Comprehensive Summaries of Uppsala Dissertations

from the Faculty of Medicine 1285

Born Small for Gestational Age

Impact of Linear Catch-up Growth

BY

MARIA LUNDGREN

ACTA UNIVERSITATIS UPSALIENSIS

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LIST OF PAPERS

This thesis is based on the following papers:

I Intellectual and psychological performance in males

born small for gestational age with and without catch-up
growth. Pediatric Research. 2001 Jul;50(1):91-6.

II Birth characteristics and different dimensions of

intellectual performance in young males-a nationwide
population-based study . Acta Paediatrica (In press).

III Linear catch-up growth does not increase the risk of

elevated blood pressure and reduces the risk of
overweight in males. J Hypertension. 2001 Sep;19(9):1533-8.

IV Prediction of adult height and risk of overweight in

females born small-for-gestational-age. Paediatric and
Perinatal Epidemiology 2003 Apr;17(2):156-63.

V Catch-up growth in females born short for gestational

age reduces the risk of giving birth to short-for-
gestational-age infants. Hormone Research (in press).

The papers will be referred to by their Roman number in the following

text.
CONTENTS

INTRODUCTION ..........................................................................................1
BACKGROUND........................................................................................2
Definition and etiology..........................................................................2
Normal growth of the fetus....................................................................2
Standards for measuring size at birth ....................................................3
Factors Influencing fetal growth............................................................4
Classification –growth restriction.........................................................5
Catch-up growth ....................................................................................6
Fetal programming ................................................................................6
AIMS OF THE STUDIES ..............................................................................8
MATERIAL AND METHODS......................................................................9
Data sources ...............................................................................................9
The Swedish Birth Register...................................................................9
The Swedish Conscript Register............................................................9
The studied cohorts ....................................................................................9
Outcome measurements ...........................................................................11
Birth characteristics..................................................................................13
Statistical methods ...................................................................................14
RESULTS .....................................................................................................16
Intellectual performance, paper I and II ...................................................16
Paper I..................................................................................................16
Paper II ................................................................................................17
Blood pressure, final height and overweight, paper III and IV ................17
Paper III ...............................................................................................17
Paper IV...............................................................................................18
Intergeneration .........................................................................................18
Paper V ................................................................................................18
Tables and Figures ...................................................................................20
Table 1 .................................................................................................20
Table 3 .................................................................................................23
Table 4 .................................................................................................24
Figure 2. Effect of relative catch-up growth (%) on the offspring’s
birth length among mothers born short for gestational age. ................25
DISCUSSION...............................................................................................26
Summary ..................................................................................................26
Methodological discussion.......................................................................26
Cohort studies......................................................................................26
Internal validity (Chance , Bias, Confounding) .......................................27
Exclusion criteria.................................................................................27
Young cohorts .....................................................................................28
Random error.......................................................................................28
External validity (Generalizability)..........................................................29
Not conscripted males .........................................................................29
Female birth characteristics, final height and offspring birth
characteristic........................................................................................30
Causation .............................................................................................30
General considerations ............................................................................30
Birth length..........................................................................................30
SGA subgroups....................................................................................31
Catch-up growth ..................................................................................32
Findings....................................................................................................32
Intellectual performance ......................................................................32
Head circumference.............................................................................33
Blood pressure .....................................................................................34
Overweight ..........................................................................................35
Intergeneration.....................................................................................35
Conclusions...................................................................................................37
References.....................................................................................................38
ABBREVIATIONS

CI Confidence interval
BMI Body Mass Index
IP Intellectual performance
OR Odds ratio
PP Psychological performance
SD Standard deviation(s)
SDS Standard deviation score(s)
SGA Small for gestational age
AGA Appropriate for gestational age
GA Gestational age
INTRODUCTION

During the past decades, size at birth has repeatedly been associated
with mortality and morbidity in adulthood (above all cardio-vascular
mortality), intellectual capacity and final stature [1-3]. Most
commonly, birth weight is used as definition of size at birth. The
importance of short birth length is less studied, even though studies
have shown that birth length is a strong predictor of adult height [4,
5].

Most infants born small for gestational age (SGA), in either birth
weight or birth length, catch-up in height during the first years, but
around 10% do not [4-6]. Short adult stature is associated with
increased risks of mortality and minor neurological damages [1, 7-9].
Whether spontaneous catch-up growth reduces the risks associated
with being born SGA is to our knowledge not known.

