Individualized growth assessment: conceptual framework and practical implementation for the evaluation of fetal growth and neonatal growth outcome

Abstract

Fetal growth abnormalities can pose significant consequences on perinatal morbidity and mortality of nonanomalous fetuses. The most widely accepted definition of fetal growth restriction is an estimated fetal weight less than the 10th percentile for gestational age according to population-based criteria. However, these criteria do not account for the growth potential of an individual fetus, nor do they effectively separate constitutionally small fetuses from ones that are malnourished. Furthermore, conventional approaches typically evaluate estimated fetal weight at a single time point, rather than using serial scans, to evaluate growth. This article provides a conceptual framework for the individualized growth assessment of a fetus/neonate based on measuring second-trimester growth velocity of fetal size parameters to estimate growth potential. These estimates specify size models that generate individualized third-trimester size trajectories and predict birth characteristics. Comparisons of measured and predicted values are used to separate normally growing fetuses from those with growth abnormalities. This can be accomplished with individual anatomical parameters or sets of parameters. A practical and freely available software (Individualized Growth Assessment Program) has been developed to allow implementation of this approach for clinical and research purposes.

Keywords: Individualized Growth Assessment Program; Rossavik growth model; customized fetal growth; individualized growth assessment; second trimester; third trimester; ultrasound.

Figure 1. Normal Prenatal Growth in A Newborn Infant Considered Small For Gestational Age

This small for gestational age newborn had a birth weight of 2,490 g at 39.1 weeks which is at the fourth percentile according to the Intergrowth-21st standard. The Growth Summary for this individual included head circumference, abdominal circumference, femur diaphysis length, and estimated fetal weight. The estimated fetal weight is calculated using biparietal diameter, head circumference, abdominal circumference, and femur diaphysis length. Fetal Growth Pathology Score 1 (FGPS1) values (head circumference, abdominal circumference, femur diaphysis length, and estimated weight) are plotted in the lower right-hand panel. All of these values are equal to zero, indicating no growth pathology. The two horizontal dashed lines define reference range boundaries for the + FGPS1 (upper) and − FPGS1 (lower) values. All three Growth Potential Realization Index values were normal (Neonatal Assessment Screen not shown): [weight: 83.0%; head circumference: (100.2%); and crown heel length: 94.5%] with an average pathological Growth Potential Realization Index of 0.0%. Apgar scores were 9/9 at birth. The infant was discharged from the low-risk nursery at four days following delivery. This case illustrates that even small newborns can grow normally during the prenatal period and this process can be verified using Individualized Growth Assessment. The finding of normal interval growth in a small fetus, based on growth potential, may provide useful information for guiding decisions about the number and frequency of antenatal surveillance tests, delivery timing, and/or postnatal therapeutic interventions (e.g. postnatal nutritional supplementation). However, optimal application of these individualized results will require additional clinical investigation.

Figure 2. Second and third trimester abdominal circumference trajectory generated by Individualized Growth Assessment of a single fetus

Individualized size trajectory is specified by the 2^nd trimester abdominal circumference growth velocity. First, data points (red dots) are used to determine the slope (growth velocity) of the solid line. Next, the predicted third trimester trajectory (dashed line) is generated by a model derived from the 2^nd trimester growth velocity. The black dots represent subsequent measurements superimposed on the predicted line. The shaded area is the abdominal circumference reference range obtained from fetuses with normal neonatal growth outcomes^, .

Figure 3. Fetal growth evaluation using Percent Deviation [%Dev] and pathological Percent Deviation [%Dev_p]

The calculation of %Dev and its associated %Dev_p are defined in the figure. The %Dev compares the measured and predicted parameter values. Pathological percent deviations can be positive (upper row, possible macrosomia) or negative (lower row, fetal growth restriction). The %Dev_p quantifies growth pathology by indicating how far the %Dev is outside its age-specific reference range (located between the vertical dashed lines). The categories within the shaded area were assigned a value of zero because they provide no information on the growth pathology being studied.

