The Effects of Low Infant Birth Weight on Metabolic Diseases

Low infant birth weight can be associated with immediate, as well as long-term,

effects for the infant that will carry on, and most likely worsen, with adulthood. Both the

thrifty phenotype and the fetal origins hypotheses connect low birth weight to insulin

resistance, type 2 diabetes, hypertension, obesity, and other metabolic complications (1,

2). Infants are characterized as being of low birth weight if they are born weighing less

than five pounds and eight ounces (3), and this cutoff is also used to identify intrauterine

growth restriction(IUGR) in babies born at term (4). Infants born at a low birth weight,

and therefore likely IUGR, almost certainly have experienced some sort of growth or

development deficiencies as a fetus and will make necessary adjustments to adapt to

these deficiencies. The discussion lies within the effects, both long-term and immediate,

on metabolic diseases or their precursors in infants of low birth weight. Considering that

diabetes and obesity are national concerns, studies regarding the possible causes of, or at

least predispositions to, these diseases may offer insight to their prevention or to

cautionary measures to be taken.

A study examined twenty-five year old subjects who were either born appropriate

for gestational age or IUGR-born to evaluate decreased insulin sensitivity (5). In the

study’s subjects, “body fat was significantly higher in the IUGR group,” even though

both groups had comparable body mass indexes, and the results revealed decreased

insulin sensitivity in IUGR subjects(5). As with the former test, glucose concentration in

the blood is tested to determine insulin resistance and will be seen in higher

concentrations in people experiencing insulin insensitivity. Observed above in young

adults, other studies observed insulin resistance in mid and late childhood (6), while still
another cited incidence of insulin sensitivity reduction as early as age one in infants born

at a low birth weight (7). Insulin plays an important role in the body’s metabolic

processes. The importance of examining insulin insensitivity is in its progression to, or

association with, hypertension, obesity, type 2 diabetes, the metabolic

syndrome/syndrome X, and cardiovascular disease which could eventually be life-

threatening (1,7). So what factors associated with low birth weight would cause insulin

resistance?

After being born at a low birth weight, most children experience a catch-up

growth period that occurs largely between birth and age two, and it is this speedy weight

gain period that is often associated with the insulin resistance and related complications

(7). In a study of low birth weight infants of age one, a marked reduction in insulin

sensitivity was already observed (8). These findings suggest that the catch-up growth

period after birth is a crucial time period in the infant’s development of insulin resistance

and future complications. After the catch up period between birth and two years, a group

of infants were studied and compared during ages two to four years: “the gains in

abdominal fat and body adiposity were strikingly higher in small for gestational

age(SGA) than appropriate for gestational age children(AGA)” (7). Also in this study, the

already increased insulin resistance in SGA infants showed a further increase in the next

years, contrasting the lack of change in the AGA infants (7). The disturbing observation

here is that despite the fact the SGA infants had already experienced their catch-up

growth period, they still continued to add extra fat tissue while their insulin sensitivity

further reduced. Perhaps the early relation of insulin resistance and fat gains continues to

be the trend in adulthood.

 In progression into childhood, school-aged children between ages five and fifteen

were studied (6) and may help provide a link between the early insulin resistance and

adult metabolic diseases. In this study, a significant difference was seen between children

born SGA versus those born AGA: SGA children had higher fasting glucose, insulin

levels, and insulin resistance. In addition, “the greatest insulin resistance was observed in

those with low birth weight and high current weight” (6). To relate a previous study, a

connection may be made between the overcompensation of catch-up growth between

birth and age two and the increased insulin levels and weight gain. So, at this stage,

regardless of obesity, insulin resistance is still present, with no indication of lessening

with age, despite catch-up growth. These findings would then advance into young

adulthood where, as earlier mentioned, insulin resistance and body fat are still

significantly higher in those born as infants small for gestational age.