The purposes of this thesis were to study associations between size at

birth, short adult stature and risks of subnormal intellectual
performance, high blood pressure, and overweight among males, and
to study associations between size at birth, short adult stature and risk
of overweight and giving birth to small for gestational age (SGA)
infants among females.

1
BACKGROUND

Definition and etiology

The term small-for-gestational-age (SGA) is generally based on a
statistical definition of size at birth and should be separated from the
more dynamic concept intrauterine growth retardation/restriction
(IUGR). There are no general standards in the definition of being born
SGA. In Sweden, an infant is considered SGA when birth length
and/or birth weight are below –2 Standard Deviation Scores (SDS) for
gestational age, compared to the Swedish birth weight standard. In
other countries centiles are used for cut off, most commonly the 10th
percentile [10]. IUGR should be defined as a pathological restriction
of fetal growth due to environmental or genetic influences. Thus, all
infants born SGA are not IUGR. Moreover, the IUGR infants do not
necessarily need to be SGA. For example, if a mother who has
previously given birth to a large infant, suffers from pre-eclampsia
and gives birth to an infant with appropriate size, the infant might be
growth restricted, but not necessarily SGA. In 40% of infants born
SGA there is no pathology to be found [10].

The size of the newborn is related to gender and gestational age and
also to maternal and paternal anthropometric and demographic factors.
It has therefore been proposed that birth weight for gestational age
standards should be constructed, taking maternal non-pathological
characteristics influencing fetal growth (i.e., ethnicity, pregnancy
weight, height and parity) into consideration [11].

Normal growth of the fetus

Embryogenesis is an autonomic process, whereas growth in later
gestation is depending on sufficient nutrition and oxygen supply. Fetal
growth is from implantation to the 16th week, primarily mediated by
cell hyperplasia. From week 16 to week 32, both the sizes and the
number of cells increase, and after 32 weeks the growth is mainly
mediated through cellular hypertrophy. The different tissues in the

2
fetal body grow and mature in different ‘critical periods’ of rapid cell
division. Growth in length takes above all place in the end of the
second trimester, and the length growth velocity has its maximum
around the 20th week. Weight gain, in contrast, is primarily processed
through cellular hypertrophy in the last trimester [12].

Standards for measuring size at birth

Growth chart standards vary in different countries and between
different ethnicities. Growth standards are normally adjusted for
gender and gestational age. Estimation of gestational age is either
based on last menstrual period (LMP) or ultrasound examinations.
Ultrasound is known to be more reliable in estimating expected date
of delivery than LMP [13-15], and reduces the proportion of postterm
births [14]. Compared to growth charts based on LMP, a higher
proportion of preterm births and a lower proportion of SGA born
infants was found after the introduction of growth charts based on
ultrasound [13], for review se Bakketeig et al [16].

The Swedish birth weight and birth length curves used in the present
studies, are based on a 5-year birth cohort (1977-81), adjusted for
gender and gestational age, where gestational age is predominantly
based on the LMP [17]. The birth data are collected when the infants
are born, and do not necessarily represent the intrauterine population.
It probably contains systematic errors, and may for example lead to
underestimation of small-for gestational age infants, especially among
those born preterm and very preterm [18, 19]. Marsal et al [19] have
shown a negatively skewed distribution when infants born before 34
weeks were plotted on a growth curve based on intrauterine data.
Among preterm born infants, the intrauterine curves showed values
almost 100g above the postnatal curves.

It has been proposed that the fetus has its own ideal growth curve,
affected not just by gestational age and sex, but also by parental
characteristics. Customized growth charts i.e., computer analyses for
each pregnancy based on maternal anthropometric and demographic
factors where an individual birth weight is predicted [11], do perhaps
have better capacity in identifying growth restricted infants due to
pathological reasons [14, 20]. The use of customized curves may
3
reduce the risk of overestimating the proportion of growth restricted
infants. Still, customized birth weight might lead to normalizing a
growth restricted infants. For example, a child born to a short mother
due to a pathological reason, might be considered normal, when it is in
fact growth restricted.

