Birth Weight Is Inversely Correlated to Adult Systolic Blood
Pressure and Pulse Pressure in Type 1 Diabetes
Johan Fagerudd, Carol Forsblom, Kim Pettersson-Fernholm, Markku Saraheimo, Johan Wadén,
Mats Rönnback, Milla Rosengård-Bärlund, Clas-Göran af Björkesten, Lena Thorn, Maija Wessman,
Per-Henrik Groop, on behalf of the FinnDiane Study Group
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
Abstract—In the general population, there is an inverse relationship between birth weight and adult systolic blood pressure.
Because blood pressure in diabetic patients at least in part seems to be regulated by different mechanisms than in
nondiabetic subjects, it is not known whether a similar correlation exists in diabetic individuals. Therefore, we obtained
data on birth weight from original birth certificates in 1543 type 1 diabetic patients. Blood pressure was measured
auscultatorily on a single occasion. In the 1225 patients born at term (after 37 weeks of gestation), the age- and
sex-adjusted regression coefficients between systolic blood pressure and birth weight was ⫺1.90 mm Hg/kg (95%
confidence interval [CI], ⫺3.71 to ⫺0.09). The finding remained unchanged after adjustment for body mass index,
current smoking, duration of diabetes, social class, antihypertensive therapy, glomerular filtration rate, glycemic control,
and elevated albuminuria. The regression coefficient between birth weight and pulse pressure was of a similar
magnitude. The age-adjusted regression coefficient between systolic blood pressure and birth weight seemed stronger
in females (⫺3.34 mm Hg/kg; 95% CI, ⫺6.06 to ⫺0.62) than in males (⫺0.42 mm Hg/kg; 95% CI, ⫺2.80 to 1.95),
although this difference was not statistically significant. As a new finding, we report an inverse relationship between
weight at birth and systolic blood pressure and pulse pressure in adult type 1 diabetic patients. Given the deleterious
effects of elevated arterial blood pressure in diabetes, the impact of intrauterine growth retardation on the development
of end-organ damage needs to be clarified. (Hypertension. 2004;44:832-837.)
Key Words: diabetes mellitus 䡲 blood pressure 䡲 epidemiology
S
alterations associated with type 1 diabetes. In animal models
of type 1 diabetes, the onset of hyperglycemia causes an
increase in arterial blood pressure.10 Furthermore, in humans,
combined kidney/pancreas transplantations have been found
to cause a dramatic decrease in blood pressure compared with
isolated kidney transplantations, a finding that underscores
the importance of the diabetic state in the pathogenesis of
hypertension in type 1 diabetes.11 In support of diabetesspecific effects on blood pressure occurring even in the
absence of renal complications in type 1 diabetes, we have
recently reported a premature age-induced increase in pulse
pressure in type 1 diabetic patients compared with nondiabetic subjects.12 Therefore, even in the absence of diabetic
kidney disease, the mechanisms and patterns of blood pressure derangements seem to differ between subjects with type
1 diabetes when compared with nondiabetic subjects.
Epidemiological studies in the general population have
consistently reported an inverse relationship between birth
weight and systolic blood pressure later in life.4 Because the
pathogenetic mechanisms of elevated blood pressure may be
mall size at birth has been linked to an increased
morbidity in adult life. For instance, individuals with low
birth weight have been found to be at increased risk for
cardiovascular disease, diabetes, renal disease, and elevated
blood pressure.1– 4 It has been postulated that the elevated
blood pressure observed in individuals with low birth weight
could be a result of the intrauterine environment: malnutrition
during the fetal period could cause permanent changes in the
organs involved in blood pressure regulation.5 Alternatively,
the relation between low birth weight and blood pressure
could result from common underlying genetic factors influencing both parameters.6 Recent studies in monozygotic and
dizygotic twin pairs have reported evidence in support of the
latter view.7,8
Elevated blood pressure is a common feature of type 2
diabetes, whereas diabetes-specific blood pressure derangements in type 1 diabetic patients generally have been thought
of as isolated to the subgroup of patients with diabetic kidney
disease.9 However, more recently, emphasis has been put on
the effects of blood pressure induced by the metabolic
Received June 9, 2004; first decision June 28, 2004; revision accepted August 3, 2004.