Syndrome X, also metabolic syndrome or metabolic syndrome X, is a condition

that relates hypertension, obesity, and type 2 diabetes; one researcher “was able to

demonstrate that the smaller the birth weight or the weight at one year, the greater was

the prevalence of this syndrome X in adult life (9). An additional study was able to

quantify the risk: “the odds increased 1.72 times for each tertile decrease in birth weight”

(10). Additionally, a study was conducted to research the factors involved in the

development of the metabolic syndrome, specifically low birth weight and current

overweight status (1). Here researchers discovered that birth weight was markedly lower

in the group of children with metabolic syndrome, while the ratio of current weight

compared with birth weight was high. “These findings indicate that in individuals with a
similar level of obesity, subjects with a lower birth weight and subsequent greater weight

gain tend to be at a higher risk of developing the MS”(1).

At increasingly smaller birth weights, the infant requires an even quicker rate of

catch up growth to reach the appropriate size by approximately age two, and therefore an

even greater alteration to the infant’s metabolic processes. A study using pre-term infants

attempted to evaluate whether the insulin resistance was actually due to the SGA/AGA

status, or the need for catch up growth after birth (11). The study of the very low birth

weight preterm infants concluded “the adverse metabolic pattern of pre-school VLBW

children seems related to post-natal events (rapid weight growth) independently of their

being born small- or appropriate-for gestational age” (11). This study still supports the

evidence that low birth weight is a definite risk factor for insulin resistance, and also adds

that an even greater risk may be connected to those low birth weight infants who

experience a faster catch-up growth during their early years.

However, catch-up growth is ultimately the result of either low birth weight or

IUGR. This restriction has proved to have a substantial effect on insulin sensitivity (12);

but is the effect due to catch-up growth or to other factors of incomplete development in

the fetus? In a study of ninety children with nonalcoholic fatty liver disease (NAFLD), “a

highly prevalent and potentially progressive condition in adults, now considered the

hepatic [liver] expression of the metabolic syndrome,” 39.9% of the children were born

SGA, which was about four times greater than the general pediatric population of the

hospital (12). This study shows that the liver disease is more prevalent in SGA children

and says that the related insulin resistance will begin to appear even during the catch up

growth period, not as a result of (12). Additionally, in a study differentiating between

SGA children who did achieve catch up growth in height within two years and those who

did not, a difference in insulin sensitivity was not found. This particular study then

concluded that childhood catch up growth was not the risk factor for future onset of type

2 diabetes (13), which somewhat contradicts the findings of the more current study

involving pre-term infants and even more recent studies using catch up growth between

zero and twenty-four months as an indicator (11). Most likely, the catch up growth is best

viewed not as a determinant, but as an indicator for future metabolic complications. In

which case, the catch up growth does not necessarily lead to diabetes or obesity, but

rather is a phase in the development of such diseases.

So then, the studies would indicate that events leading up to birth are responsible

for the negative chain of events that occurs after birth. Fetal development is a very

complicated process. Many maternal/environmental factors can affect fetal growth,

especially when the nutrient supply to the fetus is compromised. The limited supply will

cause the fetus to adapt structurally and functionally in order to survive through a process

called “programming” (1). During this critical stage of development, the fetus makes

these changes to itself for survival, but the programming “also results in permanent

damage to the metabolic status of the fetus” (1). Essentially, in the programming

adjustment, an immediate need is met and therefore proves the programming beneficial at

that time. However, remaining in this “adjusted” state will be detrimental to the infant

once the proper or sufficient nutrients are present. The unfavorable conditions may cause

adjustment by affecting growth and proper use of pancreatic beta-cells, which are related

to insulin secretion, and, when coupled with insulin resistance, provide the defects

leading to type 2 diabetes later in life (11,13). However, specifically targeting beta-cells
as a primary defect is difficult, and better is the conclusion that beta-cell deterioration in

combination with increasing insulin resistance can be a cause of later type 2 diabetes

(13). Fetal malnutrition and subsequent programming are can also be contributors to the

artery-related problems hypertension and high blood pressure and additionally may

predispose the fetus to the development of insulin resistance by regulating the types of

muscle fibers formed (1). Linking the beta-cell defects with those of the muscle type may

help explain the additional fat distribution: developing hyperinsulinemia as a result of

beta-cell compensation to muscle-specific insulin resistance could possibly promote

further peripheral and central fat deposition (7). This would explain the significantly

higher gains in abdominal and total body fat in SGA infants compared with AGA infants

during the growth period of two to four years of age (7). The gains between the two

groups in this study were actually similar in weight, height, and BMI with prominent

differences in body composition.

