Academic Publication

Critical windows for nutritional interventions against stunting

Author:
Andrew M Prentice, Kate A Ward, Gail R Goldberg, Landing M Jarjou, Sophie E Moore, Anthony J Fulford, and Ann Prentice
Source:
The American Journal of Clinical Nutrition
Contributor:
Publication Year:
2013
  • SDG 2 - Zero Hunger
  • SDG 3 - Good Health and Well-Being

ABSTRACT

An analysis of early growth patterns in children from 54 resource-poor countries in Africa and Southeast Asia shows a rapid falloff in the height-for-age z score during the first 2 y of life and no recovery until ≥5 y of age. This finding has focused attention on the period -9 to 24 mo as a window of opportunity for interventions against stunting and has garnered considerable political backing for investment targeted at the first 1000 d. These important initiatives should not be undermined, but the objective of this study was to counteract the growing impression that interventions outside of this period cannot be effective. We illustrate our arguments using longitudinal data from the Consortium of Health Oriented Research in Transitioning collaboration (Brazil, Guatemala, India, Philippines, and South Africa) and our own cross-sectional and longitudinal growth data from rural Gambia. We show that substantial height catch-up occurs between 24 mo and midchildhood and again between midchildhood and adulthood, even in the absence of any interventions. Longitudinal growth data from rural Gambia also illustrate that an extended pubertal growth phase allows very considerable height recovery, especially in girls during adolescence. In light of the critical importance of maternal stature to her children’s health, our arguments are a reminder of the importance of the more comprehensive UNICEF/Sub-Committee on Nutrition Through the Life-Cycle approach. In particular, we argue that adolescence represents an additional window of opportunity during which substantial life cycle and intergenerational effects can be accrued. The regulation of such growth is complex and may be affected by nutritional interventions imposed many years previously.

INTRODUCTION

Victora et al (1) have published an analysis of early growth in 54 countries; most from low-income settings. Their analysis updates an earlier version by Shrimpton et al (2) and uses the new WHO growth standards (3). A key finding is that, in the poorer regions of Southeast Asia and Africa, height-for-age z scores (HAZs)4 start with a deficit at birth (−0.75 HAZ for Asia and -0.35 HAZ for Africa) and decline further in the first 2 y of life (by ∼1.5 HAZ in both settings) before reaching an apparent plateau until 5 y, when the analysis ended (Figure 1).

Figure 1 - Mean anthropometric z scores for 54 studies from low- and middle-income countries relative to the WHO standard. Reproduced with permission from reference.
Mean anthropometric z scores for 54 studies from low- and middle-income countries relative to the WHO standard. Reproduced with permission from reference 1.

Both the original and the updated analysis have been influential in developing the concept that -9 to 24 mo represents the optimal “window of opportunity” within which growth-promoting nutritional interventions should be focused. This window is also articulated as the first 1000 d and has been effectively used as a rallying point for global initiatives (eg, seewww.thousanddays.org). A view has emerged that interventions outside this window are unlikely to have any effects—a view that is being increasingly adopted in many development circles.

Without seeking to undermine the importance of this period (-9 to 24 mo), or to discourage interventions during this critical period, we present here analyses showing that there are other windows of opportunity to address stunting that should not be overlooked and might well offer additional points for intervention. Our arguments are intended to stabilize the pendulum and prevent an excessive swing away from the more comprehensive approach to nutrition-related health interventions captured by the UNICEF/Sub-Committee on Nutrition model Nutrition Through the Life-Cycle (45). In particular, we argue that adolescence represents an additional window during which growth-promoting interventions, possibly initiated years before puberty, might yield substantial life cycle and intergenerational effects. Interventions outside the first 1000 d may also benefit other outcomes, especially cognitive development (67), but these are not the subject of this article.