From Folkhälsan Institute of Genetics (J.F., C.F., K.P.-F., M.S., J.W., M.R., M.R.-B., C.-G.B., L.T., M.W., P.-H.G.), Folkhälsan Research Center;
Department of Clinical Chemistry (M.W.); The Finnish Genome Center (M.W.), University of Helsinki; and Department of Medicine (J.F., C.F., K.P.-F.,
M.S., J.W., M.R., M.R.-B., C.-G.B., L.T., M.W., P.-H.G.), Division of Nephrology, Helsinki University Central Hospital, Helsinki, Finland.
Correspondence to Per-Henrik Groop, MD, DMSc, Folkhälsan Research Center, Biomedicum Helsinki (C318b), PO Box 63, FIN-00014 University
of Helsinki, Finland. E-mail [email protected]
© 2004 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.1161/01.HYP.0000147272.10646.e6
832
Fagerudd et al
Birth Weight and Blood Pressure in Type 1 Diabetes
different in diabetic subjects, the inverse relationship between
birth weight and blood pressure found in the general population cannot be directly extrapolated to diabetic subjects. We
are not aware of any previous studies addressing the issue
specifically in type 1 diabetic patients; therefore, the aim of
the present study was to assess the relationship between birth
weight and blood pressure in a large sample of type 1 diabetic
patients.
Methods
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
The Finnish Diabetic Nephropathy (FinnDiane) study is a nationwide, prospective, multicenter study that was initiated in November
1997. The patients are recruited from 20 university and central
hospitals, from 23 local hospitals, and from 16 primary health care
centers. The study protocol is in accordance with the Declaration of
Helsinki and it has been approved by the local ethics committee in
each participating study center.
The present study presents cross-sectional data from the baseline
visit. All patients with a diagnosis of type 1 diabetes (code E10 in
International Classification of Diseases, 10th version) attending the
diabetic and renal outpatient clinics and dialysis units were consecutively asked to participate. Before participation, all patients gave
their written informed consent and the response rate was 78%. Based
on medical records, the attending local physician completed a study
form assessing diabetic microvascular and macrovascular late complications. The patients were asked to complete a questionnaire
dealing with place of birth, smoking habits, alcohol intake, and social
class.
The degree of renal involvement was classified in the coordinating
center using all available data on albuminuria drawn from local
medical records. Diabetic nephropathy was defined as a urinary
albumin excretion rate (UAER) exceeding 200 ␮g/min (overnight
collections) or 300 mg/24 hours (24-hour urine collections), or as a
urinary albumin/creatinine ratio in a spot sample exceeding 35
mg/mmol (male) or 25 mg/mmol (female), in 2 out of 3 consecutive
measurements. The corresponding cutoff values for microalbuminuria were 20 to 200 ␮g/min or 30 to 300 mg/24 hours for UAER, and
3.5 to 35 mg/mmol (male) or 2.5 to 25 mg/mmol (female) for urinary
albumin/creatinine ratio. Two UAER measurements within the
normal range were required for the classification of a patient as
normoalbuminuric. The degree of renal involvement was considered
to be unclassifiable if there were insufficient data on UAER, or if
elevated UAER of an origin other than diabetes (pregnancy, nondiabetic kidney disease, duration of diabetes ⬍3 years) was clinically
suspected. The classification was based on historic data in cases in
which UAER had decreased as a result of intervention (antihypertensive therapy).
For this study, all 3115 patients with an age at onset of diabetes
younger than 36 years, who had had insulin therapy initiated within
1 year after diagnosis, and who were studied by October 31, 2002
were selected. Of the 2313 patients who reported birth at a hospital,
we were able to identify the birth hospital of 1956 patients. After
exclusion of 23 twin pregnancies, the original birth certificate with
data on birth weight was obtained for 1543 patients. Of these, 1506
had data on birth height, whereas 1433 had data on gestational age
(calculated from the last menstruation before pregnancy).
Measurements
Blood pressure measurements were performed by a trained nurse at
the outpatient clinic. The measurement was performed auscultatorily
on the right arm with a calibrated mercury sphygmomanometer with
the subject in sitting position after 5 to 10 minutes of rest. Systolic
(Korotkoff I) and diastolic blood pressures (Korotkoff V) were
recorded to the closest 2 mm Hg, and the mean value of 2 recordings
was used in the analysis.