The fetal environment and infant are then predisposed to, or at-risk of, developing

metabolic diseases, but what, beyond childhood, are the outcomes of low birth weight? In

a study of Chinese adults, obesity, hypertension, type 2 diabetes, and birth weight were

all examined and associations between birth weight and other data were assessed (2).

Birth weight proved to be a predictor for future complications, especially low birth

weight: low birth weights showed the highest incidences of type 2 diabetes and

abdominal obesity, while the effects of birth weight combined with abdominal obesity

showed a significant increase in the prevalence of type 2 diabetes (2). These findings

indicate that low birth weight is an independent risk factor for both type 2 diabetes and

abdominal obesity. Considering that low birth weight is a risk factor for both insulin
resistance and obesity and that obesity itself is related to insulin resistance, taking

specific measures to reduce obesity would be almost imperative for persons born at a low

birth weight who do not wish to develop type 2 diabetes.

Experimental studies have been/are being conducted to develop treatment for

babies born at a low birth weight, or SGA (7, 9). “Approximately ten percent of children

born SGA fail catch-up growth and remain short” (14). Growth hormone treatment has

been approved and is now a treatment for patients born short and SGA (14), but certain

risk factors do raise concern: growth hormone has previously been linked to increased

insulin levels and insulin resistance (14). Since SGA infants are already considered to be

predisposed to insulin resistance, research should be focused on the lasting effects of

growth hormone (GH) on treated SGA patients. One study compared GH treated short

SGA children with non GH treated children to evaluate this concern and found that while

insulin resistance was increased during GH treatment, baseline was recovered after

discontinuation (14). In fact, the treated short SGA children actually experienced positive

effects on blood pressure and cholesterol levels that the untreated children did not and

were also taller, as a result of the GH treatment (14). GH has also shown a rise in BMI

due to a rise in lean body mass, which is useful in comparing the two groups: the groups

had comparable BMI’s, but the treated were taller, possibly indicating that the untreated

have more fat mass, though this idea needs further research (14). Metformin has also

been used in treatment with low-birth-weight insulin resistant children to increase insulin

sensitivity, but has shown also to reduce total and abdominal fat while helping to increase

lean mass (7).

 In summary, fetal malnutrition disrupts the complicated process of fetal

development. Malnutrition then acts on fetal tissues, insulin-sensitive tissues.

Programming helps the fetus to adapt to its circumstances (1). A malnourished fetus will

mostly likely experience IUGR and be born at a low birth weight (4). In order to make up

for the inadequacy, most SGA children will experience “catch-up” growth between birth

and two years of age (7). This “resets the hypothalamus-pituitary axis, leading to an

increase in growth factors,” and the possible, likely development of hypertension and

insulin resistance (1). Insulin resistance is then linked to many other complications

including obesity, type 2 diabetes, and the metabolic syndrome (2, 9). In conclusion,

prevention of metabolic diseases begins in the fetal environment. If born at a low birth

weight, an infant can be considered at a higher risk for insulin resistance, diabetes,

obesity, hypertension, and the metabolic syndrome. If the infant experiences a rapid

catch-up growth that progresses into overcompensation, then that infant is most likely at a

greater risk for such problems. Knowing the relationship between low birth weight and

metabolic diseases is helpful in developing preventative methods for and decreasing the

prevalence of these diseases.