Figure 4. Neonatal growth evaluation using Growth Potential Realization Index [GPRI] and pathological Growth Potential Realization Index [pGPRI]

The calculation of GPRI and its associated pGPRI are defined in the figure. The GPRI compares the measured and predicted birth characteristic values. Pathological GPRI can be positive (upper row, possible macrosomia) or negative (lower row, fetal growth restriction). The pGPRI quantifies neonatal growth pathology by indicating how far the GPRI is outside its reference range. The categories within the shaded area were assigned a value of zero because they provide no information on the growth pathology being studied.

Figure 5. Neonatal growth outcomes using Modified Neonatal Growth Assessment Score [mNGAS] and pathological modified Neonatal Growth Assessment Score [pNGAS]

This figure demonstrates how the mNGAS and its associated pNGAS are calculated. The mNGAS provides a composite measure of neonatal growth outcome based on five weighted Growth Potential Realization Index (GPRI) values. The weights give the importance of specific GPRI values in separating growth restricted, normal and macrosomic neonates. The pNGAS quantifies growth outcome pathology by indicating how far the mNGAS is beyond its reference range [determined in neonates with normal growth outcomes]. The categories within the shaded area were assigned a value of zero because they provide no information on the growth pathology being studied.

Figure 6. Examples of How to Calculate Modified Prenatal Growth Assessment Scores [mPGAS]

This figure illustrates the calculation of two different types (Example 1: multiple time points for a single anatomical parameter and Example 2: multiple anatomical parameters at a single time point) of modified Prenatal Growth Assessment Scores. The pathological Percent Deviation values for four size parameters [HC, AC, FDL, EFW] were obtained in serial examinations at 30, 32, 34 and 37 weeks (menstrual age). Example 1: The −%Dev_p values for AC at different menstrual ages were averaged to give the negative abdominal circumference PGAS (−acPGAS) that quantifies AC growth pathology in the 3^rd trimester. For this fetus, the −acPGAS is −2.4%, which indicates growth restriction. Example 2: The −%Dev_p values at one time point (32 weeks) for HC, AC, FDL and EFW were averaged to give a composite parameter (−icPGAS) that quantifies overall growth pathology at 32 weeks. For this fetus, the −icPGAS is −2.5%, which indicates growth restriction at 32 weeks. AC, abdominal circumference; EFW, estimated fetal weight; FDL, femur diaphysis length; HC, head circumference; %Dev_p, pathological Percent Deviation

Figure 7. Fetal Growth Pathology Score [FGPS] (Data Calculation with Corresponding Plot)

This score represents the degree of growth pathology in the third trimester. In this example, four size parameters (head circumference, abdominal circumference, femur diaphysis length, estimated fetal weight) are being used to evaluate fetal growth at 30, 32, 34, and 37 weeks (menstrual age). The cumulative moving average of the −%Dev_p values for these specific size parameters is designated the Fetal Growth Pathology Score 1. a:

1. All −%Dev_p values available at 30 weeks (At1, all Anatomical parameters at time point 1 included) (gray shaded area) were averaged to give the Fetal Growth Pathology Score 1, which was 0% (interpreted as normal growth).

2. This process was repeated at 32 weeks (At2), which included all measurements available (gray shaded area, at both 30 and 32 weeks). The values were averaged to give the Fetal Growth Pathology Score 1 value of −1.23%. This signifies that growth restriction has occurred.

3. This process was repeated at 34 weeks (At3), which included all measurements available (gray shaded area, at 30, 32, and 34 weeks). The values were averaged to give the Fetal Growth Pathology Score 1 value of −0.85%. This signifies that growth has improved.

4. This process was repeated at 37 weeks (At4), which included all measurements available (gray shaded area, at 30, 32, 34, and 37 weeks). The values were averaged to give the Fetal Growth Pathology Score 1 value of −1.53%. This signifies that growth restriction has worsened.

5. All negative pathological percent deviations represent growth pathology (blue font).

b: Serial calculations of the Fetal Growth Pathology Scores 1 (At1, At2, At3, At4) for a single fetus in the 3^rd trimester are presented in the plot. The four Scores correspond to the data shown in Figure 6A. The horizontal dashed line represents the lower boundary of the negative Fetal Growth Pathology Score 1 reference range. %Dev_p, pathological Percent Deviation

Figure 7. Fetal Growth Pathology Score [FGPS] (Data Calculation with Corresponding Plot)

This score represents the degree of growth pathology in the third trimester. In this example, four size parameters (head circumference, abdominal circumference, femur diaphysis length, estimated fetal weight) are being used to evaluate fetal growth at 30, 32, 34, and 37 weeks (menstrual age). The cumulative moving average of the −%Dev_p values for these specific size parameters is designated the Fetal Growth Pathology Score 1. a:

1. All −%Dev_p values available at 30 weeks (At1, all Anatomical parameters at time point 1 included) (gray shaded area) were averaged to give the Fetal Growth Pathology Score 1, which was 0% (interpreted as normal growth).