Laboratory Assays
Serum creatinine concentration (normal reference values: male
⬍115 ␮mol/L, female ⬍100 ␮mol/L) was measured with a kinetic
833
Jaffé reaction. Glomerular filtration rate (GFR) was calculated with
the Cockroft–Gault formula13 ([140⫺age [years])⫻weight [kg]]/
[0.815⫻serum creatinine (␮mol/L)]⫻0.85 in women), both corrected for body surface area.14 Data on HbA1c and albuminuria were
drawn from local medical records.
Statistics
All analyses were performed using the SPSS 11.5 statistical package.
The significance of differences in categorical variables was assessed
with the ␹2 test, whereas continuous variables were analyzed with
ANOVA (normally distributed) or the Mann–Whitney test (nonnormally distributed). The correlation between birth weight and
blood pressure variables was assessed with linear regression analysis. The effect of potential confounding factors was assessed by
entering them into a statistical model one by one. Because of
previous results reporting evidence for a sex-specific effect of birth
weight in type 1 diabetes,3 and to control for the potentially
confounding effect of gestational age, stratified analyses were
performed in predefined subgroups (males versus females; preterm
versus full-term delivery). The significance of a sex-specific effect
on blood pressure was formally tested by adding an interaction term
(birth weight multiplied by sex) to the regression model consisting of
birth weight, age, and sex. P⬍0.05 was considered statistically
significant.
Results
The clinical characteristics of the studied patients are presented in Table 1. Of the 3115 type 1 diabetic patients, data on
birth weight were available in half of the patients. As
expected, birth data were more readily available in younger
patients. In addition, compared with patients without data on
birth weight, a higher frequency of the studied patients were
females, they had shorter duration of diabetes, and had less
microvascular and macrovascular complications. The patients
studied also had lower systolic blood pressure, whereas no
difference was found in diastolic blood pressure.
In a linear regression analysis adjusted for current age and
sex, the regression coefficient between systolic blood pressure and birth weight was ⫺0.96 mm Hg/kg (95% confidence
interval [CI] ⫺2.54 to 0.63). This coefficient remained
largely unchanged after further adjustments for body mass
index (BMI), current smoking, duration of diabetes, social
class, antihypertensive therapy, glomerular filtration rate,
glycemic control, and elevated urinary albumin excretion
rate. The slope between birth weight and pulse pressure was
of similar magnitude (data not shown).
When the analysis was restricted to the 1225 patients born
at term (after 37 weeks of gestation), the age- and sexadjusted regression coefficients between systolic blood pressure and birth weight was ⫺1.90 mm Hg/kg (95% CI, ⫺3.71
to ⫺0.09). Further adjustments for the aforementioned potential confounding factors strengthened this correlation slightly
(regression coefficient ⫺2.37 mm Hg/kg; 95% CI, ⫺4.08 to
⫺0.65). The patients born at term were comparable to
patients born preterm regarding current age, duration of
diabetes, gender distribution, glycemic control, BMI, blood
pressure levels, smoking habits, and social class (data not
shown).
The regression coefficients between birth weight and adult
blood pressure variables varied substantially between females
and males (Tables 2 and 3). In females, significant negative
correlations between birth weight and systolic blood pressure
and pulse pressure were found. Birth weight was also nega-
834
Hypertension
December 2004
TABLE 1. Characteristics of the Studied Patients in Comparison With Patients
Without Data on Birth Weight
Variable
Birth Weight Data
Available
Birth Weight Data
Not Available
1543
1572
49
55
No.
Males, %
P
0.001
Age, y
32.8⫾9.6
42.3⫾11.5
⬍0.001
Age at onset, y
13.9⫾7.9
16.4⫾8.9
⬍0.001
25.9⫾11.9
⬍0.001
Diabetes duration, y
19.0⫾10.6
Height, cm
170.7⫾9.3
170.6⫾9.4
NS
2
24.9⫾3.5
25.1⫾3.5
NS
BMI, kg/m
Current smokers, %
25
23
NS
Antihypertensive therapy, %
34
50
⬍0.001
Blue collar workers, %
53
63
⬍0.001
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
HbA1c, %
8.5⫾1.6
8.5⫾1.5
NS
Systolic blood pressure, mm Hg
131⫾17
138⫾20
⬍0.001
Diastolic blood pressure, mm Hg
80⫾10
80⫾10
NS
Mean arterial blood pressure, mm Hg
97⫾10
99⫾10
⬍0.001
Pulse pressure, mm Hg
51⫾14
58⫾17
⬍0.001
Elevated albuminuria, %
32
41
⬍0.001
5
12
⬍0.001
95⫾32
87⫾31
⬍0.001
31
47
⬍0.001
5
14
⬍0.001
End-stage renal disease, %
Glomerular filtration rate, mL/min per 1.73 m2*
History of laser treatment, %
History of macrovascular disease, %
Birth weight, g
3512⫾526
—
NA
Birth height, cm
50.4⫾2.1
—
NA
Gestational age, d
277⫾14
—
NA
Data are proportion or mean⫾SD.
