In Utero Programming — Birthweight and Future Health
Special Feature
In Utero Programming—Birthweight and Future Health
By Steven G. Gabbe, MD
Obstetricians have long been concerned about the implications of abnormal fetal growth as related to complications during labor and delivery and in the immediate neonatal period. Intrauterine growth restriction, commonly defined as a birthweight below the 10th percentile, has been associated with a higher risk for nonreassuring fetal heart rate patterns during labor and neonatal complications including meconium aspiration, hypoglycemia, and hyperviscosity. Investigators have recently begun to explore the long-term consequences of abnormal growth in utero as a cause for cardiovascular disease and diabetes mellitus later in life.
Dr. David Barker, an epidemiologist from Southampton, England, first proposed that intrauterine conditions could program the development of the cardiovascular system later in life—the so-called Barker hypothesis.1 Barker and colleagues took advantage of meticulous birth records maintained in several areas of England and Wales. They observed that those areas in which infant mortality was highest in 1901-1910 correlated with areas in which there was also an increased risk for coronary artery disease in men aged 35-74 during the 1960s and 1970s.2 They realized that the infant mortality would be highest in low birthweight infants and proposed that low birthweight survivors might be at greater risk for coronary artery disease. Examining birth records, which included not only the infant’s birthweight but its birth length, abdominal and head circumference measurements, and placental weight, Barker et al found that infants with a birthweight less than 5.5 pounds had a three-fold increase in death due to coronary artery disease later in life.2 The risks for stroke and hypertension were also greater. The infants at greatest risk were those who were not only low birthweight but had a smaller head circumference, were shorter, and had an increased placenta/birthweight ratio.
Martyn and colleagues studied singleton babies born in Sheffield, England, between 1922-1926.3 They were able to perform follow-up studies including ultrasonic examination of the carotid arteries and measurements of the ankle-brachial pressure index to assess atherosclerosis in the arteries of the lower limb. They found that the risk of carotid stenosis was more than five times increased for individuals who weighed 6.5 pounds or less at birth than for those who weighed more than 7.5 pounds, after adjusting for cardiovascular risk factors and gestational age at birth. The presence of atherosclerotic disease in the lower limbs was highest in individuals with the lowest recorded birthweights, but this relationship was not significant. These observations support other studies demonstrating an increased risk of hypertension, increased cholesterol and fibrinogen, and impaired glucose tolerance in low birthweight infants. Martyn et al suggest that fetal adaptations in utero may increase the risk of atherosclerotic disease. For example, it is well known that the growth-restricted fetus responds to decreased nutrient flow from its mother by increasing perfusion in the cerebral circulation. Perhaps this change in blood flow leads to a greater risk for atherosclerosis in these vessels later in life.
Why should the low birthweight infant be at greater risk for type 2 diabetes mellitus decades after birth? Insulin is the most important fetal growth hormone. The growth restricted fetus is known to have a reduced level of insulin that may be due to fewer pancreatic b cells.4 It might be that these abnormalities in insulin secretion and insulin action persist into adult life. Plante and colleagues recently reported that women who were below the 10th percentile at birth had a 3.6-fold increased risk of a pregnancy complicated by diabetes mellitus at age 20-22.5 It could also be that the fetus grows poorly because it has a genetic insulin resistance that is manifested in the adult as type 2 diabetes mellitus.6 Phillips, working with Barker et al, has demonstrated that the morning fasting plasma cortisol concentration in men who weighed less than 5.5 pounds at birth is 25% higher than the cortisol level in men who weighed more than 9.5 pounds at birth.7 These elevated cortisol concentrations were related to a higher systolic blood pressure and a higher fasting and two-hour plasma glucose concentration. Phillips has proposed that alterations in the fetal hypothalamic-pituitary-adrenal axis in response to intrauterine stress may be associated with insulin resistance and type 2 diabetes later in life.
Recently, two studies have examined long-term neurologic function in the poorly grown fetus. Martyn et al performed intelligence testing on English men and women born in the same towns studied by Barker et al.8 This study of more than 1500 people between 48 and 74 years of age revealed no relationship between body size or proportions at birth and intelligence or cognitive decline in adult life. Martyn et al hypothesized that fetal adaptation in utero appears to be successful in maintaining normal brain development. However, in a recent study of Dutch men born in urban areas during the German Army blockade of food supplies to the Netherlands, psychiatric examinations at the time of military induction revealed that men exposed prenatally to severe maternal nutritional deficiency during the first and/or second trimesters had a significantly increased risk for antisocial personality disorders, which included aggression, unlawful behavior, and disregard for the truth.9 The prevalence of antisocial personality disorder in fetuses not subjected to severe prenatal nutritional deficiency was 11.1/10,000 but rose to more than 20/10,000 in men whose mothers were nutritionally deprived. Severe nutritional deficiency was defined as a caloric intake of less than 1000-1500 kcal. Recognizing that many social factors could contribute to their findings, Neugebauer and associates propose that nutritional deficiency early in pregnancy may increase fetal susceptibility to obstetric insults.
In utero programming is an exciting new area of research. Barker et al’s unique observation, that low birthweight is associated with an increased risk of cardiovascular disease, has been confirmed in studies in many other countries including Finland, Chile, India, and Sweden. As obstetricians, whenever possible, we should recognize those factors that may impair fetal growth prior to pregnancy, counsel our patients about the associated risks, and make every effort, in cooperation with the patient, to lessen their effect. This effort should include a discussion of the patient’s nutrition as well as smoking, substance abuse, and alcohol consumption.
References
1. Nathanielsz PW. Life in the Womb: The Origin of Health and Disease. Ithaca, NY: Promethean Press; 1999:59-69.
2. Barker DJ, et al. Lancet 1986;1:1077-1081.
3. Martyn CN, et al. Lancet 1998;352:173-178.
4. Van Assche FA, et al. J Perinat Med 1998;26:337-346.
5. Plante LA, et al. Obstet Gynecol 1998;92:781-784.
6. Hattersley AT, et al. Lancet 1999;353:1789-1792.
7. Phillips DI. Diabetes Care 1998;21(Suppl 2): B150-155.
8. Martyn CN, et al. BMJ 1996;312:1393-1396.
9. Neugebauer R, et al. JAMA 1999;282:455-462.
Which of the following illnesses is increased in adults who were low birthweight infants?
a. Coronary artery disease
b. Type 1 diabetes
c. Impaired cognitive performance
d. Epilepsy
e. Asthma
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