1. Introduction
Undernutrition, caused by lack of food and/or the wrong composition of food, is a world-wide problem, causing impaired growth and pubertal development primarily in the developing world, but also, to a lesser extent, in affluent countries. In developing countries undernutrition is often combined with other conditions such as infections or malabsorption. Since it has been shown that well-nourished populations all over the world grow in a fairly similar manner, the WHO has established reference populations [
1,
2] in relation to which nutritional status can be defined in a population or an individual [
2,
3]. According to the definitions accepted by WHO, linear growth below –2 SD in height for age denotes chronic undernutrition resulting in stunting. Weight for height below –2 SD indicates wasting, which is a sign of acute undernutrition. There are also reference values for BMI for age for the preschool years [
1] and from birth to 18 years [
4] which combine height and weight parameters.
The aim of nutritional rehabilitation is improved child growth following stunting which results in a period of accelerated growth, wholly or partly compensating for the previous slower growth rate. The accelerated growth is called catch-up growth [
5,
6,
7,
8,
9,
10,
11]. Linear catch-up growth may be preceded by a period of catch-up weight gain [
7]. Unless specified otherwise, the term “catch-up growth” refers to linear growth in this paper.
Undernutrition is still a major problem in many low- and middle-income countries. In India, where the economic development is accelerating, 48% of the children below five years of age are still stunted due to chronic undernutrition [
12,
13]. This contributes heavily to child morbitity and is a major reason for death during childhood in developing countries. Respiratory infection and diarrheal disease, leading causes of morbidity and mortality, are commonly linked to impaired child nutrition [
14,
15]. In the developing world undernutrition often starts during fetal life due to maternal malnutrition, resulting in infants with low birth weight. Their postnatal life is frequently associated with growth retardation as well as delayed pubertal development.
In high-income countries, in spite of access to adequate nutrition, undernutrition still poses a problem particularly in the form of intrauterine growth retardation (IUGR) which results in infants being born small for gestational age (SGA). The work of Barker
et al. [
16,
17,
18] and other groups [
19,
20] have shown that growth impairment during fetal life may increase the risk of cardiovascular disease, hypertension and deranged glucose metabolism later in life.
In affluent societies undernutrition can also appear postnatally, due to inflammatory bowel disease, anorexia nervosa, asthma or other chronic diseases.
In many developing countries, as in India, living conditions are rapidly improving, and previously chronically undernourished children now have access to better nutrition [
14,
21,
22]. However, nutritional rehabilitation may be associated with complications. Thus, children living under conditions representing a transition from low-income to high-income situations, may be at risk of developing obesity and type 2 diabetes [
21,
23]. Several questions remain to be answered regarding how nutritional rehabilitation should best be carried out [
14].
Another transitional situation occurs when children are adopted from underprivileged circumstances where they have become chronically undernourished to a country where they have good access to food and health care. Such a favourable situation for nutritional rehabilitation may not be uncomplicated, however. Studies on children adopted from developing to high-income countries have demonstrated that catch-up growth after adoption can be associated with early pubertal development. Precocious puberty increases the risk for short adult height due to premature closure of the epiphyseal growth plates. In addition, early puberty may also lead to psychosocial difficulties. The mechanism behind the development of early/precocious puberty following catch-up growth is still unknown.
Undernutrition may occur during different time periods in life, and nutritional rehabilitation is not simply a matter of compensating for the lack of proteins, carbohydrates, lipids and micronutrients. Increased understanding of the actual state of undernutrition, and what happens metabolically during nutritional rehabilitation is essential for the design of relevant treatment as well as preventive care of mothers and children. With this in mind we will review some human and animal studies describing various types of undernutrition, subsequent catch-up growth and associated hormonal changes. A special focus will be on early pubertal development. It seems helpful to categorize undernutrition as being fetal, postnatal or combined fetal-postnatal and to discuss growth and pubertal development in each of these conditions.
Thus, the aim of this article is:
3. Postnatal Undernutrition, Growth and Puberty
Children, born AGA, may suffer postnatal undernutrition as a result of disease or an inadequate diet. Retarded growth and delayed onset of puberty are common conditions in children with chronic disease [
44].
3.1. Gastrointestinal Disease
3.1.1. Crohn’s Disease
Growth impairment and pubertal delay are frequent complications of inflammatory bowel disease, particularly Crohn’s disease. Chronic malnutrition is caused mainly by inadequate food intake and proinflammatory cytokines. Various treatments are available: corticosteroids, optimization of immunomodulatory drugs, enteral nutrition and, if necessary, surgery for ulcerative colitis and for intestinal complications of localized Crohn’s disease. Biologic agents can further be used for mucosal healing. Following adequate therapy catch-up growth can take place. It is important to utilize the “window of opportunity” for growth before puberty advances too far [
45].
3.1.2. Celiac Disease
Patients with celiac disease may present with short stature [
46]. When treated with a gluten-free diet, these children show an accelerated growth rate, with peak growth velocity occurring during the first year. The catch-up growth may not be completed after three years. Bosio
et al. [
46] reported that puberty started at a normal age.