NS indicates not significant; NA, not assessed.
*Patients with end-stage renal disease excluded (n⫽269).
tively correlated with mean arterial blood pressure, but was
not related to diastolic blood pressure. In females born at term
and after adjustment for possible confounding factors, a 1-kg
decrease in birth weight was associated with a 3- to 4-mm Hg
TABLE 2.
increase in both systolic blood pressure and pulse pressure in
adulthood. The correlation between birth weight and adult
blood pressure was substantially weaker in males. However,
irrespective of the blood pressure variable (systolic blood
Regression Coefficients Between Birth Weight and Blood Pressure in Females
Systolic BP
Regression Coefficients Adjusted for
All females
(n⫽732)
Diastolic BP
Mean BP
Pulse Pressure
Females Born
Females Born
Females Born
Females Born
at Term
All Females
at Term
All Females
at Term
All Females
at Term
(n⫽633)
(n⫽732)
(n⫽633)
(n⫽732)
(n⫽633)
(n⫽732)
(n⫽633)
Model 1: Age
⫺1.74
⫺3.34*
0.03
⫺0.48
⫺0.56
⫺1.43
⫺1.76
⫺2.86†
Model 2: Model 1⫹BMI
⫺2.04
⫺3.75†
⫺0.14
⫺0.69
⫺0.77
⫺1.71
⫺1.91*
⫺3.05†
Model 3: Model 2⫹current smoking
⫺2.07
⫺3.83†
⫺0.14
⫺0.72
⫺0.78
⫺1.76*
⫺1.92*
⫺3.10†
Model 4: Model 3⫹duration of diabetes
⫺2.40*
⫺4.27†
⫺0.19
⫺0.79
⫺0.93
⫺1.95*
⫺2.21*
⫺3.49‡
Model 5: Model 4⫹social class
⫺2.34*
⫺4.23†
⫺0.14
⫺0.75
⫺0.88
⫺1.91*
⫺2.20*
⫺3.49‡
Model 6: Model 5⫹antihypertensive therapy
⫺2.04
⫺4.01†
0.00
⫺0.63
⫺0.67
⫺1.76*
⫺2.04*
⫺3.38‡
Model 7: Model 6⫹GFR
⫺2.00
⫺3.97†
0.02
⫺0.62
⫺0.65
⫺1.74*
⫺2.01*
⫺3.35‡
Model 8: Model 7⫹HbA1c
⫺2.12
⫺4.14‡
⫺0.08
⫺0.76
⫺0.76
⫺1.88*
⫺2.04*
⫺3.38‡
Model 9: Model 8⫹elevated albuminuria
⫺2.42*
⫺4.34‡
⫺0.21
⫺0.85
⫺0.95
⫺2.02*
⫺2.22*
⫺3.51‡
Model 10: Model 9⫹height
⫺2.36*
⫺4.39‡
⫺0.48
⫺1.24
⫺1.11
⫺2.29†
⫺1.89*
⫺3.16†
The data presented are based on females with complete data on all variables (52 females with missing data were excluded).
BP indicates blood pressure.
*P⬍0.05; †P⬍0.01; ‡P⬍0.001.
Fagerudd et al
TABLE 3.
