Can growth in dichorionic twins be monitored with individualized growth assessment?

OBJECTIVE: To characterize fetal growth in dichorionic twins using individualized growth assessment (IGA), a method based on individual growth potential estimates. METHODS: This secondary analysis included 286 fetuses/neonates from 143 dichorionic twin pregnancies that were part of the ESPRiT (Evaluation of Sonographic Predictors of Restricted Growth in Twins) study. The sample was subcategorized according to birth weight into appropriate-for-gestational-age (AGA) (n = 243) and small-for-gestational-age (SGA) (n = 43) cohorts. Serial biometric scans evaluating biparietal diameter, head circumference (HC), abdominal circumference, femur diaphysis length and estimated weight at 2-week intervals were used to evaluate fetal growth, while measurements of birth weight, crown-heel length and HC determined neonatal growth outcome. Six abnormalities (hypoxic ischemic encephalopathy, periventricular leukomalacia, necrotizing enterocolitis, respiratory distress, sepsis and death) constituted the evaluated adverse neonatal outcomes (ANO). IGA was used to: evaluate differences in second-trimester growth velocities between singletons (from a published dataset) and dichorionic twins (138 AGA twins with normal third-trimester growth); describe the degree to which actual third-trimester growth in twins followed expected growth (111 AGA twins, normal fetal growth and neonatal growth outcomes); determine if the fetal growth pathology score 1 (-FGPS1) could detect, quantify and classify twin growth pathology (224 AGA, 42 SGA); and assess the relationship between -FGPS1 and ANO (24 SGA twins with progressive growth restriction confirmed by abnormal neonatal growth outcome). RESULTS: The differences in second-trimester growth velocity between singletons and twins (means and variances) were small and not statistically significant. Percent deviations from the expected third-trimester size trajectories were within the 95% reference ranges derived from singletons at 95.7% (1677/1752) of timepoints studied. Abnormal growth was detected in 37.9% of AGA twins and 85.7% of SGA twins. Growth restriction was more heterogeneous in AGA twins, while in SGA twins progressive growth restriction was the principal type (66.7%). -FGPS1 patterns previously defined in singletons classified 97.5% of pathological twin cases. In our most severe form of growth restriction (progressive), there were only three (12.5%) ANOs related to growth abnormalities, all in cases with -FGPS1 values more negative than -2.0%. Using these criteria, the frequency of ANO was 33%. CONCLUSIONS: With respect to growth, dichorionic twins can be considered as two singletons in the same uterus. Normally growing dichorionic twins have the same growth potential as singletons with normal growth outcome. These twins also follow expected third-trimester growth trajectories with the same precision as do singletons. Third-trimester growth pathology can be detected, quantified and classified using -FGPS1 as in singletons. Limited evidence of a relationship between fetal growth abnormalities and adverse neonatal outcome was found. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Second-trimester growth velocities in twin and singleton pregnancies.

OBJECTIVE: Previous small studies used individualized growth assessment (IGA) to characterize prenatal growth velocities of singletons and twins. We aimed to compare second-trimester growth velocities of individual anatomical parameters between monochorionic diamniotic (MCDA) twins, dichorionic diamniotic (DCDA) twins and singleton fetuses in a larger study. METHODS: This was a study of a novel cohort of 222 MCDA twins and previously published cohorts of 40 DCDA twins and 118 singletons with serial ultrasound data. Fetal biometric measurements of biparietal diameter, head circumference, abdominal circumference and femur diaphysis length from prenatal ultrasound examinations were used to calculate second-trimester growth velocities using direct calculation or linear regression analysis. Linear fit was assessed based on the coefficient of determination (R2 ). Mean growth velocities and variances were compared among the three groups. RESULTS: The majority of cases underwent three second-trimester ultrasound examinations with fetal biometry available. All fetuses had linear growth, with R2 > 99% for all parameters. Only 1-2% of all MCDA and DCDA anatomical parameters had abnormal growth velocity scores outside the 95% reference range for singletons. There were no significant differences in mean growth velocity for any parameter between MCDA twins and singletons. Femur diaphysis length growth velocity was significantly lower in DCDA twins than in both MCDA twins and singletons. There were no other significant differences among the groups. CONCLUSIONS: Expanding on prior work using IGA, we found that second-trimester growth velocity of the four major anatomical parameters overall was similar between twins and singletons and between MCDA and DCDA twins, supporting the use of singleton-derived growth standards for IGA in twins. Twin growth potential appears to be similar to that of singletons in the second trimester, suggesting that subsequent growth divergence may be due to third-trimester physiological or pathological changes in twin pregnancies. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Third-trimester growth diversity in small fetuses classified as appropriate-for-gestational age or small-for-gestational age at birth.

