PREVIOUS ISSUES - OCTOBER 2003
October 2003 Volume 1 Issue 2
COURSE DIRECTORS
Edward E. Lawson, M.D.
Professor
Department of Pediatrics – Neonatology
The Johns Hopkins University School of Medicine
Christoph U. Lehmann, M.D.
Assistant Professor
Department of Pediatrics – Neonatology
The Johns Hopkins University School of Medicine
Lawrence M. Nogee, M.D.
Associate Professor
Department of Pediatrics – Neonatology
The Johns Hopkins University School of Medicine
Lorraine A. Harbold, R.N., M.S.
The Johns Hopkins Hospital;
NICU Education Center
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In this issue... Volume 1, Number 2

Welcome to eNeonatology, volume 1, number 2, a CE-accredited e-newsletter designed specifically for the NICU Health Care Professional.

To receive CE credit, read the newsletter that follows and then click here to go to the Post-Test.

Our focus this month is on the fetal origins of chronic diseases of adulthood, sometimes referred to as the “Barker Hypothesis.” David Barker was the first to widely publish evidence that intrauterine growth retardation was associated with an increased incidence of cardiovascular disease later in life. The hypothesis suggests that an adverse in-utero environment causes the developing fetus to make physiologic adaptations to maximize survival. After delivery and throughout life, these adaptations persist. The result is a physiology that is no longer suited for the environment, leading to disease states.

In the last decade, this life-course approach to chronic disease has become a “hot topic” at research forums around the world. As neonatal health care professionals, we are in a unique position to identify and study intrauterine growth-retarded infants. As our understanding in this area increases, we will be able to more effectively counsel parents and primary care providers about the potential increased health risks for these infants.

Several recently published papers suggest that intrauterine growth retardation has long-term health consequences. The most active research has been in investigating the epidemiologic associations between fetal growth and the development of cardiovascular disease and diabetes later in life:
Reviews
Anusha H. Hemachandra, MD, MPH

Commentary
Jane McGowan, MD
Commentary
Our guest editor opinion
SWEDEN: BIRTH WEIGHT AS A PREDICTOR OF SYSTOLIC HYPERTENSION?
PHILLIPINES: BIRTH THINNESS AS A PREDICTOR OF HYPERTENSION?
USA: BIRTH WEIGHT AS A PREDICTOR OF GESTATIONAL DIABETES?
FINLAND: BIRTH THINNESS AS A PREDICTOR OF INSULIN RESISTANCE?
FINLAND: BIRTH SIZE AS A PREDICTOR OF SERUM CORTISOL?
UK: BIRTHWEIGHT AS A PREDICTOR OF CAROTID ATHEROSCLEROSIS?
Guest Editors of the Month
Jane McGowan, MD
Associate Professor of Pediatrics
The Johns Hopkins University School of
Baltimore, Maryland
Anusha H. Hemachandra, MD, MPH
Post Doctoral Fellow
John’s Hopkins Children’s Center
Baltimore, Maryland

Guest Faculty Disclosures

Anusha H. Hemachandra, MD, MPH
Faculty Disclosure: No relationship with commercial supporters

Jane McGowan, MD
Faculty Disclosure: No relationship with commercial supporters

Unlabelled/Unapproved Uses

No faculty member has indicated that their presentation will include information on off label products.
COMMENTARY
Since 1986, when Barker and Osmond first proposed that low birth weight (LBW) was associated with increased cardiovascular morbidity in adulthood, investigators have investigated both human populations and animal models in an effort to confirm and expand upon the so-called “Barker hypothesis”. In spite of numerous studies involving thousands of subjects, controversy still exists regarding the validity of the concept. Population studies have confirmed differences in blood pressure between the lowest birth weight members and the rest of the population, but the absolute differences are small (<5mmHg on average) and appear physiologically insignificant(1). On the other hand, the incidence of clinical hypertension has been noted to be significantly higher in LBW adults. Similarly, results in animal models are contradictory: some studies have reported a significant increase in hypertension in adults subjected to fetal growth restriction(2), while others found no differences in blood pressure(3).

