A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants

Background The aim of this study was to revise the 2003 Fenton Preterm Growth Chart, specifically to: a) harmonize the preterm growth chart with the new World Health Organization (WHO) Growth Standard, b) smooth the data between the preterm and WHO estimates, informed by the Preterm Multicentre Growth (PreM Growth) study while maintaining data integrity from 22 to 36 and at 50 weeks, and to c) re-scale the chart x-axis to actual age (rather than completed weeks) to support growth monitoring. Methods Systematic review, meta-analysis, and growth chart development. We systematically searched published and unpublished literature to find population-based preterm size at birth measurement (weight, length, and/or head circumference) references, from developed countries with: Corrected gestational ages through infant assessment and/or statistical correction; Data percentiles as low as 24 weeks gestational age or lower; Sample with greater than 500 infants less than 30 weeks. Growth curves for males and females were produced using cubic splines to 50 weeks post menstrual age. LMS parameters (skew, median, and standard deviation) were calculated. Results Six large population-based surveys of size at preterm birth representing 3,986,456 births (34,639 births < 30 weeks) from countries Germany, United States, Italy, Australia, Scotland, and Canada were combined in meta-analyses. Smooth growth chart curves were developed, while ensuring close agreement with the data between 24 and 36 weeks and at 50 weeks. Conclusions The revised sex-specific actual-age growth charts are based on the recommended growth goal for preterm infants, the fetus, followed by the term infant. These preterm growth charts, with the disjunction between these datasets smoothing informed by the international PreM Growth study, may support an improved transition of preterm infant growth monitoring to the WHO growth charts.


Background
The expected growth of the fetus describes the fastest human growth, increasing weight over six-fold between 22 and 40 weeks. Preterm infants, who are born during this rapid growth phase, rely on health professionals to assess their growth and provide appropriate nutrition and medical care.
In 2006, the World Health Organization (WHO) published their multicentre growth reference study, which is considered superior [1] to previous growth surveys since the measured infants were selected from communities in which economics were not likely to limit growth, among culturally diverse non-smoking mothers who planned to breastfeed [2]. Weekly longitudinal measures of the infants were made by trained data collection teams during the first 2 years of this study [3]. These WHO growth charts, although recommended for preterm infants after term age [4], begin at term and so do not inform preterm infant growth assessments younger than this age.
Optimum growth of preterm infants is considered to be equivalent to intrauterine rates [5][6][7] since a superior growth standard has not been defined. Perhaps the best estimate of fetal growth may be obtained from large population-based studies, conducted in developed countries [8], where constraints on fetal growth may be less frequent.
A recent multicentre study by our group (the Preterm Multicentre Growth (PreM Growth) Study) revealed that although the pattern of preterm infant growth was generally consistent with intrauterine growth, the biggest deviation in weight gain velocity between the preterm infants and the fetus and infant was just before term, between 37 and 40 weeks (Fenton TR, Nasser R, Eliasziw M, Kim JH, Bilan D, Sauve R: Validating the weight gain of preterm infants between the reference growth curve of the fetus and the term infant, The Preterm Infant Multicentre Growth Study. Submitted BMC Ped 2012). Rather than demonstrating the slowing growth velocity of the term infant during the weeks just before term, the preterm infants had superior, close to linear, growth at this age. This finding has been observed by others as well [9][10][11]. Therefore, there is evidence to support a smooth transition on growth charts between late fetal and early infant ages.
Several previous growth charts based on size at birth presented their data as completed age, which affects the interpretation and use of a growth chart [12]. The use of completed weeks when plotting a growth chart requires all the measurements to be plotted on the whole week vertical axes. However, the use of completed weeks in a neonatal unit may not be intuitive, as nursery staff and parents think of infants as their exact age, and not age truncated to previous whole weeks. The advent of computers in health care, for clinical care and health recording, allow the use of the computer to plot growth charts, daily and with accuracy. It would make sense to support plotting daily measurements continuously by shifting the data collected as completed weeks to the midpoint of the next week to remove the truncation of the data collection as completed weeks.
The objectives of this study were to revise the 2003 Fenton Preterm Growth Chart, specifically to: a) use more recent data on size at birth based on an inclusion criteria, b) harmonize the preterm growth chart with the new WHO Growth Standard, c) to smooth the data between the preterm and WHO estimates while maintaining integrity with the data from 22 to 36 and at 50 weeks, d) to derive sex specific growth curves, and to e) re-scale the chart x-axis to actual age rather than completed weeks, to support growth monitoring.

Methods
To revise the growth chart, thorough literature searches were performed to find published and unpublished population-based preterm size at birth (weight, length, and/or head circumference) references. The inclusion criteria, defined a priori, designed to minimize bias by restriction [13], were to locate population-based studies of preterm fetal growth, from developed countries with: a) Corrected gestational ages through fetal ultrasound and/or infant assessment and/or statistical correction; b) Data percentiles at 24 weeks gestational age or lower; c) Sample of at least 25,000 babies, with more than 500 infants aged less than 30 weeks; d) Separate data on females and males; e) Data available numerically in published form or from authors, f ) Data collected within the past 25 years (1987 to 2012) to account for any secular trends.