OBJECTIVE: We have shown previously that third-trimester growth in small fetuses (estimated fetal weight (EFW) < 10th percentile) with birth weight (BW) < 10th percentile is heterogeneous using individualized growth assessment (IGA). We aimed to test our hypothesis that individual growth patterns in small fetuses with BW > 10th percentile are also variable but in different ways. METHODS: This was a study of 191 cases with EFW < 10th percentile and BW > 10th percentile (appropriate-for-gestational-age (AGA) cohort), derived from the PORTO study. Composite size parameters were used to quantify growth pathology at individual third-trimester timepoints (individual composite prenatal growth assessment score (-icPGAS)). The fetal growth pathology score 1 (-FGPS1), calculated cumulatively from serial -icPGAS values, was used to characterize third-trimester growth patterns. Vascular-system evaluation included umbilical artery (UA) and middle cerebral artery (MCA) Doppler velocimetry. Outcome variables were birth age (preterm/term delivery) and BW (expressed as growth potential realization index for weight (GPRIWT ) and percentile). The findings from the AGA cohort were compared with those from small fetuses (EFW < 10th percentile) with BW < 10th percentile (small-for-gestational-age (SGA) cohort). RESULTS: The AGA cohort was found to have 134 fetuses (70%) with normal growth pattern and 57 (30%) with growth restriction based on IGA criteria. Seven growth-restriction -FGPS1 patterns were observed, including the previously defined progressive, late, adaptive and recovering types. The recovering type was the most common growth pattern in the AGA cohort (50.9%). About one-third of fetuses without any evidence of growth restriction had significant unexplained abnormalities in the UA (34%) and MCA (31%) and elevated mean GPRIWT values (113 ± 12.5%). Comparison of the AGA and SGA cohorts indicated a significant difference in the distribution of -FGPS1 growth patterns (P = 0.0001). Compared with the SGA cohort, the AGA cohort had more fetuses with a normal growth pattern (70% vs 38%) and fewer cases with growth restriction (30% vs 62%). While the recovering type was the most common growth-restriction pattern in the AGA cohort (51%), the progressive type was the primary growth-restriction pattern in the SGA cohort (44%). No difference in the incidence of MCA or UA abnormality was found between the SGA and AGA cohorts when comparing subgroups of more than 10 fetuses. CONCLUSIONS: Both normal-growth and growth-restriction patterns were observed in the AGA cohort using IGA, as seen previously in the SGA cohort. The seven types of growth restriction defined in the SGA cohort were also identified in AGA cases, but their distribution was significantly different. In one-third of cases without evidence of growth pathology in the AGA cohort, Doppler abnormalities in the UA and MCA were seen. This heterogeneity underscores the difficulty of accurate classification of fetal and neonatal growth status using conventional population-based methods. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

ISUOG Practice Guidelines: ultrasound assessment of fetal biometry and growth.

INTRODUCTION These Guidelines aim to describe appropriate assessment of fetal biometry and diagnosis of fetal growth disorders. These disorders consist mainly of fetal growth restriction (FGR), also referred to as intrauterine growth restriction (IUGR) and often associated with small­for­gestational age (SGA), and large­for­gestational age (LGA), which may lead to fetal macrosomia; both have been associated with a variety of adverse maternal and perinatal outcomes. Screening for, and adequate management of, fetal growth abnormalities are essential components of antenatal care, and fetal ultrasound plays a key role in assessment of these conditions. The fetal biometric parameters measured most commonly are biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC) and femur diaphysis length (FL). These biometric measurements can be used to estimate fetal weight (EFW) using various different formulae1. It is important to differentiate between the concept of fetal size at a given timepoint and fetal growth, the latter being a dynamic process, the assessment of which requires at least two ultrasound scans separated in time. Maternal history and symptoms, amniotic fluid assessment and Doppler velocimetry can provide additional information that may be used to identify fetuses at risk of adverse pregnancy outcome. Accurate estimation of gestational age is a prerequisite for determining whether fetal size is appropriate­for­gestational age (AGA). Except for pregnancies arising from assisted reproductive technology, the date of conception cannot be determined precisely. Clinically, most pregnancies are dated by the last menstrual period, though this may sometimes be uncertain or unreliable. Therefore, dating pregnancies by early ultrasound examination at 8­14 weeks, based on measurement of the fetal crown­rump length (CRL), appears to be the most reliable method to establish gestational age. Once the CRL exceeds 84 mm, HC should be used for pregnancy dating2­4. HC, with or without FL, can be used for estimation of gestational age from the mid­trimester if a first­trimester scan is not available and the menstrual history is unreliable. When the expected delivery date has been established by an accurate early scan, subsequent scans should not be used to recalculate the gestational age1. Serial scans can be used to determine if interval growth has been normal. In these Guidelines, we assume that the gestational age is known and has been determined as described above, the pregnancy is singleton and the fetal anatomy is normal. Details of the grades of recommendation used in these Guidelines are given in Appendix 1. Reporting of levels of evidence is not applicable to these Guidelines.