Birth Weight and Blood Pressure in Type 1 Diabetes
835
Regression Coefficients Between Birth Weight and Blood Pressure in Males
Systolic BP
Diastolic BP
Mean BP
All Males
(n⫽703)
Males Born
at Term
(n⫽591)
All Males
(n⫽703)
Males Born
at Term
(n⫽591)⬍
All Males
(n⫽703)
Model 1: Age
⫺0.14
⫺0.42
0.36
0.38
0.20
Model 2: Model 1⫹BMI
⫺0.21
⫺0.48
0.27
0.30
Model 3: Model 2⫹current smoking
⫺0.21
⫺0.49
0.27
0.30
Model 4: Model 3⫹duration of diabetes
⫺0.17
⫺0.56
0.27
Model 5: Model 4⫹social class
⫺0.14
⫺0.51
Model 6: Model 5⫹antihypertensive therapy
⫺0.17
Model 7: Model 6⫹GFR
⫺0.13
Model 8: Model 7⫹HbA1c
Pulse Pressure
All Males
(n⫽703)
Males Born
at Term
(n⫽591)
0.12
⫺0.50
⫺0.81
0.11
0.04
⫺0.48
⫺0.79
0.11
0.04
⫺0.44
⫺0.79
0.31
0.12
0.02
⫺0.41
⫺0.87
0.26
0.31
0.20
0.04
⫺0.41
⫺0.82
⫺0.56
0.24
0.28
0.18
0.00
⫺0.38
⫺0.83
⫺0.56
0.25
0.27
0.12
0.00
⫺0.38
⫺0.82
⫺0.13
⫺0.54
0.24
0.31
0.12
0.02
⫺0.38
⫺0.85
Model 9: Model 8⫹elevated albuminuria
⫺0.05
⫺0.53
0.29
0.31
0.18
0.03
⫺0.34
⫺0.84
Model 10: Model 9⫹height
⫺0.35
⫺1.02
0.19
0.11
0.23
⫺0.27
⫺0.54
⫺1.13
Regression Coefficients Adjusted for
Males Born
at Term
(n⫽591)
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
The data presented are based on males with complete data on all variables (56 males with missing data were excluded). None of the regression coefficients reached
statistical significance.
pressure or pulse pressure) used as the dependent variable, the
interaction term of birth weight and sex did not reach
statistical significance (P⫽0.14 for both comparisons).
As depicted in the Figure, the age- and sex-adjusted
regression coefficient between birth weight and systolic
blood pressure was negative and of similar magnitude in
patients with normoalbuminuria, microalbuminuria, overt
diabetic nephropathy, and end-stage renal disease. However,
the regression coefficient failed to reach statistical significance in the patient groups with elevated UAER. The regression coefficient was ⫺2.77 mm Hg/kg (P⫽0.005) in patients
with normal renal function (GFR ⬎90 mL/min per 1.73 m2)
and ⫺2.40 (P⫽NS) in patients with mild renal dysfunction
(GFR 60 to 90 mL/min per 1.73 m2), whereas it was
⫹2.26 mm Hg/kg (P⫽NS) in patients with moderate to
severe renal dysfunction (GFR ⬍60 mL/min per 1.73 m2).
One-third of the studied patients received blood pressurelowering medication. The correlation between birth weight
and systolic blood pressure was slightly more pronounced in
The birth weight–systolic blood pressure regression coefficients
(adjusted for age and sex) in patients with different degrees of
albuminuria. Data are presented as regression coefficient and
95% CI. Patients whose degree of albuminuria was not classifiable (n⫽196) or who were born preterm (n⫽211) are not
included in the analysis. The 95% CI for patients with end-stage
renal disease is from ⫺18.9 to 10.7 mm Hg/kg.
those without antihypertensive therapy (regression coefficient
⫺1.52; 95% CI, ⫺3.06 to 0.26 mm Hg/kg; P⫽0.054) compared with those receiving treatment for hypertension
(⫺0.04; 95% CI, ⫺3.00 to 2.92 mm Hg/kg; P⫽NS). There
was no statistically significant differences between different
types of antihypertensive drugs (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, ␤-blockers,
calcium channel blockers or diuretics; data not shown).
Discussion
As a new finding, we report an inverse relationship between
birth weight and both systolic blood pressure and pulse
pressure in patients with type 1 diabetes.
In the general population, a 1-kg decrease in birth weight
has been found to increase systolic blood pressure by 2 to
4 mm Hg.4 The clinical importance of this finding remains to
be elucidated. To our knowledge, the present study is the first
to address the relation between factors operating in utero and
adult blood pressure specifically in individuals exposed to
type 1 diabetes. This is an important difference, because
individuals with diabetes are especially susceptible to blood
pressure-induced end-organ damage.15–17 Consequently, even
a small effect of birth weight on blood pressure may be
clinically relevant.