Factors Influencing fetal growth

Fetal growth is not just a result of nutrition and oxygen supply, but it
is also influenced by several physiological and pathological factors.
Anthropometric factors, such as maternal height, BMI and weight gain
during pregnancy is known to be positively associated with the
infants’ size at birth [21, 22]. Paternal anthropometric factors do have
an impact, but maternal size is thought to be more important [23].
Demographic factors are also known to influence fetal size [21]. SGA
born infants are more common among young [24] and older (>45)
mothers compared mothers in their 20ties and 30ties and
primegravidas are more likely to give birth to SGA infants than
multiparous women [25]. Inter-pregnancy interval has been found to
be associated with SGA birth, with the highest risk with the shortest
intervals. Socioeconomic factors might also be of importance [21];
however, socioeconomic factors might be confounded by smoking
habits, parity and age at delivery. Toxic exposures and maternal
diseases are well-known risk factors of fetal growth restriction.
Smoking is one of the best identified toxic exposures associated with
fetal size and dose-response relations have been reported [20, 21, 26].
Other toxic agents known to influence size at birth are alcohol and
narcotics and even moderate alcohol consumption during pregnancy
affects the fetal size negatively [27]. Fetal infections, such as Rubella
and cytomegalo virus (CMV) may have severe consequences on fetal
growth [28]. Hypertension is one of the most important maternal
factors influencing fetal growth negatively. Preeclampsia and other
hypertensive diseases may cause thickening and infarction in the
placental wall and restriction of blood supply to the fetus. Other
diseases such as cyanotic heart disease, cystic fibrosis, severe asthma
and other pulmonary diseases may impair maternal oxygen delivery to
the fetus. Inflammatory bowel diseases such as ulcerative colitis and
Crohn’s disease impair the maternal absorption from the intestines and
may influence the nutrition supply to the fetus. Other well known
4
maternal diseases affecting fetal size are diabetes mellitus and renal
diseases, for review see Pollack et al [29].

Intrauterine growth also depends on the genetic potential of the fetus.

Short parents have smaller infants than taller and maternal size seems
to be more important than paternal size [23]. Male fetuses, tend to be
bigger than females fetuses, especially in late pregnancy [19]. Various
genetic abnormalities have also been associated with growth
restriction, including trisomi 21, trisomi 13, Turner’s syndrome and
also a number of congenital malformations [29].

Classification –growth restriction.

The body composition of the newborn indicates the timing of the
growth disturbance during fetal life. Infants with a normal head
circumference and slightly reduced birth length but a low birth weight
are often referred to as asymmetric. Their ponderal index (weight /
length3) is low. The growth restriction is believed to be due to
extrinsic factors in the last trimester, such as reduced placental
capacity of nutritional supply. Asymmetrical growth restriction is
more common and postnatal catch-up growth is often seen. The brain
and skeletal growth is generally not affected in asymmetrical growth
restricted infants. In contrast, growth restricted infants with a
symmetric body have a growth disturbance in all tissues. The etiology
is quite different, including prolonged starvation [10, 30], but the
fetus is often also influenced by factors such as genetic diseases,
congenital syndromes, infections and toxic effects. Symmetric growth
retardation is considered to be the most severe form with a higher risk
of short adult stature [30]. However, the classification of growth-
retardation into symmetric and asymmetric has been criticized. It has
been argued that asymmetric growth-retardation is merely a reflection
of the severity of fetal malnutrition [21]. Kramer et al found that the
more severely growth restricted infants were more disproportional
than less severely affected infants, with longer birth length and larger
heads for their weight, and the main factor influencing the degree of
disproportionality was the severity of growth restriction [21].

5
Catch-up growth
Most infants born SGA catch-up in height during the first years, but
about 10% do not and end up with short adult stature [4-6]. Growth in
children and height in adults are often used as indicators of nutrition
and well-being [31-33]. A positive correlation between height and
intelligence has generally been reported [34, 35], and also between
height and morbidity [36]. In a study of young Danish men,
intelligence test scores were above the mean among tall men, but
below in short men [37]. A Swedish study recently demonstrated that
apparently healthy short young men had lower intellectual
performance compared to taller men, and mean intelligence test score
generally increased with height [38].
Whether catch-up growth is associated with cardiovascular disease is
debated. It has been suggested that a catch-up growth in height might
lead to raised blood pressure [3, 39], whereas others claim the
opposite [40]. Studies from Finland indicate that there is an
association between increased risk of cardiovascular disease in
females born short with tall adult stature, and an increased risk in
males born with low birth weight and being overweight as adults [41].
It has recently been demonstrated that catch-up growth in SGA
children induced by growth hormone treatment does not influence
blood pressure or BMI in adolescence [42].