Pautas de ISUOG para la práctica: evaluación ecográfica de la biometría y el crecimiento fetal INTRODUCCIÓN: El objetivo de estas Pautas es describir la evaluación adecuada de la biometría fetal y el diagnóstico de los trastornos del crecimiento fetal. Estos trastornos consisten principalmente en la restricción del crecimiento fetal (RCF), también conocida como restricción del crecimiento intrauterino (RCIU), que a menudo está asociada con un tamaño pequeño para la edad gestacional (PEG) o grande para la edad gestacional (GEG), que pueden dar lugar a la macrosomía fetal; ambos se han asociado con una variedad de resultados maternos y perinatales adversos. La detección y el tratamiento adecuado de las anomalías del crecimiento fetal son componentes esenciales de la atención prenatal, y la ecografía fetal desempeña un papel fundamental en la evaluación de estas afecciones. Los parámetros biométricos fetales medidos con mayor frecuencia son (todas las siglas procedentes del inglés) el diámetro biparietal (BPD), el perímetro cefálico (HC), el perímetro abdominal (AC) y la longitud de la diáfisis del fémur (FL). Estas mediciones biométricas se pueden utilizar para estimar el peso del feto (PEF) mediante fórmulas diferentes1 . Es importante diferenciar entre el concepto de tamaño fetal en un momento dado y el crecimiento fetal en sí, siendo este último un proceso dinámico cuya evaluación requiere al menos dos ecografías separadas en el tiempo. La historia y los síntomas de la madre, la evaluación del líquido amniótico y la velocimetría Doppler pueden proporcionar información adicional que se puede utilizar para identificar los fetos bajo riesgo de resultados adversos del embarazo. La estimación precisa de la edad gestacional es un prerrequisito para determinar si el tamaño del feto es apropiado para la edad gestacional (AEG). Excepto en el caso de los embarazos procedentes de tecnologías de reproducción asistida, la fecha de concepción no se puede determinar con precisión. Clínicamente, la fecha de la mayoría de los embarazos se establece en función del último período menstrual, aunque a veces esto puede ser incierto o poco fiable. Por lo tanto, el fechado de los embarazos mediante ecografía temprana a las 8-14 semanas, mediante la medición de la longitud céfalo-caudal (LCC) fetal, parece ser el método más fiable para establecer la edad gestacional. Una vez que la LCC excede los 84 mm, se debe usar el HC2-4 para establecer la fecha del embarazo. El HC, con o sin FL, se puede utilizar para estimar la edad gestacional a partir de la mitad del primer trimestre si no se dispone de una ecografía del primer trimestre y el historial menstrual no es fiable. Cuando se ha establecido la fecha prevista del parto mediante una exploración temprana precisa, no se deben utilizar exploraciones posteriores para recalcular la edad gestacional1 . Las exploraciones en serie se pueden utilizar para determinar si el intervalo del crecimiento ha sido normal. En estas Pautas se asume que la edad gestacional es conocida y ha sido determinada según lo anterior, que el embarazo es de feto único y que la anatomía fetal es normal. En el Apéndice 1 se detallan los grados de recomendación utilizados en estas Pautas. El informe sobre los niveles de evidencia no es aplicable a estas Pautas.

Longitudinal assessment of lung area measurements by two-dimensional ultrasound in fetuses with isolated left-sided congenital diaphragmatic hernia.

OBJECTIVE: To evaluate lung growth in healthy fetuses and those with congenital diaphragmatic hernia (CDH) using two-dimensional (2D) ultrasound. METHODS: Fetal right lung measurements obtained by 2D ultrasound between 19 and 37 weeks' gestation were evaluated longitudinally in 66 healthy fetuses and 52 fetuses with isolated left-sided CDH. Right lung areas were determined by the 'tracing' and 'longest-diameters' methods and, subsequently, lung area-to-head circumference ratios (LHRs) were calculated. Functions fitted to these size parameters with respect to gestational age were evaluated for three sets of group-wise comparisons: (1) healthy vs CDH fetuses; (2) different degrees of severity of CDH; and (3) CDH fetuses that survived vs those that died by 6 months postpartum. RESULTS: There was a significantly slower increase in right lung areas and LHRs with advancing gestational age in CDH fetuses than in healthy individuals (P < 0.05). Compared to those with milder forms of CDH, lung areas and LHRs of fetuses with more severe forms displayed a smaller increase (P < 0.05) and LHRs of fetuses with severe CDH did not increase during pregnancy (P > 0.05). Individuals who died postpartum did not show any increase in LHR (P > 0.05) throughout gestation. CONCLUSIONS: The right lung area and LHR, calculated using either the longest-diameters or tracing method, display reduced growth rates during gestation in cases of isolated left-sided CDH as compared with healthy fetuses. The growth curve characteristics of fetal lung areas and LHRs may be useful for predicting neonatal mortality.

New fetal weight estimation models using fractional limb volume.

