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Individualized fetal growth assessment: critical evaluation of key concepts in the specification of third trimester size trajectories.

ABSTRACT: OBJECTIVES:To characterize second and third trimester fetal growth using Individualized Growth Assessment methods in a larger cohort of fetuses with normal neonatal growth outcomes. METHODS:A prospective longitudinal study of 119 pregnancies was performed from 18 weeks, MA, to delivery. Measurements of several 1D and 3D fetal size parameters were obtained from 3D volume data sets at 3-4 week intervals. Regression analyses were used to determine Start Points (SP) and Rossavik model (P?=?c {t} (k?+?st)) coefficients c. k and s for each parameter in each fetus. Second trimester growth velocity reference ranges were determined and size model specification functions re-established, the latter used to generate individual size models. Actual measurements were compared to predicted third trimester size trajectories using Percent Deviations. New age-specific reference ranges for the Percent Deviations of each parameter were defined using 2-level statistical modeling. RESULTS:Rossavik models fit the data for all parameters very well (R(2): 99%), with SP's and k values similar to those found in much smaller cohorts. The c* values were strongly related to the second trimester slope (R(2): 97%), as was predicted s* to estimated c* (R(2): 54--95%). Rossavik models predicted third trimester growth with systematic errors close to 0%; random errors (95% range) ranged between 5.7 and 10.9% and 20.0 and 24.3% for 1D and 3D parameters, respectively. CONCLUSIONS:IGA procedures for evaluating second and third trimester growth are now established based on a larger cohort (4-6 fold larger). New, more rigorously defined, age-specific standards for the evaluation of third trimester size deviations are now available for nine anatomical parameters and a weight estimation procedure that incorporates a soft tissue parameter (fractional thigh volume). These results provide a means for more reliably assessing fetal growth on an individualized basis, thus minimizing the effect of biological differences in growth.

SUBMITTER: Deter RL

PROVIDER: S-EPMC4530800 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Individualized fetal growth assessment: critical evaluation of key concepts in the specification of third trimester size trajectories.

Deter Russell L RL Lee Wesley W Sangi-Haghpeykar Haleh H Tarca Adi L AL Yeo Lami L Romero Roberto R

The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 20130912 6

<h4>Objectives</h4>To characterize second and third trimester fetal growth using Individualized Growth Assessment methods in a larger cohort of fetuses with normal neonatal growth outcomes.<h4>Methods</h4>A prospective longitudinal study of 119 pregnancies was performed from 18 weeks, MA, to delivery. Measurements of several 1D and 3D fetal size parameters were obtained from 3D volume data sets at 3-4 week intervals. Regression analyses were used to determine Start Points (SP) and Rossavik model ...[more]

PMID: 23962305

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Project description:OBJECTIVES:To study fetal growth in pregnancies at risk for growth restriction (GR) using, for the first time, the fetal growth pathology score (FGPS1). METHODS:A retrospective cohort study of GR was carried out in 184 selected SGA singletons using a novel, composite measure of growth abnormalities termed the FGPS1. Serial fetal biometry was used to establish second trimester Rossavik size models and determine FGPS1 values prior to delivery. FGPS1 data were compared to neonatal growth outcomes assessed using growth potential realization index (GPRI) values (average negative pathological GPRI (av?-?pGPRI)). Growth at the end of pregnancy was evaluated from differences in negative, individual composite prenatal growth assessment scores (-icPGAS) measured at the last two ultrasound scans. The FGPS1 and av?-?pGPRI values were used to classify fetal growth and neonatal growth outcomes, respectively, as Normal (N) or Abnormal (A). RESULTS:The risk of neonatal GR (based on birth weight (BW)) was moderate (MR: between 5th and10th percentiles (n?=?113)) or significant (SR:<5th percentile) (n?=?71)). Individual pregnancies were grouped into four categories, two representing agreement (N-N (29%), A-A (40%)) and two representing discordance (N-A (11%), A-N (20%)). In the largest and most variable subgroup (A-A,<5%tile, n?=?49), there was a statistically significant correlation (0.63, p?<?.0001) between the FGPS1 and av?-?pGPRI. In N-A, all 20 cases (100%) had long last-scan-to-delivery intervals (1.9 weeks or greater), suggesting late development of the growth abnormality. For A-N, in approximately equal proportions, GR was improving, progressing or unclassifiable at the end of pregnancy. CONCLUSIONS:Significant agreement between prenatal and postnatal growth assessments was found using a novel approach for quantifying fetal growth pathology (FGPS1). Discordances appear to be due to lack of appropriate prenatal scans or an inadequate set of neonatal measurements. Evidence for a quantitative relationship between assessment methods was seen in the largest and most variable subgroup. The FGPS1 has the potential for characterizing GR in the third trimester and may provide a means for predicting the severity of corresponding abnormal neonatal growth outcomes.