We have recently reported an earlier age-related increase in
systolic blood pressure and an earlier decrease in diastolic
blood pressure resulting in a premature increase in pulse
pressure in type 1 diabetic patients when compared with the
nondiabetic background population.12 Most interestingly, this
premature increase in pulse pressure was evident even in
patients without any signs of diabetic kidney disease. Similarly, several other lines of evidence have underlined the
importance of metabolic factors in the pathogenesis of hypertension in type 1 diabetes.10,11 Despite potential differences in the pathogenesis of elevated blood pressure, birth
weight seems to have a similar effect on adult blood pressure
in type 1 diabetes as in the general population. Interestingly,
in contrast with our findings, a recent study in Taiwanese type
2 diabetic school children revealed that those with a high
836
Hypertension
December 2004
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
birth weight were those who had the highest blood pressure at
the age of 6 to 18 years.18 We are not aware of any other
studies assessing the birth weight– blood pressure relationship
specifically in diabetic individuals. However, based on these
diverging results in type 1 and type 2 diabetes, the impact of
size at birth on blood pressure later in life may be modulated
by factors associated with the diabetic state itself.
In type 1 diabetic subjects susceptible to diabetic kidney
disease, blood pressure increases as renal injury progresses.19
However, although the regression coefficient was not significant within the subgroups, the inverse relationship between
birth weight and blood pressure seems to persist despite
considerable evidence of renal injury, either based on elevated albuminuria or on diminished glomerular filtration rate.
However, the inverse relationship was no longer evident in
patients with moderate to severe renal dysfunction.
In line with findings in the general population, birth weight
was related to systolic, but not to diastolic, blood pressure.
Sympathetic overactivity is thought to particularly influence
systolic blood pressure via mechanisms such as increased
cardiac output, reduced arterial compliance, and increased
arteriolar vasoconstriction, resulting in an enhanced reflection
of the arterial wave from the periphery. A recent study in
nondiabetic twins found that the inverse relationship between
birth weight and blood pressure to a large extent was
explained by increased sympathetic activity in patients with
low birth weight.8 Although not studied in diabetic patients,
effects on the sympathetic nervous system could offer an
explanation for the stronger effect of birth weight on the
pulsatile component of blood pressure.
A sex-stratified analysis revealed that the inverse correlation between birth weight and systolic blood pressure was
stronger in females, although the difference between females
and males did not reach statistical significance. Because
intrauterine growth retardation has been suggested to predispose not only to systemic hypertension but also to intraglomerular hypertension and progressive renal disease,20 it is
interesting that in the only study published thus far that deals
with the impact of low birth weight on development of
diabetic kidney disease in type 1 diabetes, the finding was
isolated to female patients.3 In the general population, although occasionally reported, no overall sex-specific difference in the birth weight– blood pressure relationship seems to
exist.21 Although the impact of size at birth on health in later
life may be stronger in female than in male type 1 diabetic
patients, this is still a mere hypothesis that urges further
testing before further conclusions can be drawn.
The impact of birth weight on adult blood pressure was
more pronounced in patients born at term. This could imply
that inappropriate intrauterine growth for a certain gestational
age, rather than the actual birth weight, is a stronger determinant of blood pressure in adulthood. Alternatively, the last
weeks of a pregnancy of normal duration may be required for
some pathological mechanisms to emerge. Recent results
speak in favor of the latter explanation as intrauterine growth
retardation was associated with endothelial dysfunction at 3
months of postnatal age only in children born at term, but not
in children born preterm.22 Beyond doubt, our data demonstrate that gestational age is a central variable in studies
assessing the impact of size at birth on blood pressure later in
life.
Our study has some limitations. We are aware that the
cross-sectional study design is susceptible to selection bias.