OBJECTIVES: The main goal of this study was to determine the accuracy and precision of new fetal weight estimation models, based on fractional limb volume and conventional two-dimensional (2D) sonographic measurements during the second and third trimesters of pregnancy. METHODS: A prospective cross-sectional study of 271 fetuses was performed using three-dimensional ultrasonography to extract standard measurements-biparietal diameter (BPD), abdominal circumference (AC) and femoral diaphysis length (FDL)-plus fractional arm volume (AVol) and fractional thigh volume (TVol) within 4 days of delivery. Weighted multiple linear regression analysis was used to develop 'modified Hadlock' models and new models using transformed predictors that included soft tissue parameters for estimating birth weight. Estimated and observed birth weights were compared using mean percent difference (systematic weight estimation error) and the SD of the percent differences (random weight estimation error). The proportion of newborns with estimated birth weight within 5 or 10% of actual birth weight were compared using McNemar's test. RESULTS: Birth weights in the study group ranged from 235 to 5790 g, with equal proportions of male and female infants. Six new fetal weight estimation models were compared with the results for modified Hadlock models with sample-specific coefficients. All the new models were very accurate, with mean percent differences that were not significantly different from zero. Model 3 (which used the natural logarithms of BPD, AC and AVol) and Model 6 (which used the natural logarithms of BPD, AC and TVol) provided the most precise weight estimations (random error = 6.6% of actual birth weight) as compared with 8.5% for the best original Hadlock model and 7.6% for a modified Hadlock model using sample-specific coefficients. Model 5 (which used the natural logarithms of AC and TVol) classified an additional 9.1% and 8.3% of the fetuses within 5% and 10% of actual birth weight and Model 6 classified an additional 7.3% and 4.1% of infants within 5% and 10% of actual birth weight. CONCLUSION: The precision of fetal weight estimation can be improved by adding fractional limb volume measurements to conventional 2D biometry. New models that consider fractional limb volume may offer novel insight into the contribution of soft tissue development to weight estimation.

Fetal growth parameters and birth weight: their relationship to neonatal body composition.

OBJECTIVES: The main goal was to investigate the relationship between prenatal sonographic parameters and birth weight in predicting neonatal body composition. METHODS: Standard fetal biometry and soft tissue parameters were assessed prospectively in third-trimester pregnancies using three-dimensional ultrasonography. Growth parameters included biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), mid-thigh circumference and femoral diaphysis length (FDL). Soft tissue parameters included fractional arm volume (AVol) and fractional thigh volume (TVol) that were derived from 50% of the humeral or femoral diaphysis lengths, respectively. Percentage of neonatal body fat (%BF) was determined within 48 h of delivery using a pediatric air displacement plethysmography system based on principles of whole-body densitometry. Correlation and stepwise multiple linear regression analyses were performed with potential prenatal predictors and %BF as the outcome variable. RESULTS: Eighty-seven neonates were studied with a mean +/- SD %BF of 10.6 +/- 4.6%. TVol had the greatest correlation with newborn %BF of all single-parameter models. This parameter alone explained 46.1% of the variability in %BF and the best stepwise multiple linear regression model was: %BF = 0.129 (TVol) - 1.03933 (P < 0.001). Birth weight similarly explained 44.7% of the variation in %BF. AC and estimated fetal weight (EFW) accounted for only 24.8% and 30.4% of the variance in %BF, respectively. Skeletal growth parameters, such as FDL (14.2%), HC (7.9%) and BPD (4.0%), contributed the least towards explaining the variance in %BF. CONCLUSIONS: During the late third trimester of pregnancy %BF is most highly correlated with TVol. Similar to actual birth weight, this soft tissue parameter accounts for a significant improvement in explaining the variation in neonatal %BF compared with fetal AC or EFW alone.

Fractional limb volume--a soft tissue parameter of fetal body composition: validation, technical considerations and normal ranges during pregnancy.

OBJECTIVES: The main goals were to provide normal reference ranges for fractional limb volume as a new index of generalized fetal nutritional status, to evaluate the reproducibility of fractional fetal limb volume measurements during the second and third trimesters of pregnancy, and to demonstrate technical considerations for this technique. METHODS: This was a prospective, cross-sectional study of gravid women during mid to late pregnancy. Fractional limb volumes were based on either 50% of humeral or femoral diaphysis length. Each partial volume was subdivided into five equidistant slices that were centered along the mid-arm or mid-thigh. Slices were traced manually to obtain fractional arm (AVol) or fractional thigh (TVol) volume. Reproducibility studies were performed, using Bland-Altman plots, to assess blinded interobserver and intraobserver measurement bias and agreement. Selected images were chosen to demonstrate technical factors for the acquisition and analysis of these parameters. Reference charts were established to describe normal ranges for AVol and TVol. RESULTS: Three hundred and eighty-seven subjects were scanned to include 380 AVol (range, 1.1-68.3 mL) and 378 TVol (range 2.0-163.2 mL) measurements between 18.0 and 42.1 weeks' menstrual age. No gender differences were found in these soft tissue measurements (AVol, P = 0.90; TVol, P = 0.91; Mann-Whitney test). Intraobserver mean bias +/- SD and 95% limits of agreement (LOA) for fractional limb volumes were: 2.2 +/- 4.2% (95% LOA, - 6.0 to 10.5%) for AVol and 2.0 +/- 4.2% (95% LOA, - 6.3 to 10.3%) for TVol. Interobserver bias and agreement were - 1.9 +/- 4.9% (95% LOA, - 11.6 to 7.8%) for AVol and - 2.0 +/- 5.4% (95% LOA, - 12.5 to 8.6%) for TVol. Technical factors were related to image optimization, transducer pressure, fetal movement, soft tissue compression and amniotic fluid volume. CONCLUSIONS: Fractional limb volume assessment may improve the detection and monitoring of malnourished fetuses because this soft tissue parameter can be obtained quickly and reproducibly during mid to late pregnancy. Careful attention should be placed on technical factors that can potentially affect optimal acquisition and analysis of these volume measurements.