2. This process was repeated at 32 weeks (At2), which included all measurements available (gray shaded area, at both 30 and 32 weeks). The values were averaged to give the Fetal Growth Pathology Score 1 value of −1.23%. This signifies that growth restriction has occurred.

3. This process was repeated at 34 weeks (At3), which included all measurements available (gray shaded area, at 30, 32, and 34 weeks). The values were averaged to give the Fetal Growth Pathology Score 1 value of −0.85%. This signifies that growth has improved.

4. This process was repeated at 37 weeks (At4), which included all measurements available (gray shaded area, at 30, 32, 34, and 37 weeks). The values were averaged to give the Fetal Growth Pathology Score 1 value of −1.53%. This signifies that growth restriction has worsened.

5. All negative pathological percent deviations represent growth pathology (blue font).

b: Serial calculations of the Fetal Growth Pathology Scores 1 (At1, At2, At3, At4) for a single fetus in the 3^rd trimester are presented in the plot. The four Scores correspond to the data shown in Figure 6A. The horizontal dashed line represents the lower boundary of the negative Fetal Growth Pathology Score 1 reference range. %Dev_p, pathological Percent Deviation

Figure 8. Patterns of fetal growth restriction during the 3^rd trimester using Fetal Growth Pathology Score

Different 3^rd trimester patterns of the Fetal Growth Pathology Score 1(FGPS1) were observed in 73 small-for-gestational age fetuses with confirmed postnatal growth restriction. Each fetus had an abnormal 3^rd trimester: Fetal Growth Pathology Score 1 and an abnormal average pathological Growth Potential Realization Index value as a neonate. Seventy of the 73 cases (95%) could be classified into one of five patterns which are distinct, few in number, seen repeatedly and have plausible biological interpretations. Fetal Growth Pathology Score 1 values are plotted for individual fetuses as a function of menstrual age (black dots).

1. Pattern 1: There is a constant decline in the Fetal Growth Pathology Score 1 with advancing menstrual age. This pattern was observed in 37% (27/73) of small for gestational age fetuses.

2. Pattern 2: This fetus had several Fetal Growth Pathology Score 1 values of zero, indicating that the fetus was following its own expected growth trajectory. However, fetal growth restriction developed at the last examination (36 weeks). This pattern was observed in 27% (20/73) of small for gestational age fetuses.

3. Pattern 3: There was an initially very low Fetal Growth Pathology Score 1 that leveled off and remained approximately constant in subsequent third trimester examinations. This pattern was observed in 12% (9/73) of small for gestational age fetuses.

4. Pattern 4: After an initial low Fetal Growth Pathology Score 1, there was evidence of recovery followed by subsequent worsening of the growth restriction process. This pattern was observed in 11% (8/73) of small for gestational age fetuses.

5. Pattern 5: The initial low Fetal Growth Pathology Score 1 was followed by a continuous regression towards normal during the latter part of the third trimester. This pattern was observed in 8% (6/73) of small for gestational age fetuses.

Figure 9. Individualized Growth Assessment Program (iGAP)

This freely available software uses Individualized Growth Assessment to evaluate changes in fetal size parameters over time by comparing current and expected size trajectories. Actual measurements are compared to third trimester size predictions, based on second trimester size models that have been previously established for the individual fetus (each fetus being its own control). iGAP can be found at: (https://igap.research.bcm.edu).

Figure 10. iGAP Home Page Screen

This page allows the user to navigate between Instructions, Measurement Definitions, Video Tutorials, Glossary of Terms, and Frequently Asked Questions. Patient selection is made on this page. The main functions of iGAP are listed under Data Entry and Data Analysis (left-hand side of screen).