We may therefore have missed patients born small and,
according to the hypothesis, at higher risk for cardiovascular
morbidity and mortality. However, this would lead to an
underestimation rather than overestimation of the birth
weight– blood pressure relationship. Also, we did not have
birth data on the whole cohort, because the data were often
not available in older patients, for instance, those born before
the 1950s. Because the patients with birth data available were
younger, this may have contributed to the fact that they had
lower blood pressure, less antihypertensive medication, and
less microvascular and macrovascular complications. In the
older patients without birth data, especially those born during
and after World War II, birth weight was probably lower than
in the studied patients. Because both systolic blood pressure
and pulse pressure were higher in the proportion of patients
without birth data, it seems plausible to assume that the actual
impact of birth weight on blood pressure could be even
stronger than what we were able to observe.
We measured the blood pressure on one occasion, and the
use of repeated measurements or more sophisticated methods
would have resulted in a more precise estimation of the actual
blood pressure levels. Our methodology, however, is more
robust than the one used in many large-scale studies in the
general population, in which patient-reported blood pressure
levels have been used.23,24 One additional strength of our
study is that we had the opportunity to extract birth data
directly from original birth certificates instead of using
self-reported data.
Perspectives
Birth weight is inversely related to systolic blood pressure
and pulse pressure in adulthood in patients with type 1
diabetes. This association is especially pronounced in female
patients, in whom a 1-kg lower birth weight is associated with
a 3- to 4-mm Hg higher systolic blood pressure. Given the
deleterious effects of elevated arterial blood pressure in
diabetes, the impact of intrauterine growth retardation on the
development and progression of end-organ damage in diabetic subjects needs to be further evaluated.
Acknowledgments
This study would not have been possible without the assistance of the
whole Finnish Diabetic Nephropathy Study Group, previously presented in detail.25,26 Maija Rinne, Johan Groop, Maikki Parkkonen,
and Tarja Vesisenaho are especially acknowledged for their contributions. This work has been financially supported by The Folkhälsan
Research Foundation, Samfundet Folkhälsan, The Else och Wilhelm
Stockmann Foundation, The Liv och Hälsa Foundation, The Finnish
Medical Society, The Perklen Foundation, The K Albin Johansson
Foundation, The Finnish Association for Kidney Diseases, and the
European Commission (The Euragedic Study; Contract
QLG2-CT-2001-01669).
References
1. Barker DJ, Winter PD, Osmond C, Margetts B, Simmonds SJ. Weight in
infancy and death from ischaemic heart disease. Lancet. 1989;2:577–580.
Fagerudd et al
Birth Weight and Blood Pressure in Type 1 Diabetes
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
2. Eriksson JG, Forsen T, Tuomilehto J, Osmond C, Barker DJ. Early
adiposity rebound in childhood and risk of Type 2 diabetes in adult life.
Diabetologia. 2003;46:190 –194.
3. Rossing P, Tarnow L, Nielsen FS, Hansen BV, Brenner BM, Parving HH.
Low birth weight. A risk factor for development of diabetic nephropathy?
Diabetes. 1995;44:1405–1407.
4. Huxley RR, Shiell AW, Law CM. The role of size at birth and postnatal
catch-up growth in determining systolic blood pressure: a systematic
review of the literature. J Hypertens. 2000;18:815– 831.
5. Barker DJ. In utero programming of chronic disease. Clin Sci (Lond).
1998;95:115–128.
6. Hattersley AT, Tooke JE. The fetal insulin hypothesis: an alternative
explanation of the association of low birthweight with diabetes and
vascular disease. Lancet. 1999;353:1789 –1792.
7. Ijzerman RG, Stehouwer CD, Boomsma DI. Evidence for genetic factors
explaining the birth weight-blood pressure relation. Analysis in twins.
Hypertension. 2000;36:1008 –1012.
8. IJzerman RG, Stehouwer CD, de Geus EJ, van Weissenbruch MM,
Delemarre-van de Waal HA, Boomsma DI. Low birth weight is associated with increased sympathetic activity: dependence on genetic factors.
Circulation. 2003;108:566 –571.
9. Nørgaard K, Feldt-Rasmussen B, Borch-Johnsen K, Saelan H, Deckert T.
Prevalence of hypertension in type 1 (insulin-dependent) diabetes
mellitus. Diabetologia. 1990;33:407– 410.
10. Brands MW, Fitzgerald SM. Arterial pressure control at the onset of type
I diabetes: the role of nitric oxide and the renin-angiotensin system. Am J
Hypertens. 2001;14:126S–131S.