Individualized growth assessment of fetal thigh circumference using three-dimensional ultrasonography.

OBJECTIVES: To develop individualized growth assessment (IGA) standards for upper (ThC(u)) and middle (ThC(m)) fetal thigh circumferences using three-dimensional ultrasonography. METHODS: A prospective, longitudinal sonographic study of 30 fetuses was performed beginning at 18 weeks' menstrual age. Second-trimester sonographic parameters were measured from three-dimensional volume data to establish IGA standards. Normal infant growth outcomes were confirmed using modified Neonatal Growth Assessment Scores (m(3)NGAS(51)). ThC(u) and ThC(m) were studied in more detail. Rossavik growth model specification procedures, based on the slopes of the second-trimester growth curves, were developed for both ThC(u) and ThC(m). Third-trimester growth trajectories and birth measurements were subsequently predicted for these parameters. Percentage deviations during the third trimester and percentage differences at actual birth age were used to compare observed and predicted measurements. The 95% ranges for Growth Potential Realization Index (GPRI) values for both types of thigh circumference were determined. Values for m(3)NGAS(51) using GPRI(ThC(u)), GPRI(ThC(m)) and GPRI(ThC(o)) (original method) were compared. RESULTS: The 30 newborns had no postnatal evidence of abnormal growth. Two examiners demonstrated a satisfactory measurement bias of mean +/- SD 2.1 +/- 3.6 (95% limits of agreement,-4.9 to 9.1)% for ThC(m) and 3.3 +/- 4.1 (95% limits of agreement,-4.8 to 11.4)% for ThC(u). Rossavik functions fitted parameter trajectories well, with mean R(2) values of 99.5 +/- 0.4% for ThC(u) and 99.6 +/- 0.3% for ThC(m). By fixing coefficients k at their mean values, their respective fits did not change, and the variabilities of coefficients c and s were significantly reduced. For ThC(u), coefficient c was significantly related to the second-trimester slope (R(2)=98.6%), as was s to c(R(2)=91.0%). For ThC(m), coefficient c was significantly related to the second-trimester slope (R(2)=98.6%), as was s to c(R(2)=85.6%). Third-trimester growth trajectories, derived from second-trimester slopes for individual fetuses, had third-trimester deviations of 0.07 +/- 3.7% for ThC(u) and-0.04 +/- 3.7% for ThC(m). Percentage differences at birth age were 16.8 +/- 10.2% for ThC(u) and 8.9 +/- 9.5% for ThC(m). With correction for systematic overestimations, the mean GPRI values were 103.7 (95% range, 90-121)% for ThC(u) and 101.6 (95% range, 88-118)% for ThC(m). Corresponding mean +/- SD m(3)NGAS(51) values, using GPRI(ThC(u)), GPRI(ThC(m)) and GPRI(ThC(o)), were 203 +/- 11%, 201 +/- 10% and 200 +/- 9%, respectively. CONCLUSIONS: Fetal thigh circumference can be measured reliably and evaluated using standard IGA methods. Both ThC(u) and ThC(m) give similar results in the third trimester but neonatal thigh circumference predictions are improved by using ThC(m). Corresponding GPRI(ThC(m)) values are closer to the ideal value of 100% and can be used in m(3)NGAS(51) calculations for assessment of neonatal growth outcome.

Quantitative assessment of gestational sac shape: the gestational sac shape score.

OBJECTIVE: To develop a quantitative method for characterizing gestational sac shape. METHODS: Twenty first-trimester gestational sacs in normal pregnancies were studied with three-dimensional (3D) ultrasonography. The 3D coordinates of surface-point sets were obtained for each sac using 30-, 15- and six-slice sampling. Cubic spline interpolation was used with the 15- and six-slice surface-point samples to generate coordinates for those 30-slice surface points not measured. Interpolated and measured values, the latter from the 30-slice sample, were compared and the percent error calculated. Cubic spline interpolation was used to determine the coordinates of a standard surface-point sample (3660) for each sac in each slice sample. These coordinate data were used to give each sac a standard configuration by moving its center of gravity to the origin, aligning its inertial axes along the coordinate axes and converting its volume to 1.0 mL. In this form, a volume shape descriptor could be generated for each sac that was then transformed into a vector containing only shape information. The 20 shape vectors of each slice sample were subjected to principal components analysis, and principal component scores (PCSs) calculated. The first four PCSs were used to define a gestational sac shape score (GSSS-30, GSSS-15 or GSSS-6) for each sac in a given slice sample. The characteristics of each set of GSSSs were determined and those for the GSSS-15 and GSSS-6 were compared with the GSSS-30 characteristics. RESULTS: Cubic spline interpolations were very accurate in most cases, with means close to 0%, and approximately 95% of the errors being less than 10%. GSSS-30 accounted for 67.6% of the shape variance, had a mean of zero and an SD of 1.1, was normally distributed and was not related to menstrual age (R=-0.16, P=0.51). GSSS-15 and GSSS-6 had essentially the same characteristics. No significant differences between individual GSSS-30 values and those for GSSS-15 or GSSS-6 were found, indicating the absence of a slice sample effect. CONCLUSION: Using sophisticated mathematical methods, the gestational sac shape, initially represented by the 3D coordinates of 3660 surface points, was converted to a single number, the GSSS. This score had the appropriate properties for quantitatively characterizing normal, first-trimester gestational sac shapes. As it can be obtained from as few as six slices, it should be useful in many clinical situations. This novel approach has the potential for providing quantitative shape information about a variety of biological shapes and how they change over time.