References

1. Abe Y, Kikucki T, Nagasaki K, Hiura M, Tanaka Y, Ogawa Y, Uchiyama M. Lower birth weight
associated with current overweight status is related with the metabolic syndrome in obese
Japanese children. Hypertens Res. 2007 Jul;30(7):627-34. PMID:17785931 [PubMed – indexed
for MEDLINE] Accessed February 15, 2008.
2. Tian JY, Cheng Q, Song XM, Li G, Jiang GX, Gu YY, Luo M. Birth weight and risk of type 2
diabetes, abdominal obesity and hypertension among Chinese adults. Eur J Endocrinol. 2006
Oct;155(4):601-7. PMID: 16990660 [PubMed – indexed for MEDLINE] Accessed February 15,
2008.
3. Iyasu S, Tomashek K, Barfield. Infant mortality and low birth weight among black and white
infants – United States, 1980-2000. MMWR Weekly. 2002 Jul 12;51(27):589-92. Available at
www.cdc.gov. Accessed March 2, 2008.
4. Peleg D, Kennedy CM, Hunter SK. Intrauterine growth restriction: identification and
management. Am Fam Physician. 1998 Aug;58(2): 453-60, 466-7. PMID:9713399 [PubMed –
indexed for MEDLINE] Accessed February 15, 2008.
5. Jaquet D, Gaboriau A, Czernichow P, Levy-Marchal C. Insulin resistance early in adulthood born
with intrauterine growth retardation. J Clin Endocrinol Metab. 2000 April; 85(4):1401-6. PMID:
10770173 [PubMed – indexed for MEDLINE] Accessed February 15, 2008.
6. Gupta M, Gupta R, Pareek A, Bhatia R, Kaul V. Low birth weight and insulin resistance in mid
and late childhood. Indian Pediatr. 2007 Mar;44(3):177-84. PMID: 17413193 [PubMed – indexed
for MEDLINE] Accessed February 15, 2008.
7. Ibanez L, Ong K, Dunger DB, de Zegher F. Early development of adiposity and insulin resistance
after catch-up weight gain in small-for-gestational-age children. J Clin Endocrinol Metab. 2006
Jun;91(6):2153-8. Epub 2006 Mar 14. PMID:16537681 [PubMed – indexed for MEDLINE]
Accessed February 15, 2008.
8. Soto N, Bazaes RA, Pena V, Salazar T, Avila A, Iniguez G, Ong KK, Dunger DB, Mericq MV.
Insulin sensitivity and secretion are related to catch-up growth in small-for-gestational-age infants
at age 1 year: results from a prospective cohort. J Clin Endocrinol Metab. 2003 Aug;88(8):3645-
50. PMID: 12915649 [PubMed - indexed for MEDLINE] Accessed February 15, 2008.
9. Chatelain P. Children born with intra-uterine growth retardation (IUGR) or small for gestational
age (SGA): long term growth and metabolic consequences. Endocr Regul. 2000 Mar;34(1):33-6.
Review. PMID: 10808251 [PubMed - indexed for MEDLINE] Accessed February 15, 2008.
10. Valdez R, Athens MA, Thompson GH, Bradshaw BS, Stern MP. Birthweight and adult health
outcomes in a biethnic population in the USA. Diabetologia 1994 Jun; 37(6):624-31. PMID:
7926349 [PubMed - indexed for MEDLINE] Accessed February 20, 2008.
11. Bo S, Bertino E, Bagna R, Trapani A, Gambino R, Martano C, Mombro’ M, Pagano G. Insulin
resistance in pre-school very-low-birth weight pre-term children. Diabetes Metab. 2006
Apr;32(2):151-8. PMID: 16735964 [PubMed – indexed for MEDLINE] Accessed February 15,
2008.
12. Nobili V, Marcellini M, Marchesini G, Vanni E, Manco M, Villani A, Bugianesi E. Intrauterine
growth retardation, insulin resistance, and nonalcoholic fatty liver disease in children. Diabetes
Care. 2007 Mar;44(3):177-84. PMID 17413193 [PubMed - indexed for MEDLINE] Accessed
February 15, 2008.
13. Veening MA, van Weissenbruch MM, Heine RJ, Delemarre-van de Waal HA. Beta-cell capacity
and insulin sensitivity in prepubertal children born small for gestational age: influence of body
size during childhood. Diabetes. 2003 Jul;52(7):1756-60. PMID: 12829643 [PubMed – indexed
for MEDLINE] Accessed February 20, 2008.
14. van Dijk M, Bannink EM, van Pareren YK, Mulder PG, Hokken-Koelega AC. Risk factors for
diabetes mellitus type 2 and metabolic syndrome are comparable for previously growth hormone-
treated you adults born small for gestational age (sga) and untreated short SGA controls. J Clin
Endocrinol Metab. 2007 Jan;92(1):160-5. Epub 2006 Oct 24. PMID: 17062774 [PubMed –
indexed for MEDLINE] Accessed February 23, 2008.