % CI , 0.01 to 0.99 kg ) , and 12 months ( MD , 0.32 kg ; 95 % CI , 0.12 to 0.52 kg ) . Subgroup analysis by doses showed that low-dose vitamin D supplementation ( ⩽2000 IU/d ) was associated with a reduced risk of fetal or neonatal mortality ( RR , 0.35 ; 95 % CI , 0.15 to 0.80 ) , but higher doses ( > 2000 IU/d ) did not reduce this risk ( RR , 0.95 ; 95 % CI , 0.59 to 1.54 ) . Conclusions and Relevance Vitamin D supplementation during pregnancy is associated with a reduced risk of SGA and improved infant growth without risk of fetal or neonatal mortality or congenital abnormality . Vitamin D supplementation with doses of 2000 IU/d or lower during pregnancy may reduce the risk of fetal or neonatal mortality CONTEXT Inconsistent associations between maternal  vitamin D status and fetal size have been published in small studies . OBJECTIVE Our objective was to examine the association between maternal  25-hydroxyvitamin D [ 25(OH)D ] levels and measures of newborn and placental weight . DESIGN AND SETTING We measured maternal 25(OH)D in mothers from the Collaborative Perinatal Project , an observational cohort conducted in 12 U.S. medical centers from 1959 to 1965 . PARTICIPANTS Women delivering singleton , term , live births with 25(OH)D measured at a gestation of 26 wk or less ( n = 2146 ) . MAIN OUTCOME MEASURES Birth weight , ponderal index , placental weight , the placental to fetal weight ratio , and small for gestational age were measured . Hypotheses were formulated after data collection . RESULTS After confounder adjustment , mothers with 25(OH)D of 37.5 nmol/liter or greater gave birth to newborns with 46 g [ 95 % confidence interval ( CI ) , 9 - 82 g ] higher birth weights and 0.13 cm ( 0.01 - 0.25 cm ) larger head circumferences compared with mothers with less than 37.5 nmol/liter . Birth weight and head circumference rose with increasing 25(OH)D up to 37.5 nmol/liter and then leveled off ( P < 0.05 ) . No association was observed between 25(OH)D and ponderal index , placental weight , or the placental to fetal weight ratio . Maternal 25(OH)D of 37.5 nmol/liter or greater vs. less than 37.5 nmol/liter in the first trimester was associated with half the risk of small for gestational age ( adjusted odds ratio 0.5 ; 95 % CI 0.3 - 0.9 ) , but no second-trimester association was observed . CONCLUSIONS Maternal vitamin D status is independently associated with markers of physiological and pathological growth in term infants . Adequately powered r and omized controlled trials are needed to test whether maternal vitamin D supplementation may improve fetal growth
INTRODUCTION To date , there is no robust enough test to predict  small-for-gestational-age ( SGA ) infants , who are at increased lifelong risk of morbidity and mortality .
OBJECTIVE To determine the accuracy of metabolomics in predicting  SGA babies and eluci date which metabolites are predictive of this condition .