Quantitative and morphological assessment of early gestational sacs using three-dimensional ultrasonography.

OBJECTIVE: Our main objective was to determine the value of three-dimensional ultrasonography (3DUS) and Virtual Organ Computer-aided AnaLysis (VOCAL) in the evaluation of gestational sac volume and morphology during early pregnancy. METHODS: Twenty-eight normal early pregnancies were scanned approximately every 2 weeks using transabdominal (TAS) and transvaginal (TVS) sonography. The VOCAL technique was used to create computerized surface models to classify gestational sac shapes as discoid or ellipsoid. Serial sac volume changes were analyzed using repeated measures ANOVA. Bland-Altman plots determined examiner bias and limits of agreement (LOA) for sac volume measurements. Gestational sac volumes were compared between the two-dimensional (2D) ellipsoid and VOCAL techniques. Differences between volume measurements were tested using the two-tailed paired t-test with statistical significance at the P < 0.05 level. RESULTS: Each subject was examined at a mean +/- SD menstrual age of 7.9 +/- 0.6 weeks (Scan 1), 9.9 +/- 0.6 weeks (Scan 2), and 11.9 +/- 0.6 weeks (Scan 3). Sac volumes significantly increased over time from 22 +/- 11 mL at Scan 1, to 57 +/- 21 mL at Scan 2 and 116 +/- 35 mL at Scan 3 (P < 0.001). Predominant sac shapes were classified as ellipsoid (76.2%) or discoid (23.8%). Additional descriptors included: concave (60.7%), irregular (53.6%), or smooth (7.1%), with 19% of the overall group having more than one additional shape attribute. Clinically acceptable volume measurement bias and agreement were found for the following comparisons: (1) TAS versus TVS; (2) interobserver volume measurements; and (3) intraobserver volume measurements. The VOCAL technique yielded slightly greater sac volumes (64 +/- 45.4 mL) when compared to the 2D ellipsoid model (48.6 +/- 36.8 mL) (28.9 +/- 24.3% (95% limit of agreement range, - 18.7 to 76.5%), P < 0.001). CONCLUSIONS: Reproducible sac volume measurements can be obtained using VOCAL with either TAS or TVS. Early gestational sacs variably appear as discoid or ellipsoid structures with a concave indentation from the placenta. Sac volumes can be underestimated if an ellipsoid shape is assumed. Morphological and quantitative analysis of the gestational sac may provide baseline parameters for studying patients at risk for early pregnancy failure.

Individualized growth assessment of fetal soft tissue using fractional thigh volume.

OBJECTIVES: The main goals of this study were to introduce fractional thigh volume (TVol) as a new soft tissue parameter for fetal growth evaluation, define its relationship to menstrual age, and develop individualized fetal growth standards based on Rossavik growth models. METHODS: A prospective, longitudinal study of 22 fetuses was conducted with conventional biometry and TVol measurements by three-dimensional ultrasonography. Infant growth outcomes were determined from modified neonatal growth assessment scores. Rossavik functions (P = c(t)k+s(t)) were used to fit complete datasets to examine relationships between TVol and model coefficients. Second-trimester models were subsequently specified from the linear slopes of growth curves before 28.0 menstrual weeks with each fetus acting as its own control. Third-trimester trajectories and birth measurements were predicted for standard growth parameters and TVol. Observed and predicted measurements were compared using percent deviations and growth potential realization index values. Four additional infants, with serial prenatal scans and postnatal evidence of intrauterine growth restriction (IUGR), were also evaluated. RESULTS: All 22 fetuses had no evidence of growth abnormalities after delivery. Accelerated soft tissue deposition occurred in the fetal thigh by 28 menstrual weeks. A mean TVol start point of 9.0 +/- 1.4 menstrual weeks was consistent with embryological studies of thigh development. Rossavik functions fitted all TVol trajectories well (mean R2 = 0.998 +/- 0.002). By fixing the coefficient k at its mean value (2.976), the fit did not change and the variabilities of coefficients c and s were reduced. The mean percent deviation between observed and predicted third-trimester TVol measurements was -0.048 +/- 7.5%. Relatively early pathological deviations were observed for TVol in all four fetuses with IUGR; in these cases the abdominal circumference was abnormal in only one fetus and thigh circumference in none. CONCLUSIONS: Individualized growth assessment can be used to accurately predict TVol during the third trimester of pregnancy and at birth. Expected growth trajectories, from second-trimester data, do not rely on population-based standards because each fetus serves as its own control. This new parameter may allow earlier detection and improved monitoring of fetal soft tissue abnormalities such as IUGR.