A. Data selection and combination
Major bibliographic databases were searched: MEDLINE (using PubMed) and CINHAL, by both authors back to year 1987 (given our 25 year limit), with no language restrictions, and foreign articles were translated. The following search terms as medical subject headings and textwords were used: ("Preterm infant" OR "Premature All of the found data was reported as completed weeks except for the German Perinatal Statistics, which were reported as actual daily weights [14]. To combine the datasets, the German data was temporarily converted to completed weeks. A final step converted the meta-analyses to actual age.
B. Combine the data to produce weighted intrauterine growth curves for each sex The located data (3rd, 10th, 50th, 90th, and 97th percentiles for weight, head circumference, and length) that met the inclusion criteria were extracted by copying and pasting into spreadsheets. The male and female percentile curves from each included data set for weight, head circumference and length were plotted together so they could be examined visually for heterogeneity (Figures 1, 2, and 3). The data for each gender were combined by using the weekly data for the percentiles: 3rd, 10th, 50th, 90th, and 97th, weighted by the sample sizes. The combined data was represented by relatively smooth curves.

C. Develop growth monitoring curves
To develop the growth monitoring curves that joined the intrauterine meta-analysis data with the WHO Growth Standard (WHOGS) smoothly, the following cubic spline procedure was used to meet two objectives: a) To maintain integrity with the meta-analysis curves from 22 to 36 weeks. Integrity of the fit was assumed to be agreement within 3% at each week. b) To ensure fit of the data to the WHO values at 50 weeks, within 0.5%.
3) The final percentile curves were produced from the smoothed LMS values. 4) A grid similar to the 2003 growth chart was used, but the growth curves were re-scaled along the x-axis from completed weeks to allow clinicians to plot infant growth by actual age in weeks, and a slight modification (scaled to 60 centimeters instead of 65) was made to the y-axis.

D. Compared the revised charts with the 2003 version
The revised growth charts were compared graphically with the original 2003 Fenton preterm growth chart. To make the differences in chart values more apparent, the 2003 chart data was also shifted to actual weeks for these comparison figures.
The individual datasets from the literature showed good agreement with each other, especially along the 50th and lower centiles (Figures 1, 2, and 3) and the meta-analysis curves had a close fit with the individual datasets up to 36 weeks and at 50 weeks ( Figures 5, 6, 7). The final splined weight curves were within 3% of the meta-analysis curves for 24 through 36 weeks for both genders, except for a 3.8% difference for girls at 32 weeks along the 90th centile. None of the length measurements differed by more than 1.8% percent between the meta-analysis and the splined curves; all weeks of the head circumference curves were within 1.5%. The meta-analyses for head   circumference and length for girls and boys were close enough to normal distributions that normal distributions were used to summarize the data. The measures at 50 weeks were within 0.5% of the WHOGS values.
Girl and boy charts were prepared (Figure 8 and 9), by shifting the age by 0.5 weeks to allow plotting by exact age instead of completed weeks. The LMS Parameters [15] were used to develop the exact z-score and percentile calculators for the new growth chart.
In the two graphical comparisons between the revised growth charts, one for each sex, with the 2003 Fenton preterm growth chart revealed that the curves were quite similar (Figures 10 and 11). Generally the new girls' curves were slightly lower ( Figure 10) and the new boys' slightly higher ( Figure 11) for all 3 parameters (weight, head circumference, and length) than the 2003 curves. The most dramatic visual and numerical difference between the new charts and the 2003 chart was the higher shift of the boys' weight curves after 40 weeks compared to the 2003 chart, reaching a maximum difference at 50 weeks of 650, 580, and 740 grams at the 3rd, 50th, and 97th percentiles, respectively. The second biggest visual difference was the lower pattern of the girls' length curves below 37 weeks; the difference in length reached a maximum numerical value of 1.7 centimeters at 24 weeks along the 97th percentile.

Discussion
We used a strict set of inclusion criteria to include only the best data available to convert fetal and infant size data into fetal-infant growth charts for preterm infants. The revised sex-specific actual-age (versus completed weeks) growth charts (Figure 9 and 10), are based on birth size information of almost four million births with confirmed or corrected gestational ages, born in developed countries (See Features of the new growth chart). The revised charts are based on the recommended growth goal for preterm infants, the fetus and the term infant, with smoothing of the disjunction between these datasets, based on the findings of our international multicentre validation study (Fenton TR, Nasser R, Eliasziw M, Kim JH, Bilan D, Sauve R: Validating the weight gain of preterm infants between the reference growth curve of the fetus and the term infant, The Preterm Infant Multicentre Growth Study. Submitted BMC Ped 2012). These charts are consistent with the meta-analysis data up to and including 36 weeks, thus they can be used for the assessment of size for gestational age for preterm infants under 37 weeks of gestational age. This growth chart is likely applicable to preterm infants in both developed and developing countries since the data was selected from developed countries to minimize the influence from circumstances that may not have been ideal to support growth.