Fetal programming
It has been argued that coronary heart disease originates in utero [43].
Undernutrition leading to growth restricted infants has been found to
be associated with increased risk of insulin resistance, hypertension
and lipid disorders in adulthood [1, 3, 44]. The fetal programming
hypothesis suggests that the fetus adapts to undernutrition and may
permanently change its metabolism and physiology. This may lead to
impaired insulin response to glucose and changes in cholesterol
metabolism, to changes in blood pressure and to increased mortality
and morbidity in coronary heart disease. For review see Barker [45].
However this hypothesis has been debated. Some authors claim that
the infants have a genetic programming in both being small and
ending up with insulin resistance syndrome [46]. Barker et al [47]
suggested that different body proportions are linked to different adult

6
abnormalities, and that the body proportions reflect the time of growth
restriction during fetal life. Infants born short (stunted) tend to
develop hypertension exclusively, whereas infants born thin are
predominantly at increased risk of developing the insulin resistance
syndrome, previously known as syndrome X (insulin resistance,
hypertension, lipid disorders).

7
AIMS OF THE STUDIES

The overall aim was to analyze the effect of catch-up growth on risk
factors for individuals born SGA. In the papers the specific aims were:

I. To analyze if body size at birth among males is associated with

subsequent intellectual and psychological performance, and if there is
any associations between catch-up growth in height in boys born SGA
and intellectual or psychological performance in early adulthood.

II. To study the relations between size at birth, gestational age, final
height and different dimensions of intellectual performance.

III. To investigate the relationship between size at birth and risks of

high adult blood pressure and overweight in males, and to study
whether catch-up growth in height modifies these associations.

IV. To estimate the risk of short adult stature in women born small for
gestational age, and to study if catch-up growth in height is related to
the risk of overweight in females born SGA.

V. To study the effect of catch-up growth on the offspring’s length at

birth among females born short-for-gestational-age.

8
MATERIAL AND METHODS

Data sources

The Swedish Birth Register

The Swedish Birth Register, held by the National Board of Health and
Welfare contains data on more than 99% of all births in Sweden since
1973 [48]. The registry includes data on maternal demographics,
reproductive history, and complications during pregnancy, delivery
and the neonatal period. All births and deaths are validated every year
against the Register of Total Population, held by Statistics Sweden,
using the mothers’ and the infants’ unique personal identification
number, assigned to each Swedish resident at birth.

The Swedish Conscript Register

The Swedish Conscript Register includes information about Swedish
males conscripted for military service. Conscription is mandatory and
enforced by law. Most men are conscripted at 18–25 years of age.
Those with known severe handicaps, congenital malformations or
chronic diseases are not conscripted (about 2.4% in each birth cohort).

The studied cohorts

In papers I, II and III, information on young males’ birth
characteristics were obtained from the Birth Register and linked to the
Conscript Register by using the males’ unique personal identification

9
numbers. The Swedish Birth Register contained information about
312 159 live-born male infants in the period 1973-78. In all, 3 402
males died before 18 year. In order to increase the homogeneity of the
study population, multiple births, infants with congenital
malformations and infants to non-Nordic mothers were excluded
(n=32 724).Of the remaining 276 033 boys, 21 607 (7.8%) males
were not conscripted between January 1991 and January 1997. Of 254
426 conscripted males, data on intellectual performance and
psychological performance were available in 97 % and 91 %
respectively (paper I). Information about blood pressure and body
mass index (BMI) were available in 94% and 97%, respectively
(paper III). Paper II was restricted to males born between 1973 and
1976 who where conscripted before 1994 (n=168 068).