Perinatal morbidity and mortality rates in severe twin-twin transfusion syndrome: results of the International Amnioreduction Registry.

OBJECTIVE: Serial aggressive amnioreduction is the most widely used therapy for pregnancies that are complicated by twin-twin transfusion syndrome. Survival rates reported with this therapy are 33% to 83%, the wide range attributable to the small number of patients in these case series. Similarly, data on morbidity in survivors are imprecise. We instituted the international twin-twin transfusion syndrome registry to determine the perinatal survival and morbidity rates and the factors that influence perinatal outcome in patients with twin-twin transfusion syndrome who were treated with serial aggressive amnioreduction from 1990 to 1998. STUDY DESIGN: A total of 223 sets of twins who were diagnosed with twin-twin transfusion syndrome before 28 weeks' gestation from 20 fetal medicine referral centers were analyzed, with follow-up data until 4 weeks after birth. RESULTS: Three hundred forty-six twins (78%; 182 recipients and 164 donors) were born alive. Two hundred sixty-six twins (60%; 144 recipients and 122 donors) were alive 4 weeks after birth. Both fetuses survived to 4 weeks in 108 pregnancies (48.4%), whereas, at least 1 fetus survived in 158 pregnancies (70.8%). The interval between the last amnioreduction and delivery ranged from zero to 138 days (median, 17.5 days). In the infants who survived to 4 weeks after birth, abnormalities on neonatal cranial scan were diagnosed in 24% of recipients and in 25% of donors. Logistic regression analysis indicated that the survival rate was significantly related to gestational age at diagnosis, presence of end-diastolic blood flow in the umbilical artery velocity waveforms, presence of hydrops, mean volume of amniotic fluid removed per week, larger birth weight, and gestational age at delivery. The hemoglobin level difference at birth was the only significant parameter to predict abnormal cranial ultrasonography in newborns. CONCLUSION: These data document perinatal survival and neonatal morbidity rates in severe twin-twin transfusion syndrome that were treated by serial aggressive amnioreduction. Outcome was influenced by several perinatal risk factors, which may be used to counsel patients before and during therapy.

Birth weight prediction by three-dimensional ultrasonography: fractional limb volume.

OBJECTIVE: To introduce fractional limb volume as a new ultrasonographic parameter, validate reliability of fractional limb volume measurements, develop new birth weight prediction models, and examine their practical utility for estimating fetal weight during late pregnancy. METHODS: Healthy late-third-trimester fetuses were prospectively scanned by two- and three-dimensional ultrasonography within 4 days of delivery. Volume data sets were subsequently used to extract several standard ultrasonographic measurements. Fractional limb volumes of the upper arm and thigh were based on 50% of diaphyseal bone length. Intraclass correlation was used to analyze interobserver and intraobserver reliability of fractional limb volume measurements. Several weight prediction models were developed by linear regression analysis. New prediction models were prospectively compared with the Hadlock formula in 30 healthy late-third-trimester fetuses. RESULTS: One hundred fetuses were scanned at a mean +/- SD menstrual age of 39.2 +/- 1.2 weeks. Intraclass correlation indicated a significant degree of interobserver and intraobserver reliability for fractional thigh volume. Fractional thigh volume (r = 0.86), fractional upper arm volume (r = 0.83), abdominal circumference (r = 0.83), and midthigh circumference (r = 0.82) were most highly correlated with birth weight. The best prediction model (abdominal circumference and fractional thigh volume) gave weight estimates that deviated from actual birth weight by -0.025% +/- 7.8%. For late-third-trimester fetuses, the Hadlock model yielded errors of 9.0% +/- 9.0%. Prospective testing confirmed superior performance of the new prediction model, which gave accuracy of 2.3% +/- 6.6% (Hadlock method, 8.4% +/- 8.7%). It correctly predicted 20 of 30 birth weights to within 5% of actual weight. By comparison, the Hadlock model predicted only 6 of 30 birth weights to within 5% of actual weight. CONCLUSIONS: A new birth weight prediction model, based on fractional thigh volume and abdominal circumference, is reliable during the late third trimester. It provides a means for including soft tissue evaluation for birth weight prediction. This rapid technique avoids technical limitations that currently hinder the practical implementation of three-dimensional ultrasonography for estimating birth weight.

An endothelial nitric oxide synthase gene polymorphism is associated with preeclampsia.