The source of the controversy most likely involves the heterogeneity of the underlying causes of low birth weight and cardiovascular disease. However, that heterogeneity is also likely to be the key to determining the mechanisms underlying the clinical observations of the past 17 years. It seems unlikely that maternal malnutrition, placental insufficiency, and constitutional small stature would have the same effects on both fetal and postnatal physiology. Rather, fetuses exposed to each of these factors would be predicted to respond in a specific manner, with each response associated with a different adult outcome. Unfortunately, such heterogeneity tends to be lost in large population studies, at least with regard to determining mean differences among weight cohorts within a population. Investigators might benefit from determining variance from the “norm” for each LBW subject and comparing the characteristics of LBW individuals who have the largest variance with those LBW individuals who demonstrate little or know difference compared to normal birth weight subjects. The results of such comparisons could elucidate potential mechanisms to explain the clinical observations. Other potential contributors to heterogeneity within the LBW cohort that have generally not been investigated include the presence of maternal risk factors, e.g., smoking, and the prenatal or childhood environment, each of which may interact with physiologic status in the pathogenesis of cardiovascular disease. The paucity of prospective studies designed to follow individuals from birth into adulthood also limits our ability to confirm previous results. While completion of such a study is, admittedly, a Herculean undertaking, it remains the true test of the Barker hypothesis.

References
1. Huxley R, Neil A, Collins R. Unravelling the fetal origins hypothesis: is there really an inverse association between birthweight and subsequent blood pressure? Lancet 2002; 360:659-65.

2. Alexander BT. Placental insufficiency leads to development of hypertension in growth-restricted offspring. Hypertension 2003; 41:457-62.

3. Jansson T, Lambert GW. Effect of intrauterine growth restriction on blood pressure, glucose tolerance and sympathetic nervous system activity in the rat at 3-4 months of age. J Hypertens 1999; 17:1239-48.
SWEDEN: BIRTH WEIGHT AS A PREDICTOR OF SYSTOLIC HYPERTENSION? 
Leon DA, Johansson M, Rasmussen F. Gestational age and fetal mass are inversely associated with systolic blood pressure in young adults: An epidemiologic study of 165,136 Swedish men aged 18 years.

Of the many studies on intrauterine growth retardation and increased blood pressure later in life, Leon et al. published data on the largest cohort studied to date.

By linking records from the Swedish Medical Birth Registry and the Military Conscription Register, investigators identified 165,136 men born between 1973 and 1976 who were conscripted into the military between 1990 and 1996. The birth registry includes 99% of all children born in Sweden, and includes data on birth weight, length, and gestational age (measured in days from the last menstrual period). The military conscription exam is compulsory at age 18. During this exam blood pressure, height, and weight are measured. The analysis was restricted to men born between 35 and 44 completed gestational weeks, which comprised 95% of the available data.
Systolic blood pressure at age 18 years was independently associated with birth weight for gestational age. A 1 kg decrease in birth weight was associated with a 1.47 mmHg increase in systolic blood pressure (95% CI 1.37-1.57). When the study sample was divided into quintiles by birth weight for gestational age, the lowest quintile had a mean increase in systolic blood pressure of 1.61 mmHg over the highest birthweight/gestational age quintile (95% CI 1.40-1.81). In addition, gestational age was independently associated with blood pressure at 18 years, with each 1 week increase in gestational age decreasing systolic blood pressure by 0.25 mmHg (95% CI 0.29-0.22).
The absolute size of the blood pressure effects reported in this study are small; however, with the amplification of blood pressure over the life course, a small increase in blood pressure at age 18 may be clinically significant later in life. The authors concluded that these data are consistent with the fetal programming hypothesis.
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PHILLIPINES: BIRTH THINNESS AS A PREDICTOR OF HYPERTENSION?
Adair LS, Cole TJ. Rapid child growth raises blood pressure in adolescent boys who were thin at birth. Hypertension. 2003;41:451-456.

Adair and Cole investigated the interaction between prenatal and postnatal environments by studying the effect of “catch-up growth” on blood pressure.
Data were collected from the Cebu Longitudinal Health and Nutrition Survey. This community-based survey followed up a birth cohort of 3080 infants born between 1983 and 1984 in Cebu, Phillipines. They were followed from birth until 2 years of age, and at 8 years, 11 years, and 15-16 years of age. From this cohort, 2026 adolescents were included in the latest follow-up survey (1998). At each visit, detailed anthropometric measurements were taken. At the age 15-16 visit, blood pressure measurements were done.

After controlling for birth length, current body mass index, age and height, the odds of high blood pressure in males were significantly decreased with each kilogram increase in birth weight (OR 0.53; 95%CI 0.29-0.94; p<.05). The highest odds of elevated blood pressure occurred among males who were relatively thin at birth but relatively heavy as adolescents (OR 2.25; 95% CI 1.03-4.89; p<.05). When the timing of this weight gain was examined, boys who gained weight rapidly between birth and 2 years had a slightly decreased odds of increased blood pressure at age 16 years (OR 0.80, 95%CI 0.65-0.98, p<.05) than those who gained weight rapidly between 8 and 11 years or 11 and 15 years (OR 1.12 and 1.10 respectively, 95%CI 1.04-1.20 and 1.05-1.15 respectively, both p<.01). There were no consistent significant associations identified for girls.