We base our reasoning on the following arguments: 1) that the cross-sectional ecologic analyses of Shrimpton et al (2) and Victora et al (1) have been overinterpreted in some quarters; 2) that data on the timing of cell proliferative potential of organ systems across the life span do not support the concept of a catch-up window closing at 24 mo; 3) that an analysis of data from various sources shows that catch-up in HAZ occurs after 24 mo in many poor populations, even in the absence of interventions; 4) that an analysis of our own data from rural Gambia confirms this post-24 mo catch-up and shows very significant prolonged catch-up growth during adolescence and into young adulthood (again in the absence of interventions); and 5) that, unfortunately, meta-analyses indicate limited efficacy of nutritional interventions between conception and birth and in early postnatal life. Given the importance of maternal stature to reproductive outcomes in the Nutrition Through the Life-Cycle model, we argue that careful studies could be undertaken to explore whether it is feasible, through nutritional interventions, to augment the pubertal catch-up potential of girls while preventing the possible adverse sequelae of early pregnancies, excess weight gain, and/or accelerated closure of growth plates that might reverse the intended effect.

SUMMARY ANALYSES OF NATIONAL DATA ON POSTNATAL GROWTH SHOULD BE INTERPRETED WITH CAUTION

The Shrimpton et al (2) and Victora et al (1) analyses of length/HAZ (the latter reproduced as Figure 1) capture the widely observed fall-off in length growth that occurs in infancy in poor populations and make a very powerful case for focusing interventions on early life. The figure seems to suggest little or no recovery up to the age of 5 y, but must be interpreted with due caution based as they are on an amalgamation of large-scale nationally representative data sets that were not collected for research purposes. Note that the apparent troughs before 24, 36, and 48 mo suggest evidence of age rounding up during data collection (where, for instance a 3.75-y-old is recorded as 4 y and hence appears smaller than in reality). In addition, an analysis of the African data sets presented in Table 4 of the Victora et al summary (1) shows that two-thirds of the data sets show some catch-up between 24 and 48 mo even in the absence of interventions (Figure 2), albeit very modest compared with the initial decline.

Figure 2 - Changes in HAZs between 24 and 48 mo in 30 African countries. Calculated from data provided in Table 4 of reference 1. HAZ, height z score.
Changes in HAZs between 24 and 48 mo in 30 African countries. Calculated from data provided in Table 4 of reference 1. HAZ, height z score.

CELL PROLIFERATIVE POTENTIAL OF ORGAN SYSTEMS ACROSS THE LIFE SPAN

The timing of the growth of major organ systems in humans relative to the final attained size is shown in Figure 3. These patterns of normal tissue development have been extensively studied in relation to the age-related sensitivity of organs to radiation damage (8). In relation to musculoskeletal tissues, the subject of the current discussion, growth is partitioned into 2 periods of sensitivity (<5 y and puberty) and an intervening period of relative growth quiescence. These periods are clearly shown in Figure 3.

Figure 3 - Differential timing of the growth of body systems in humans.
Differential timing of the growth of body systems in humans.

Karlberg (9) has taken an alternative approach in the development of his infancy-childhood-puberty model of human growth in which he identifies 3 partly superimposed and additive phases: 1) a sharply decelerating infancy component representing a continuation of fetal growth; 2) a very slowly decelerating childhood component that begins in the second half of infancy and continues to maturity; and 3) a sigmoid-shaped pubertal phase that is superimposed on the continuing childhood growth. The hormonal regulators of these 3 phases differ markedly; hence, their positive modulation by nutritional intervention may also require different approaches. Regulation of the infancy phase is likely to involve numerous interacting systems, especially insulin and the insulin-like growth factors and their competitive binding proteins. The childhood phase corresponds to the additional effect of growth hormone on these axes and in the pubertal phase growth is further augmented by sex steroids: estrogen in girls and testosterone in boys. Karlberg (9) proposes that the profound early faltering in HAZ seen in poor populations represents a developmental delay in the initiation of the childhood phase, which starts in the second 6 mo of life in well-nourished children and is much delayed in undernourished children. This interesting suggestion has not gained wide currency and merits closer scrutiny because it may point to hitherto unexplored intervention strategies.