OBJECTIVE: We sought to test the hypothesis that a polymorphism of the endothelial nitric oxide synthase gene (NOS3) is associated with preeclampsia. METHODS: We collected and performed polymerase chain reaction (PCR) on genomic DNA from pregnant patients with and without preeclampsia. Patient history and clinical course were evaluated. MAIN OUTCOME MEASURE(S): Frequency of the intron 4 polymorphism of NOS3 (designated allele A) among patients with preeclampsia compared with controls. Clinical features of patients with preeclampsia and the A allele compared with those patients with preeclampsia who did not have the A allele. RESULTS: The frequency of the A allele was 0.10 among controls versus 0.39 among patients with preeclampsia (p < 0.01). The odds ratio of developing preeclampsia when at least one A allele was present was 6.5 [95% confidence interval (CI): 2.1-19.7]. After adjusting for ethnic variation, the odds ratio increased to 7.2 (95% CI: 2.0-25.5). Among patients with preeclampsia, systolic blood pressure at the time of admission was higher for patients with at least one A allele compared with patients homozygous for the B allele (168 versus 156 mm Hg; p = 0.03), independent of gestational age (p = 0.01). CONCLUSION: These data provide evidence for an association between NOS3 and preeclampsia. In defined ethnic groups, this NOS3 may offer predictive information regarding the subsequent development of preeclampsia and its clinical course.

Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses.

BACKGROUND: Invasive techniques such as amniocentesis and cordocentesis are used for diagnosis and treatment in fetuses at risk for anemia due to maternal red-cell alloimmunization. The purpose of our study was to determine the value of noninvasive measurements of the velocity of blood flow in the fetal middle cerebral artery for the diagnosis of fetal anemia. METHODS: We measured the hemoglobin concentration in blood obtained by cordocentesis and also the peak velocity of systolic blood flow in the middle cerebral artery in 111 fetuses at risk for anemia due to maternal red-cell alloimmunization. Peak systolic velocity was measured by Doppler velocimetry. To identify the fetuses with anemia, the hemoglobin values of those at risk were compared with the values in 265 normal fetuses. RESULTS: Fetal hemoglobin concentrations increased with increasing gestational age in the 265 normal fetuses. Among the 111 fetuses at risk for anemia, 41 fetuses did not have anemia; 35 had mild anemia; 4 had moderate anemia; and 31, including 12 with hydrops, had severe anemia. The sensitivity of an increased peak velocity of systolic blood flow in the middle cerebral artery for the prediction of moderate or severe anemia was 100 percent either in the presence or in the absence of hydrops (95 percent confidence interval, 86 to 100 percent for the 23 fetuses without hydrops), with a false positive rate of 12 percent. CONCLUSIONS: In fetuses without hydrops that are at risk because of maternal red-cell alloimmunization, moderate and severe anemia can be detected noninvasively by Doppler ultrasonography on the basis of an increase in the peak velocity of systolic blood flow in the middle cerebral artery.

Individual growth patterns in the first trimester: evidence for difference in embryonic and fetal growth rates.

OBJECTIVE: To evaluate individual fetal growth during the first trimester in pregnancies resulting from spontaneous and in vitro fertilization (IVF). METHODS: The growth of 11 fetuses conceived by spontaneous fertilization (known dates of ovulation) in nine patients and 15 fetuses conceived by IVF in 12 patients were evaluated at weekly intervals from 6 weeks, menstrual age, to 14 weeks. Fetal length was determined at each examination. Measures of fetal length included the crown-rump length (CRL), maximum straight line length (MSLL) and maximum axial length (MAL). Comparisons of CRL and MSLL to MAL were carried out. The MSLL was used as the measure of length except when the MAL was available. Linear and quadratic functions were fitted to the complete data sets of individual fetuses in the two groups. Individual data sets from ten fetuses in each group were then divided into early and late growth phases, and linear functions were fitted to each data subset. Start points and pivotal points for each fetus were estimated from the coefficients of these two functions. Growth in these two groups of fetuses was compared, on the basis of slope values. RESULTS: Evaluation of length measures indicated that, before 8 weeks, only MSLL could be measured. After 8 weeks, all three measures could be obtained, with the MAL being the largest. Both the linear and quadratic models performed well with individual data sets (mean R2(+/- SD): linear 98.1 (1.0)%; quadratic 99.4 (0.4)%), with no differences found between spontaneous and IVF groups (maximum possible differences in mean slopes (95% probability): 5-8%). Similar findings were obtained for the early and late growth phase data subsets. Slope values in the early and late growth phases showed low variability (CV: early 13.5%; late 11.6%), but were significantly different (early 0.72 (+/- 0.10 SD) cm/week; late 1.21 (+/- 0.14 SD) cm/week). The mean start point was 5.9 (+/- 0.3 SD) weeks' menstrual age, while the mean pivotal point was 9.2 (+/- 0.7 SD) weeks, menstrual age. CONCLUSIONS: First-trimester growth studies in individual fetuses indicate that there is a change in length growth rate between 9 and 10 weeks, menstrual age. This is consistent with a shift in development from organogenesis to growth. These results can be used for more accurate assessment of first-trimester growth and may aid in the detection of fetal problems that manifest themselves as growth abnormalities.