3.2. Asthma
Growth problems sometimes occur in children with poorly controlled asthma [
47]. There may be a chronic delay of both growth and puberty. Systemic corticosteroids suppress growth for as long as the treatment is maintained. When treatment is withdrawn, catch-up growth may occur, and partly compensate for the growth retardation. Inhaled corticosteroids may also suppress growth, depending on the dose and administration regimen.
3.3. Eating Disorders
Swenne [
48] has demonstrated that girls afflicted with eating disorders are growth retarded. This may be followed by catch-up growth after treatment. Since this may take many years, some loss of adult height is often a consequence of the eating disorder. Consistent with this Lanzouni
et al. [
49] reported that patients with anorexia nervosa and stunting undergo catch-up growth, although not complete, after treatment. Similar results have been reported by Modan-Moses
et al. [
50].
Following treatment, girls with eating disorders and primary amenorrhea progress rather slowly through puberty [
51]. The weight required to reach menarche can be predicted by the prepubertal weight which may represent the individual’s normal growth track unaffected by the eating disorder.
IGF-1 has been identified as a useful indicator for monitoring the nutritional rehabilitation [
52].
3.4. Early Postnatal Undernutrition and Critical Periods
If rats are fed a protein-energy deficient diet, total pancreatic beta cell weight and individual beta cell size are diminished. Thus, protein-energy malnutrition early in life may result in a diminished reserve for insulin production, which in turn may predispose to glucose intolerance or even manifest diabetes during conditions of increased insulin demand [
53,
54]. This may also influence the growth process.
Winick and Noble [
55] have shown that in the early postnatal life in the rat there is a cell proliferation phase which lasts until weaning. During that time catch-up growth is possible. After this the number of cells does not increase, instead the cells increase in volume. It was observed that undernutrition during the cell proliferation phase could limit the number of new cells formed. Full catch-up following undernutrition during this period was not possible due to the lesser number of cells. If undernutrition took place after the final formation of all cells, only the cell content was affected and full catch-up was possible after refeeding. Thus, it follows that there may be critical periods for the potential for catch-up growth, depending on whether cellular proliferation or cellular hypertrophy predominates.
Human fetal growth is initially due to multiplication of cells and to some degree to an increase of cell size. During the late pregnancy fetal growth mainly takes place through increase of cell size [
56]. There may exist critical periods with regard to the ability for catch-up growth in humans, since studies on adopted children indicate different potentials depending on their nutritional status on arrival [
57].
Thus:
- Well-nourished children may become undernourished due to inadequate diet or disease. Their growth may be retarded and puberty delayed.
- After successful treatment, catch-up growth can occur, but may be prolonged. There are conflicting reports regarding whether full catch-up is possible.
- There may be critical periods for the potential for catch-up growth.
- To the best of our knowledge, catch–up growth in children, following undernutrition which occurs only postnatally, has not been reported to be associated with earlier pubertal development.
4. Combined Fetal-Postnatal Undernutrition, Growth and Puberty
Low birth weight (LBW) due to maternal malnutrition, is common in the developing world where around 16% of infants are estimated to have a birth weight <2500 g [
58]. In South-Central Asia 27% are born with LBW [
58]. Thus, a great number of children begin their life chronically undernourished. In a developing country the LBW child mostly has to continue with limited access to food and may later in childhood have to participate in energy demanding labour, necessary for the survival of the family. These children thus represent combined fetal and postnatal undernutrition. In these populations the children grow on average along –2 SD in height according to the WHO [
1,
2,
3,
58] reference. In addition, they enter puberty relatively late compared to privileged children. Their adult height corresponds to about –2 SD. However, it has been shown that the pubertal growth component is similar both in undernourished and privileged groups of boys. This means that the height gain during puberty is the same in both groups. The lower adult height of the chronically undernourished boy is thus due to a lower height at the start of puberty [
59].
4.1. Catch-Up Growth
In a review of studies on stunted children, Martorell
et al. [
60,
61] reported that these children continue to be stunted if they remain in the environment in which they became chronically undernourished. Moreover, the potential for catch-up growth increased as maturation was delayed and the growth period prolonged. In addition, the effect of a poor environment leading to continued stunting despite a period of treatment for malnutrition, has been pointed out by Graham
et al. [
62].
International adoptions offer possibilities to study undernourished children in an environment where food supply is abundant, which in turn leads to catch-up growth. Proos
et al. [
63,
64] studied 114 boys and girls adopted in Sweden from India at arrival and during a follow-up period of 2 years. The majority of the children were stunted on arrival in Sweden and catch-up growth was observed continuously during the 2 years, with no signs of levelling off. In 37 cases the birth weight was known. Thirty (81%) of these had a birth weight <2500 g. Although data on birth weight were lacking for the remaining children, it is likely that the majority also had a low birth weight and thus were subject to combined fetal-postnatal undernutrition.
Golden [
10] has reviewed studies regarding whether complete catch-up is possible after malnutrition, and has reported that catch-up growth appears to be adequate under favourable circumstances. However, it can be interrupted by an early pubertal development.