11. Elliott MD, Kapoor A, Parker MA, Kaufman DB, Bonow RO, Gheorghiade M. Improvement in hypertension in patients with diabetes
mellitus after kidney/pancreas transplantation. Circulation. 2001;104:
563–569.
12. Rönnback M, Fagerudd J, Forsblom C, Pettersson-Fernholm K, Reunanen
A, Groop P. Altered age-related blood pressure pattern in type 1 diabetes.
Circulation. 2004;110:1076 –1082.
13. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum
creatinine. Nephron. 1976;16:31– 41.
14. DuBois D, DuBois EF. A formula to estimate the approximate surface
area if height and weight are known. Arch Intern Med. 1916;17:863– 871.
837
15. Tight blood pressure control and risk of macrovascular and microvascular
complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes
Study Group. BMJ. 1998;317:703–713.
16. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S,
Menard J, Rahn KH, Wedel H, Westerling S. Effects of intensive bloodpressure lowering and low-dose aspirin in patients with hypertension:
principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet. 1998;351:1755–1762.
17. Parving HH, Andersen AR, Smidt UM, Svendsen PA. Early aggressive
antihypertensive treatment reduces rate of decline in kidney function in
diabetic nephropathy. Lancet. 1983;1:1175–1179.
18. Wei JN, Sung FC, Li CY, Chang CH, Lin RS, Lin CC, Chiang CC,
Chuang LM. Low birth weight and high birth weight infants are both at
an increased risk to have type 2 diabetes among schoolchildren in Taiwan.
Diabetes Care. 2003;26:343–348.
19. Poulsen PL, Hansen KW, Mogensen CE. Ambulatory blood pressure in
the transition from normo- to microalbuminuria. A longitudinal study in
IDDM patients. Diabetes. 1994;43:1248 –1253.
20. Brenner BM, Chertow GM. Congenital oligonephropathy and the
etiology of adult hypertension and progressive renal injury. Am J Kidney
Dis. 1994;23:171–175.
21. Lawlor DA, Ebrahim S, Davey Smith G. Is there a sex difference in the
association between birth weight and systolic blood pressure in later life?
Findings from a meta-regression analysis. Am J Epidemiol. 2002;156:
1100 –1104.
22. Norman M, Martin H. Preterm birth attenuates association between low
birth weight and endothelial dysfunction. Circulation. 2003;108:
996 –1001.
23. Curhan GC, Chertow GM, Willett WC, Spiegelman D, Colditz GA,
Manson JE, Speizer FE, Stampfer MJ. Birth weight and adult hypertension and obesity in women. Circulation. 1996;94:1310 –1315.
24. Curhan GC, Willett WC, Rimm EB, Spiegelman D, Ascherio AL,
Stampfer MJ. Birth weight and adult hypertension, diabetes mellitus, and
obesity in US men. Circulation. 1996;94:3246 –3250.
25. Pettersson-Fernholm K, Forsblom C, Hudson BI, Perola M, Grant PJ,
Groop PH. The functional ⫺374 T/A RAGE gene polymorphism is
associated with proteinuria and cardiovascular disease in type 1 diabetic
patients. Diabetes. 2003;52:891– 894.
26. Pettersson-Fernholm K, Forsblom C, Perola M, Groop PH. Polymorphisms in the nephrin gene and diabetic nephropathy in type 1
diabetic patients. Kidney Int. 2003;63:1205–1210.
Birth Weight Is Inversely Correlated to Adult Systolic Blood Pressure and Pulse Pressure
in Type 1 Diabetes
Johan Fagerudd, Carol Forsblom, Kim Pettersson-Fernholm, Markku Saraheimo, Johan Wadén,
Mats Rönnback, Milla Rosengård-Bärlund, Clas-Göran af Björkesten, Lena Thorn, Maija
Wessman and Per-Henrik Groop, on behalf of the Finn Diane Study Group
Downloaded from http://hyper.ahajournals.org/ by guest on June 16, 2017
Hypertension. 2004;44:832-837; originally published online October 18, 2004;
doi: 10.1161/01.HYP.0000147272.10646.e6
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2004 American Heart Association, Inc. All rights reserved.
Print ISSN: 0194-911X. Online ISSN: 1524-4563
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://hyper.ahajournals.org/content/44/6/832
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Hypertension is online at:
http://hyper.ahajournals.org//subscriptions/