Features of the new growth chart
Based on the recommended growth goal for preterm infants: The fetus and the term infant Girl and boy specific charts Equivalent to the WHO growth charts at 50 weeks gestational age (10 weeks post term age). Large preterm birth sample size of 4 million infants; Recent population based surveys collected between 1991 to 2007 Data from developed countries including Germany, Italy, United States, Australia, Scotland, and Canada Curves are consistent with the data to 36 weeks, thus can be used to assign size for gestational age up to and including 36 weeks. Chart is designed to enable plotting as infants are measured, not as completed weeks. The x axis was adjusted for this chart so that infant size data can be plotted without age adjustment, i.e. Babies should be plotted as exact ages, that is a baby at 25 3/7 weeks should be plotted along the x axis between 25 and 26 weeks. Exact z-score and percentile calculator available for download from http://ucalgary.ca/fenton. Data is available for research upon request.
It may be more intuitive to plot on growth charts using exact ages rather than on the basis of complete weeks. Several years ago, the WHO used completed age for growth chart development [12]. This recommendation was likely due to the way data had been collected in the past, that is all 26 0/7 through 26 6/7 week infants were included in the 26 week completed week category. However, with the use of computers to plot on growth charts comes the potential to more accurately plot measurements to the exact day of data collection. Thus the time scale of the horizontal axes of these new growth charts were re-scaled to actual age, for ease of use and understanding. For example, a baby at 25 3/7 can be intuitively plotted between 25 and 26 weeks.
Exact z-score and centile calculators for the revised charts are available for download: http://ucalgary.ca/ fenton. Data is available for research upon request.
The data revealed that between 22 weeks to 50 weeks post menstrual age, the fetus/infant multiplies its weight tenfold, for example, the girls' median weight increased from a median of 520 to 5360 grams. Using a fetal-infant growth chart allows clinicians to compare preterm infants' growth to an estimated reference of the fetus and the term infant.
There was a remarkably close fit of the included preterm surveys for weight, head circumference and length from the 6 countries, especially at the 50th percentile, even though the data came from different countries.
The splining procedures we used have produced a chart that has integrity and good agreement with the original data. Smoothing of the LMS parameters is recommended since minor fluctuations are more likely due to sampling errors rather than physiological events [15]. Experts recommend that growth charts be developed based on smoothed L, M and S, to constrain the adjacent curves so that they relate to each other smoothly [15]. The World Health Organization set their L parameter to 1 for head circumference and length, while they maintained the exact L values for infants' weights [58]. The data under study here revealed the same effect as the WHO data; we found that both head circumference and length were close enough to normal distributions that normal distributions could summarize the data, while the exact L's were needed to retain the nuances of the weight curves.
The differences between the revised growth charts and the 2003 Fenton preterm growth chart may reflect improvements since the selected preterm growth references for the new versions are more likely globally representative of fetal and infant growth. Some of the differences between the current charts and the 2003 version are likely due to the separation into girl and boy charts, since the shifts of the girls' curves tend to be downward and the boys' curves upward. The weight shifts after 40 weeks were upward for both sexes, due to the higher values for the WHOGS compared to the CDC growth reference [59] at 10 weeks post term.
The ideal growth pattern of preterm infants remains undefined. These revised growth charts were developed based on the growth patterns of the fetus (as has been determined by size at birth in the large population studies) and the term infant (based on the WHO Growth Standard) [2]. Ultrasound studies and comparison of subgroups of prematurely born infants suggest that the fetal studies, such as those used in this development, may be biased by the premature birth since fetuses who remain in utero likely differ in important ways from babies who are born early [60,61]. However, fetal size from these imperfect studies may be the best data available at this point in time for comparing the growth of preterm infants since the alternative, to compare to in utero infants requires extrapolation from ultrasound measurements. To use other premature infants as the growth reference for preterm infants may not be ideal since the ideal growth of preterm infants has not been defined, has been changing over time [62], and is influenced by the nutrition and medical care received after birth [63,64].
Although the WHOGS is considered to be a growth standard, the infants in the population-based surveys of size at birth are more likely representative of the reference populations and were not selected to be healthy. Thus these growth charts are growth references and are not a growth standard. The INTERGROWTH study, currently underway, will rectify this problem, since their purpose is to develop prescriptive standards for fetal and preterm growth [65].

Conclusion
The inclusion of data from a number of developed countries increases the generalizability of the growth chart. The revised preterm growth chart, harmonized with the World Health Organization Growth Standard at 50 weeks, may support an improved transition of preterm infant growth monitoring to the WHO charts.