In papers IV and V, we used information from the Birth Register to

link birth characteristics of women to anthropometric characteristics
when these women gave birth to their first child. This linkage was
made possible by using the personal identification number, assigned to
each Swedish resident at birth. Since 1982, data is collected using
copies of standardized antenatal, obstetric, and pediatric records,
which are forwarded to the National Board of Health and Welfare
[48]. At the first visit to antenatal care, the women are interviewed by
midwives about current health, smoking habits, family situation,
previous pregnancies, deliveries, and information about diseases in the
family. Weight is measured and current height is either measured or, if
known, self reported. Information about complications during
pregnancy and delivery, delivery hospital, mode of delivery as well as
age and parity is collected when the females leave the hospital. At the
same time, information of the baby is collected including sex, birth
weight, birth length, head circumference, single or multiple birth,
congenital malformations, and other diagnoses. Complications and
malformations are classified according to the Swedish versions of
ICD-8, ICD-9 or ICD-10, according to year of birth.

In papers IV and V, we used information from the Swedish Birth

Register on birth characteristics of 47 781 females, who were included
in the Birth Register both as babies and mothers. These women were
born from 1973 through 1983, and delivered their first infant between

10
1989 and 1999. As in the male cohort, females born in multiple births,
having congenital malformations, and females born to non-Nordic
mothers (n=3 602), were excluded in order to increase the
homogeneity of the study population. To improve the probability that
the women had reached their final height when becoming pregnant,
we also excluded all women younger than 16 years at delivery
(n=280). Moreover, women with very low final height (<130 cm) or
weight (<39 kg) were excluded (n=27). The remaining 43 872 females
constituted the study population in paper IV.

In paper V, we also excluded women with offspring born in multiple

births or with congenital malformation (n=1 238). Of the remaining 42
634 females, 1 363 (3.2%) were born short for gestational age, i.e.,
with birth length more than 2 standard deviation scores (SDS) below
the mean birth length for gestational age [17]. These women
constituted the study population in paper V.

Outcome measurements
At conscription (papers I, II and III), all males undergo a thorough
health examination, including height and weight, blood pressure
measurements, and a number of tests. The information is
computerized and the personal identification number of each subject
ensures individual record linkage to other information sources. Height
is recorded in cm without shoes and weight in kg in light indoor
clothes. Right arm blood pressure (BP) is measured after five minutes
rest in a sitting position by trained nurses. If BP is elevated (systolic
BP t 135 or diastolic BP t85), a second measurement is performed,
and the lowest value is recorded. Diastolic BP is determined as the
disappearance of Korotkoff sounds.

General intellectual performance (IP) is measured by a time-limited

test package including four dimensions: logical/inductive, verbal,
spatial, and theoretical/technical. The test questionnaire contains 160
items, 40 from each dimension, and is computerized since 1994 [38].

11
Psychological performance during mental stress (PP) is evaluated by
specialized psychologists using semi-structured interviews with the
aim of measuring how the conscript might be able to manage difficult
situations during stress. The results are acknowledged to reflect
different aspects of personality. The results are presented in a
numerical scale, standard nine score (stanine scores), from 1 to 9,
where 5 is mean and 9 is the best result. In paper I, the general
intellectual performance was measured, whereas the different
dimensions of the test were analyzed in paper II. Subnormal
performance was defined in both papers as a stanine score of 3 or
lower (i.e. <–1 SD). The 10% scoring 2 or less in intellectual
performance can be expected to have difficulties in ordinary basic
education programs (i.e., the compulsory nine years of school), and
the 20% scoring 3 or less can not be expected to be successful in
higher education. In paper II, data on the different dimensions of
intellectual performance were available for 86% of all conscripts.
Around 10 000 individuals were recorded with stanine score 0 in
theoretical performance and these data were considered as missing.
The individuals with stanine score 0 did not differ from the cohort
with regard to mean values of the other dimensions of intellectual
performance, birth characteristics, preterm birth and final stature.

In paper III, a high systolic and diastolic blood pressure was defined
as a blood pressure above the 90th percentile, based on the distribution
of blood pressure in the studied cohort. As systolic blood pressure is
positively correlated to height [49], we calculated a height-
standardized systolic blood pressure by forming 9 groups of 5 cm
intervals according to the height at conscription. For each group, the
90th percentile cut-point for systolic blood pressure was calculated. A
high height-standardized systolic blood pressure was defined as a
systolic blood pressure equal to or above the 90th percentile (•140-144
mm Hg for the different heights). Risks of high diastolic blood
pressure were examined similarly.