4.2. Pubertal Development
Kulin
et al. [
65] compared 342 privileged urban children in Nairobi, Kenya with 347 impoverished rural adolescents. They found that the poor children had a delayed pubertal maturation. The authors also showed [
66] that the levels of gonadotropins in urine from rural adolescents were lower than from those living in urban areas. However, following matching for pubertal stages there were no significant differences in the levels of gonadotropins.
Gupta and Singh [
67] have reported that girls from rural areas were shorter and weighed less as compared to those from urban slums. At a certain age a higher degree of pubertal development was associated with a higher mean body weight and height. Quamra
et al. [
68] reported that girls with an insufficient energy intake had approximately one year later onset of breast and pubic hair development. The authors concluded that onset of puberty, although under genetic control, is strongly influenced by the environment.
Adair [
69] studied 997 girls from rural and urban communities in the Philippines. Girls who were long and thin at birth reached menarche up to 6 months earlier than did girls who were short and light. Thinness at birth had the most pronounced effect on menarche among girls who grew rapidly during the first 6 months of life. The data confirm that programming of postnatal growth and maturation is established already in utero.
4.3. Adoption
Adolfsson and Westphal [
70] reported in 1981 on observing early pubertal development in seven girls adopted from Far-Eastern countries.
In order to investigate the occurrence of early puberty in adopted children Proos
et al. [
71,
72] studied 107 girls from India adopted in Sweden through the same adoption agency and born 1971 or earlier. The study was the first to analyse the characteristics of a large population of adopted girls, selected only according to time of birth and country of origin, enabling comparison with national growth references.
The majority was stunted on arrival and subsequently underwent catch-up growth. This continued until the start of the pubertal growth spurt, which occurred about 1.5 years earlier than that of the reference population. The girls, as a group, had menarche 1.2–1.5 years earlier than well-nourished reference populations in India and Sweden [
72]. Analysis of the pubertal growth component showed that it was normal with regard to extent and duration, but also that it started 1.5 years earlier than that of the reference population [
73,
74]. In addition, the girls with the most pronounced stunting and fastest catch-up growth had the lowest menarcheal age [
75]. Interestingly, menarche occurred at similar height and weight in the adopted girls as in girls in an Indian underprivileged reference population, even though the start of puberty was delayed almost three years in the latter group [
71]. Further, the two groups ended up with similar adult heights. The common denominator for the two populations was the initial chronic undernutrition.
Several other researchers have also reported occurrence of early or precocious puberty among internationally adopted children [
76,
77,
78,
79,
80,
81,
82,
83,
84,
85]. Virdis
et al. [
77] studied 19 adopted girls, who were examined due to early puberty. The girls who were above five years at arrival had the earliest development. The authors hypothesize that catch-up growth leads to development of early puberty and propose that fat accumulation contributes by increasing availability of estradiol.
In a large population-based study in Denmark, Teilmann
et al. [
86] reported that internationally adopted girls run a 10–20 times increased risk of developing precocious puberty. They also showed that 5–8 years old adopted girls had increased levels of gonadotropins without any clinical signs of puberty. The authors concluded that the early onset of puberty in adopted girls is of central origin [
87]. The studies are important since they define the risk for precocious puberty in internationally adopted girls and add to the knowledge of the hormonal status during their prepubertal period.
Thus:
- Children who have been undernourished in utero and continue life in an environment where food is scarce, will not experience catch-up growth. They will enter puberty later than a well-nourished reference population.
- On the other hand, chronically undernourished children who are transferred to an environment with abundant food supply will undergo catch-up growth of varying degrees, and may develop early puberty.
- The timing for the onset of puberty is dependent on the degree of undernutrition as well as the rate of catch up growth.
- Prepubertal adopted children have been reported to have elevated gonadotropins.
6. Conclusions
This article reviews research regarding catch-up growth after the three modes of undernutrition: during fetal life, after isolated postnatal undernutrition and after combined fetal-postnatal undernutrition.
The major conclusions are:
Following nutritional rehabilitation catch-up growth is possible after fetal, postnatal and combined fetal-postnatal undernutrition.
Studies on adopted children arriving in their new environment at various ages show that catch-up growth can take place at any time during childhood but may be limited by critical periods.
Early/precocious puberty following catch-up growth after fetal or fetal-postnatal undernutrition has been reported in a number of studies.
Early pubertal development does not seem to follow catch-up growth after isolated postnatal undernutrition.
The timing for the onset of puberty is dependent on the degree of undernutrition as well as the rate of the catch-up growth.
Experiments in sheep have shown that catch-up growth after undernutrition is associated with an increased frequency of LH-pulses,
Gonadotropins have been found to be elevated in adopted girls, who are still prepubertal.
It seems reasonably well documented that nutritional rehabilitation after persistent undernutrition leads to catch–up growth, coinciding with increased gonadotropin secretion, eventually leading to early puberty.
The nature of the mechanisms behind the early/precocious pubertal onset in adopted children is not yet fully known. Further studies on metabolic and endocrine status during catch-up growth following the three modes of undernutrition are needed. Such studies may eventually clarify how nutritional rehabilitation should be carried out in order to avoid early or precocious puberty.