The fact that birth weight was significantly associated with high blood pressure only after controlling for birth length suggests that it is thinness at birth, rather than birth weight, that predicts raised blood pressure later in life. Additionally, the rate and the timing of weight gain in childhood modifies this risk in boys.
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USA: BIRTH WEIGHT AS A PREDICTOR OF GESTATIONAL DIABETES?
Innes KE, Byers TE, Marshall JA, Baron A, Orleans M, Hamman RF. Association of a woman’s own birthweight with subsequent risk for gestational diabetes. JAMA. 2002;287:2534-2541.

Innes et al. demonstrated that low birth weight, more than high birth weight, predisposes women to develop gestational diabetes as young adults.
Data for this case-control study were obtained from the New York State Department of Health Live Birth Registry, as well as hospital discharge records. Women who delivered a liveborn infant during a first pregnancy in upstate New York between 1994 and 1998, and were born in New York state, were eligible. Women with pre-existing diabetes, heart disease, hypertension, renal disease, any other chronic condition requiring monitoring, as well as pregnancy-induced hypertension, were excluded. Cases were defined as eligible women with a diagnosis of gestational diabetes mellitus (GDM) on their infant’s birth certificate or their own hospital discharge record. Using these criteria, 440 cases were identified. Controls were defined as all remaining eligible subjects (n=22,955).

Data collected included maternal age, multifetal gestation, parental education levels at the time of the woman’s birth, complications of the pregnancy of the woman’s mother, race, marital status, educational level, employment, participation in welfare programs, onset of prenatal care, alcohol and tobacco use during pregnancy, pre-pregnancy BMI, and pregnancy weight gain.

Using multiple logistic regression, the investigators evaluated trends in the effects of birth weight, gestational age, and other explanatory variables on the risk for developing gestational diabetes. They found that birth weight showed a U-shaped relationship to a woman’s risk of GDM in her first pregnancy, with the highest risks associated with low and high birth weights. After adjustment for potential confounding variables, particularly pre-pregnancy body mass index and diabetes in the woman’s mother, the odds ratio for low birth weight was 4.23 (95% CI, 1.55-11.51), compared to 0.92 for high birth weight. Overall, there was a strong inverse dose-response relationship between birth weight and the risk of GDM (p<.001).

The authors demonstrated a strong inverse association between a woman’s own birth weight and her subsequent risk for gestational diabetes, independent of family history, body mass index, co-morbidities, or socioeconomic status.
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FINLAND: BIRTH THINNESS AS A PREDICTOR OF INSULIN RESISTANCE?
Eriksson JG, Forsen T, Tuomilheto J, Jaddoe VW, Osmond C, Barker DJ. Effects of size at birth and childhood growth on the insulin resistance syndrome in elderly individuals. Diabetologia. 2002;45:342-348.

Erikkson et al. measured insulin resistance as a marker of risk for the development of type II diabetes in adulthood after they previously reported an increased incidence of type II diabetes in subjects with fetal growth restriction.
A cohort of 7086 men and women born at Helsinki University Central Hospital in Finland between 1924 and 1933, who also went to school in the city, was identified. Of these eligible subjects, 674 people who were still living in the area in 2000 were invited to participate. After excluding subjects with type II diabetes controlled by medication, 176 men and 298 women were enrolled.
Participants underwent an oral glucose tolerance test with serum glucose, insulin and proinsulin levels, as well as serum cholesterol levels, blood pressure and anthropometric measurements. In addition, from the hospital records, data was collected on maternal height, weight, and body mass index, as well as neonatal weight, length, and ponderal index. Childhood height, weight, and ponderal index were collected from school records.

After adjusting for age, gender, and current body mass index, plasma insulin and proinsulin concentrations during the oral glucose challenge fell with increasing birthweight (p=0.02 and 0.03, respectively). There were similar trends with ponderal index at birth. When assessing growth in childhood, the authors found that with each age from 7 to 15 years, a lower body mass index was associated with a higher plasma insulin and proinsulin level during the glucose tolerance test. These associations were not changed with adjustment for birth weight or birth ponderal index.

Insulin resistance was found to be associated with thinness at birth, even after adjusting for adult body mass index. The study results may have been affected by predominance of women, as well as the possibility of preferential survival of subjects with a particular glucose-insulin profile. However, the authors argue that this study population is representative of the general elderly population in Finland.

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FINLAND: BIRTH SIZE AS A PREDICTOR OF SERUM CORTISOL?
Kajantie E, Phillips DI, Andersson S, Barker DJ, Dunkel L, Forsen T, Osmond C, Tuominen J, Wood PJ, Eriksson J. Size at birth, gestational age and cortisol secretion in adult life: Foetal programming of both hyper- and hypocortisolism. Clinical Endocrinology. 2002;57:635-641.