Body mass index (BMI) was calculated as the ratio between adult
weight and squared adult height (kg/m2) for all subjects. In the male
cohort (paper III) BMI was calculated using weight and height
measures collected at conscription, whereas in females (papers IV and
V), we used weight and height measured at the first visit to antenatal
care (e.g. usually at 8-12 weeks of gestation). Normal BMI for both
12
males and females was defined as BMI between 18.5 and 24.9,
overweight as BMI •25, and obesity as BMI•30, as suggested by the
World Health Organization [49]. Since the cohort was young, the risk
of overweight is underestimated when using the cut off BMI•25
kg/m2. Adult height SDS was computed as: (individual measurement
minus cohort mean measurement)/cohort SD, and stratified into short
adult stature (<-2 SDS), normal adult stature (-2 to 2 SDS) and tall
adult stature (>2 SDS).

Birth characteristics
Information about birth weight, birth length, and gestational age was
obtained from the Birth Register. Gestational age was estimated from
the date of the last menstrual period and stratified into very preterm
(<32 completed weeks), moderately preterm (32-36 weeks) and term
births (> 37 weeks). Birth weight for gestational age was categorized
into three categories. Light for gestational age was defined as more
than 2 standard deviation scores (SDS) below mean birth weight for
gestational age, appropriate weight for gestational age as birth weight
between –2 and +2 SDS, and heavy for gestational age was defined as
birth weight more than 2 SDS above the mean [17]. Birth length for
gestational age and head circumference was defined analogously.
Small for gestational age (SGA) was defined as < -2 SDS in either
birth length or weight for gestational age, and divided into three
different subgroups: born short only, born light only, and born both
short and light for gestational age, as suggested by Albertsson-
Wikland [4]. The cut off at –2 SDS (i.e. around the 3rd percentile) is
commonly used to define small size for gestational age. Children
shorter than –2 SDS are also those, in whom investigation for growth
hormone deficiency may be considered. Linear “catch-up growth” was
defined as being born SGA and being above –2 SDS in height at
conscription. In papers I and III, individual catch-up growth was
analyzed, defined as being born SGA and gaining at least 1 SDS in
height. As a similar pattern was seen when using continuous variables,
the results were dichotomized and presented as on group level to
improve the understanding.

13
In paper V, we introduced the term relative catch-up growth. This was
done in order to analyze the effect of growth in height, controlling for
maternal birth length. Relative catch-up growth was defined as:
100 * ( HSDS  BLSDS )
Where :
 BLSDS
HSDS= Maternal adult height SDS
BLSDS= Maternal birth length SDS,

Relative catch-up growth in per cent measures the increase towards

population mean height = 0 SDS. Accordingly, this measure is
dependent on the females’ birth length and final height. For example,
females born with birth length =-4,-3 or-2 need 100% catch-up to
reach height=0 SDS. To reach –1 SDS in height a relative catch-up
growth of 75, 67 and 50% respectively is needed.

Statistical methods
For all papers the standard statistical package SPSS (version 10.0 for
paper I and version 10.1 for paper II and IV, version 11.0 for paper II
and V) for WINDOWS was used in the statistical calculations. The
analyzes of risks were performed by using bivariate and multiple
logistic and linear regression analyzes. Odds ratios (OR) were
presented with 95% confidence intervals (CI). In analyses of data
from huge populations, most associations tend to be statistically
significant. When presenting the results, we therefore have chosen to
dichotomize the outcome variables as well as birth characteristics and
we have used logistic regression analyses instead of linear regression
analysis. Both types of analyses yielded similar results.

In paper II, data on the different dimensions and the total index of
intellectual performance are given as stanine scores. In theory for the
studied cohort these scores should have a mean of 5 and a standard

14
deviation of 2. However, data in this study yielded values somewhat
different from these figures (Table y).
In order to make the different dimensions numerically comparable, Z-
transformations were performed:
(Observed value  mean cohort value)
Z5=
cohort standard deviation
These Z-values have a mean of 0 and a standard deviation of 1. In
order to further make data conform to stanine scores the Z-values
were transformed:
Z5 = Z*2 + 5,
where Z5 now will have a mean of 5 and a standard deviation of 2.