In total, these data on the normal patterns of human development remind us that, although a high proportion of neuronal tissue is in place by 24 mo, most other tissues grow and develop after this age.

CATCH-UP IN HAZ OCCURS AFTER 24 MO IN MANY POOR POPULATIONS

Early height growth in 5 populations (Brazil, Guatemala, India, Philippines, and South Africa), each studied longitudinally and brought together in the Consortium of Health Oriented Research in Transitioning Societies (COHORTS) collaboration (10), is shown in Figure 4. The data confirm the rapid fall-off in HAZ between birth and 24 mo in all 5 countries, but show significant regain between 24 and 48 mo in 4 of the 5 cohorts. Both the fall-off and catch-up occur irrespective of the final height attained. India is a distinct outlier with no signs of catch-up. Data from our own studies in rural Gambia confirm the former pattern and show mean HAZ scores of -2.44 (95% CI: -2.50, -2.39) at 24 mo, -2.31 (-2.36, -2.25) at 48 mo, and -1.78 (-1.85, 1.72) at 72 mo (see Height Growth in Poor Rural Gambians Throughout the Life Cycle for more detail).

Figure 4 - Mean height-for-age z scores and changes in height-for-age z scores for participants in the Consortium of Health Oriented Research in Transitioning Societies studies, divided by tertiles of adult height. Reproduced with permission from reference.
Mean height-for-age z scores and changes in height-for-age z scores for participants in the Consortium of Health Oriented Research in Transitioning Societies studies, divided by tertiles of adult height. Reproduced with permission from reference 10.

These examples of height catch-up in young children, even in the absence of external nutritional interventions, clearly contradict the widely held impression that a window of opportunity closes at 24 mo of age. The data in Figures 2 and 4 both emphasize that the extent of catch-up after 24 mo is highly context specific and presumably reflects the availability of foods, food-consumption patterns, the composition of diets, and the prevailing burden of infections (especially those affecting gastrointestinal function). Epigenetically mediated early life and/or intergenerational effects may also contribute to population diversity in later growth.

HEIGHT GROWTH IN POOR RURAL GAMBIANS THROUGHOUT THE LIFE CYCLE

The Medical Research Council’s field station in Keneba, The Gambia has been monitoring the anthropometric status of the poor subsistence-farming population of 3 rural villages for >6 decades. LOWESS-smoothed curves through 36,828 cross-sectional length/height measurements for males and females, expressed as HAZs against the UK 1990 reference curves, are shown in Figure 5, A and B (11). The similarity of the patterns when separated into data logged before and after 1970 confirms the robustness of patterns. Both sexes showed a characteristic pattern of being short at birth (∼-0.75 HAZ), falling off precipitately to 24 mo (to ∼-2.25 to -2.5 HAZ), followed by some catch-up to 5 y (to ∼-1.75 HAZ), a period of stability, followed by a further apparent drop off (which is solely an artifact arising from their later entry into puberty than the children in the UK standards), followed by an extended catch-up until a late achievement of adult stature (at ∼-1.5 HAZ in males and ∼-0.75 HAZ in females). The first phase of this adolescent catch-up is the reversal of the artifact caused by delayed initiation of puberty, but there is an additional important component represented by a prolonged growth to the age of ∼22–24 y in boys and 18–19 y in girls. The weight-for-age curves show very similar patterns (see Supplemental Figure 1 under “Supplemental data” in the online issue). This maturational delay, which allows catch-up by prolonging the childhood and pubertal growth phases, was previously described in developing countries (eg, 1213), together with the differential timing in boys and girls (14). Studies in previously malnourished children have also shown catch-up against unaffected siblings, with some evidence that girls show a greater potential for pubertal catch-up (15). Intriguingly, there is a parallel between the catch-up growth shown after infancy and in adolescence, which suggests that both might be explained by a developmental delay in entering the next phase of growth.