Intrauterine programming of the hypothalamus-pituitary-adrenal axis has been suggested to be a central mechanism linking intrauterine growth and adult cardiovascular disease and diabetes. To test this mechanism, these European investigators examined the relationship between size at birth and adult cortisol concentrations.
Study participants were recruited from a previous study cohort of 7086 singleton individuals born between 1924 and 1933 in Helsinki, Finland. At that time, birth weight, placental weight, and gestational age were recorded. A total of 646 randomly selected subjects born at 37 weeks gestation or above were invited to participate, and 421 agreed. Participants had fasting plasma cortisol and corticosteroid-binding globulin levels drawn, blood pressure measurements, and an oral glucose tolerance test. The subjects were ages 65-75 years at the time of examination.

The investigators reported a significant positive association between cortisol and ponderal index at birth (p=0.02 for men, p=0.04 for women). When this relationship was adjusted for gestational age, two patterns emerged: Among both men and women born before 39 weeks gestation, short length at birth predicted both higher total cortisol (p=.001) and higher free cortisol (p=.02), while among those born after 40 weeks gestation, low ponderal index was associated with both reduced total and free cortisol levels (p=.003 for both).

There was no significant correlation between fasting cortisol concentrations and birthweight in either men or women. However, among subjects born before 39 weeks gestation, a 1 kg increase in birthweight was associated with an 80 nmol/l decrease in fasting cortisol (95% CI: 12-148 nmol/l; p=0.02). By contrast, in those born after 40 weeks gestation, there was a positive association between birthweight and cortisol levels, but this was not statistically significant.

This study confirms previous findings that size at birth is linked to serum cortisol concentrations in adult life, and it suggests two distinct patterns of fetal growth are associated with altered hypothalamus-pituitary adrenal axis function in adult life.
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UK: BIRTHWEIGHT AS A PREDICTOR OF CAROTID ATHEROSCLEROSIS?
Martyn CN, Gale CR, Jespersen S, Sherriff SB. Impaired fetal growth and atherosclerosis of carotid and peripheral arteries. Lancet. 1998;352:173-178.

Martyn et al. hypothesized that atherosclerotic plaque formation was the underlying link between fetal growth and cardiovascular disease later in life.
Using detailed birth records at Jessop Hospital in England, the researchers traced 829 surviving subjects born between 1922 and 1926. After obtaining permission from private physicians, 395 subjects were invited to participate; 322 subjects agreed to a health questionnaire and blood pressure measurements, and of these, 186 consented to a physical examination, electrocardiogram, serum cholesterol measurements, and duplex ultrasonography of the carotid arteries.

Participants were grouped into three birthweight categories: Under 6.5 lbs., between 6.5 and 7.5 lbs., and over 7.5 lbs. The lowest birthweight group had a higher mean total cholesterol level (p=0.038). There were no associations between birthweight and adult body mass index, serum fibrinogen or HDL cholesterol levels, smoking, or social class.

Results from the duplex ultrasonography of the carotid arteries were divided into four categories: No carotid stenosis, less than 30% stenosis, between 31-50% stenosis, and more than 50% stenosis. Mean birthweight was highest in participants with no narrowing of the carotids, and it trended downward as the degree of stenosis increased (p<0.001). Participants who weighed less than 6.5 lbs. at birth were 5.5 times more likely to have carotid stenosis than those who weighed more than 7.5 lbs. at birth (95%CI 2.4-12.4). There was no association between degree of stenosis in adulthood and length at birth, abdominal circumference at birth, or placental weight.

The authors demonstrated a relationship between poor fetal growth and atherosclerotic narrowing of the carotid arteries at age 66-71 years. This association was independent of gestational age at birth, and was strengthened by the exclusion of infants less than 37 weeks gestation, suggesting that intrauterine growth retardation, rather than prematurity, was the predisposing factor.
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This activity has been developed for Neonatologists, NICU Nurses and Respiratory Therapists working with Neonatal patients. There are no fees or prerequisites for this activity.
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The Johns Hopkins University School of Medicine and The Institute for Johns Hopkins Nursing take responsibility for the content, quality, and scientific integrity of this CE activity. At the conclusion of this activity, participants should be able to:
Evaluate the research presented as to how it supports/refutes/modifies the "Barker Hypothesis";
Determine if the current research warrants counseling parents about the cardiovascular and other risk factors LBW may portend;
Use your increased awareness of Barker Hypothesis to provide more optimal neonatal care.
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Anusha H. Hemachandra, MD, MPH
Faculty Disclosure: No relationship with commercial supporters

Jane McGowan, MD
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No faculty member has indicated that their presentation will include information on off label products.
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