Figure 11. Parameter Selection Screen

The user must select a combination of four parameters: Profile Diameter Selection, Weight Estimation Selection, mPGAS Selection, and Normal Growth Limit Selection. Once this set of parameters is selected by the user, IGA analysis is initiated by clicking on “Processed Fetal Data”.

Figure 12. Processed Fetal Data Screen

This screen summarizes ultrasound data for several fetal size parameters at each scan date and menstrual age.

Figure 13. Model Validation/Second Trimester Growth Evaluation Screen

On the left hand side, data for Start Point, 2^nd trimester Growth Velocity, and the model Prediction at 28 weeks are presented. Such data are used to detect abnormal values that would result in poor model performance. The right side of the screen depicts the growth velocity measurements compared to their respective reference ranges, and calculation of the Abnormal Growth Velocity Scores.

Figure 14. Growth Summary Screen

Several size parameters are summarized for an individual fetus (in this example, the fetus is normally grown). Red dots indicate the measurements used to calculate second trimester growth velocities. Rossavik models generate expected size trajectories, and actual measurements (black dots) are superimposed on each curve for different size parameters (e.g. head circumference). The blue shaded areas represent the range of normal variation based on fetal growth in pregnancies with confirmed normal neonatal growth outcomes. The graph in the lower right corner presents the Fetal Growth Pathology Score (FGPS), calculated at different time points in the third trimester. For this fetus, the dots are on the zero line because there is no growth pathology present.

Figure 15. Growth Abnormalities/Modified Prenatal Growth Assessment Score (mPGAS) Screen

The table shows the positive (upper panel) and negative (lower panel) individual PGAS values (%) for each individual anatomical parameter at each time point in the 3^rd trimester. The average values (apPGAS) for the 3^rd trimester are shown in the gray shaded area in two rows. The two columns in the gray shaded area present the individual composite PGAS values (%) and the Fetal Growth Pathology Scores (FGPS) calculated at each time point. For this fetus, all measured values were zero, indicating that this was a normally growing fetus.

Figure 16. Neonatal Growth Assessment Screen

The measured and predicted values for neonatal birth characteristics and their associated Growth Potential Realization Indexes (GPRI) are presented for the anatomical parameters measured postnatally. The GPRI values are compared to their reference ranges and the pathological GPRI (pGPRI) values calculated. The predicted values depend on the gestational age at delivery being used, which can be selected in the lower left-hand corner (Growth Cessation Age, Birth Age). The averages for pGPRI values (gray shaded row) are presented below the pGPRI columns. If appropriate data is available, the modified Neonatal Growth Assessment Score (mNGAS) is presented in the lower right-hand corner of the screen. The mNGAS is compared to its reference range to give the pathological NGAS (pNGAS). The measures of pathology (pGPRI, average pGPRI, pNGAS) are all zero in this example, indicating normal neonatal growth outcome.

Figure 17. Fetal Growth Restriction Example

Growth assessments are graphically summarized in an individual fetus for head circumference, abdominal circumference, femur diaphysis length, thigh circumference, and estimated fetal weight. The fetal weight estimation procedure utilizes biparietal diameter, head circumference, abdominal circumference, and femur diaphysis length. All parameters show abnormal values (black dots below blue shaded reference ranges) except for thigh circumference (lower left panel). Fetal Growth Pathology Score 7 (FGPS7) values incorporate five anatomical parameters (lower right panel). Two horizontal dashed lines define the reference range boundaries for the + FGPS7 (upper) and − FPGS7 (lower) values. This graph shows an initial borderline value (black dot) followed by three persistently low values, indicating growth restriction after 34 weeks. The neonate had a birthweight of 2,305 g at 39.0 weeks gestation (< 3^rd percentile based on Intergrowth-21^st standard). The analysis indicated abnormally low Growth Potential Realization (GPRI) values for four of five neonatal parameters [weight: 71.1%; head circumference: (93.8%); thigh circumference: (82.0%) and crown heel length: 91.0%] with a substantially negative average pathological GPRI of −3.82, confirming growth restriction (Neonatal Assessment Screen not shown). In this case, the antenatal suspicion of fetal growth restriction was confirmed by postnatal findings based on Individualized Growth Assessment.