Project description:ObjectiveTo compare third-trimester size trajectory prediction errors (average transformed percent deviations) for three individualized fetal growth assessment methods.MethodsThis study utilized longitudinal measurements of nine directly measured size parameters in 118 fetuses with normal neonatal growth outcomes. Expected value (EV) function coefficients and variance components were obtained using two-level random coefficient modeling. Growth models (IGA) or EV coefficients and variance components (PLM and CPM) were used to calculate predicted values at ∼400 third-trimester time points. Percent deviations (%Dev) calculated at these time points using all three methods were expressed as percentages of IGA MA-specific reference ranges [transformed percent deviations (T%Dev)]. Third-trimester T%Dev values were averaged (aT%Dev) for each parameter. Mean ± standard deviation's for sets of aT%Dev values derived from each method (IGA, PLM and CPM) were calculated and compared.ResultsMean aT%Dev values for nine parameters were: (i) IGA: -4.3 to 5.2% (9/9 not different from zero); (ii) PLM: -32.7 to 25.6% (4/9 not different from zero) and (iii) CPM: -20.4 to 17.4% (5/9 not different from zero). Seven of nine systematic deviations from zero were statistically significant when IGA values were compared to either PLM or CPM values. Variabilities were smaller for IGA when compared to those for PLM or CPM, with (i) 5/9 being statistically significant (IGA versus PLM), (ii) 2/9 being statistically significant (IGA versus CPM) and (iii) 5/9 being statistically significant (PLM versus CPM).ConclusionsSignificant differences in the agreement between predicted third-trimester size parameters and their measured values were found for the three methods tested. With most parameters, IGA gave smaller mean aT%Dev values and smaller variabilities. The CPM method was better than the PLM approach for most but not all parameters. These results suggest that third-trimester size trajectories are best characterized by IGA in fetuses with normal growth outcomes.

Project description:Pregnancy-induced changes in plasma pharmacokinetics of many antiretrovirals (ARV) are well-established. Current knowledge about the extent of ARV exposure in lymphoid tissues of pregnant women and within the fetal compartment is limited due to their inaccessibility. Subtherapeutic ARV concentrations in HIV reservoirs like lymphoid tissues during pregnancy may constitute a barrier to adequate virological suppression and increase the risk of mother-to-child transmission (MTCT). The present study describes the pharmacokinetics of three ARVs (efavirenz, dolutegravir, and rilpivirine) in lymphoid tissues and fetal plasma during pregnancy using materno-fetal physiologically-based pharmacokinetic models (m-f-PBPK). Lymphatic and fetal compartments were integrated into our previously validated adult PBPK model. Physiological and drug disposition processes were described using ordinary differential equations. For each drug, virtual pregnant women (n = 50 per simulation) received the standard dose during the third trimester. Essential pharmacokinetic parameters, including Cmax, Cmin, and AUC (0-24), were computed from the concentration-time data at steady state for lymph and fetal plasma. Models were qualified by comparison of predictions with published clinical data, the acceptance threshold being an absolute average fold-error (AAFE) within 2.0. AAFE for all model predictions was within 1.08-1.99 for all three drugs. Maternal lymph concentration 24 h after dose exceeded the reported minimum effective concentration (MEC) for efavirenz (11,514 vs. 800 ng/ml) and rilpivirine (118.8 vs. 50 ng/ml), but was substantially lower for dolutegravir (16.96 vs. 300 ng/ml). In addition, predicted maternal lymph-to-plasma AUC ratios vary considerably (6.431-efavirenz, 0.016-dolutegravir, 1.717-rilpivirine). Furthermore, fetal plasma-to-maternal plasma AUC ratios were 0.59 for efavirenz, 0.78 for dolutegravir, and 0.57 for rilpivirine. Compared with rilpivirine (0 h), longer dose forgiveness was observed for dolutegravir in fetal plasma (42 h), and for efavirenz in maternal lymph (12 h). The predicted low lymphoid tissue penetration of dolutegravir appears to be significantly offset by its extended dose forgiveness and adequate fetal compartment exposure. Hence, it is unlikely to be a predictor of maternal virological failure or MTCT risks. Predictions from our m-f-PBPK models align with recommendations of no dose adjustment despite moderate changes in exposure during pregnancy for these drugs. This is an important new application of PBPK modeling to evaluate the adequacy of drug exposure in otherwise inaccessible compartments.

Project description:BACKGROUND:Preterm birth, small size for gestational age (SGA) and large size for gestational age (LGA) at birth are major risk factors for neonatal and long-term morbidity and mortality. It is unclear which periods of pregnancy are optimal for ultrasound screening to identify fetuses at risk of preterm birth, SGA or LGA at birth. We aimed to examine whether single or combined second and third trimester ultrasound in addition to maternal characteristics at the start of pregnancy are optimal to detect fetuses at risk for preterm birth, SGA and LGA. METHODS:In a prospective population-based cohort among 7677 pregnant women, we measured second and third trimester estimated fetal weight (EFW), and uterine artery pulsatility and umbilical artery resistance indices as placenta flow measures. Screen positive was considered as EFW or placenta flow measure < 10th or > 90th percentile. Information about maternal age, body mass index, ethnicity, parity, smoking, fetal sex and birth outcomes was available from questionnaires and medical records. Screening performance was assessed via receiver operating characteristic (ROC) curves and area under the curve (AUC) along with sensitivity at different false-positive rates. RESULTS:Maternal characteristics only and in combination with second trimester EFW had a moderate performance for screening for each adverse birth outcome. Screening performance improved by adding third trimester EFW to the maternal characteristics (AUCs for preterm birth 0.64 (95%CI 0.61 to 0.67); SGA 0.79 (95%CI 0.78 to 0.81); LGA 0.76 (95%CI 0.75; 0.78)). Adding third trimester placenta measures to this model improved only screening for risk of preterm birth (AUC 0.72 (95%CI 0.66 to 0.77) with sensitivity 37% at specificity 90%) and SGA (AUC 0.83 (95%CI 0.81 to 0.86) with sensitivity 55% at specificity 90%). Combining second and third trimester fetal and placental ultrasound did not lead to a better performance as compared to using only third trimester results. CONCLUSIONS:Combining single third trimester fetal and placental ultrasound results with maternal characteristics has the best screening performance for risks of preterm birth, SGA and LGA. As compared to second trimester screening, third trimester screening may double the detection of fetuses at risk of common adverse birth outcomes.

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Individualized fetal growth assessment: critical evaluation of key concepts in the specification of third trimester size trajectories.

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Individualized fetal growth assessment: critical evaluation of key concepts in the specification of third trimester size trajectories.

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