Figure 5 - LOWESS-fitted curves applied to semilongitudinal data on growth collected between 1951 and 2006 in rural Gambia (n = 36,828 data points). Height-for-age z scores were calculated against the UK 1990 reference (11). Panel A = males, panel B = females. Curves drawn for data collected before and after 1970 illustrate the robustness of the growth patterns. The slightly higher lines in adulthood are the post-1970 data.
LOWESS-fitted curves applied to semilongitudinal data on growth collected between 1951 and 2006 in rural Gambia (n = 36,828 data points). Height-for-age z scores were calculated against the UK 1990 reference (11). Panel A = males, panel B = females. Curves drawn for data collected before and after 1970 illustrate the robustness of the growth patterns. The slightly higher lines in adulthood are the post-1970 data.

In this cross-sectional analysis, the observed catch-up growth after 24 mo could arise as a result of selective mortality of the most stunted infants. To check for this we repeated the analysis using only subjects surviving beyond 15 y and showed essentially identical values (see Supplemental Figure 2 under “Supplemental data” in the online issue). Note also that, in this cross-sectional analysis, there is no statistical requirement to adjust for regression to the mean, as is indicated for longitudinal assessments of catch-up (16) and as should be applied to the COHORTS longitudinal data cited above to differentiate the components of catch-up attributable to regression to the mean from true population catch-up. Our interpretation of childhood catch-up after 24 mo is that a combination of the normal postnatal maturation of the children’s immune systems and the development of a broad repertoire of adaptive responses against previously encountered pathogens reduces the frequency and severity of growth-impairing infections—a hypothesis that is supported by morbidity surveillance and clinic records.

We also studied cohorts of 80 boys and 80 girls longitudinally from 8 to 12 y (mean age 10 y; prepuberty in this setting) to 24 y (1718). Their height data are plotted in Figure 6, which again shows substantial catch-up during an extended pubertal growth phase; boys caught up from -1.25 to -0.5 HAZ and girls caught up from -1.1 to -0.2 HAZ.

Figure 6 - Changes in height relative to the UK 1990 reference (11) in cohorts of 80 boys and 80 girls (17, 18) measured longitudinally in rural Gambia. Loss-to-follow up rates were low, as indicated at the base of the figure. Ht, height; SDS, SD score.
Changes in height relative to the UK 1990 reference (11) in cohorts of 80 boys and 80 girls (1718) measured longitudinally in rural Gambia. Loss-to-follow up rates were low, as indicated at the base of the figure. Ht, height; SDS, SD score.

The COHORTS data from 5 countries (10) also show variable levels of HAZ catch-up between midchildhood (defined as 48 mo in their analysis) and adulthood; the most malnourished populations (Guatemala, India, and Philippines) had an average gain in HAZ of 0.72 (Table 1). Between 24 mo and adulthood, these 3 cohorts showed catch-up averaging +0.97 HAZ; among all 5 cohorts, it was notable that those most stunted at 24 mo showed the greatest height gain to adulthood. Our longitudinal Gambian data (-2.25 HAZ at 24 mo and 2.0 HAZ catch-up to adulthood) fits this general observation but shows even greater catch-up. Note that, as indicated above, a component of catch-up between successive ages can relate to regression to the mean; however, because children in COHORTS were in some cases recruited at birth, this adjustment is less critical for subsequent age intervals. Much of the analysis of COHORTS data are performed by using anthropometric changes conditional on the previous measurement to overcome these complexities, and readers are referred to the source articles for a full description of these analyses (1019).

Click to read the full article, this analyzes previous findings regarding the critical windows of opportunity against stunting during childhood and presents data that illustrates that adolescence is another window of opportunity for growth and nutritional intervention. The authors use data from a range of countries, including Brazil, Guatemala, India, Philippines, South Africa, and Gambia.

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