15
RESULTS

Intellectual performance, paper I and II

Paper I
Males with birth length below –2SDS for gestational age had a lower
mean intellectual performance score than those born above –2SDS,
and similar patterns were seen when analyzing birth weight and head
circumference. Males born preterm, especially those born very
preterm, had lower mean intellectual performance scores than those
born at term or postterm. Mean intellectual performance consistently
increased with height at conscription. A similar pattern was seen when
analyzing psychological performance during stress.

When analyzing men born SGA exclusively, low mean scores in

intellectual and psychological performance were constantly more
common among those without catch-up growth than those with catch-
up. The highest mean score in intellectual performance was seen in the
subgroup born short with a normal adult height, and the lowest score
was obtained in the group born both short and light, who still were
short at conscription (Table 1).

Among males born short, those with short adult stature had a 45 %
increased risk of subnormal intellectual performance compared with
those with normal adult stature. Compared with males born short with
normal adult height, males born light who were short at conscription
had an almost 90 % increased risk of subnormal intellectual

16
performance. In those born short and light, the corresponding risk was
doubled. A similar pattern was seen for psychological performance.

Distribution of stanine scores of intellectual performance of infants

born both short and light is shown in Figure 1. Low mean scores of
intellectual performance were constantly more common among those
without compared to those with catch-up growth, and a similar
tendency was seen for psychological performance. We also analyzed
the distribution of stanine scores in the other subgroups of SGA
infants (born short only and born light only), and found very similar
results.

Paper II
Intellectual performance was further analyzed by studying the four
different dimensions, logical, theoretical, verbal, and spatial
performance (paper II). In males born SGA, the increased risk of
subnormal performance was found in all four subtests of intellectual
capacity, and being born short for gestational age or light for
gestational age was associated with around 20 % increased risk in all
subtests. However, within the subgroups of males born SGA, being
born with a small head circumference or ending up with a short adult
stature further increased the risk of subnormal performance, and the
risk was most pronounced in the logical dimension (Table 2).

Blood pressure, final height and overweight, paper III

and IV

Paper III
Compared to males not being SGA at birth, males being light for
gestational age were at increased risk of adult high systolic blood
pressure [OR 1.33 (95% CI 1.20-1.46)], and a short adult stature was
associated with a further increased risk [OR 1.65 (95% CI 1.13-2.40)].
Being born short for gestational age was associated with a slightly
increased risk of high systolic blood pressure [OR 1.16 (95% CI 1.04-

17
1.29)], and linear catch–up growth in height did not significantly
increase this risk. Males born short-for-gestational-age, who also were
short at conscription, had an increased risk of overweight, expressed
as a BMI >25.0 [OR 1.65 (95% CI 1.25-2.19)].

Paper IV
In females, being born SGA was associated with increased risk of a
short adult stature but the risk varied substantially within the different
subgroups born SGA: being born light-for-gestational-age was
associated with a two-fold increased risk [OR1.90 (95% CI 1.41-
2.54)] of a short adult stature, and short for gestational age was
associated with a five-fold increase in risk [OR 4.86 (95% CI 3.72-
6.35)]. Among females born short-for-gestational-age, lack of linear
catch-up growth was associated with an increased risk of a high BMI
in early pregnancy.

Intergeneration

Paper V
Among females born short for gestational age, maternal height and
BMI were positively associated with the offspring’s birth length and
birth weight, while maternal smoking was associated with reduced
birth length and birth weight. Short adult stature was associated with a
three-fold increased risk of giving birth to a short infant [OR 3.08,
95% CI (1.73-5.50)], whereas overweight (BMI 25-29.9 kg/m2) was
associated with a 50% reduced risk [0.46 (0.22-0.96)]. Smoking
during pregnancy was associated with a dose-dependent increased risk
of short-for-gestational-age births.

The effect of short adult stature on the offspring’s birth length was
further studied by analyzing relative catch-up growth. Women with a
catch-up growth of 50% or less gave birth to the shortest infants
(Figure 2), Thereafter, the association between relative catch-up

18
growth and the infant’s birth length was positive and linear up to a
catch-up growth of 150 %. Even if catch-up growth to normal height
was associated with a reduced risk of giving birth to a short infant, the
mean birth length of the infants was still lower compared to the infants
of mothers born appropriate for gestational age (mean difference 1.2
cm (95 % CI 1.0-1.4 cm).

19
Tables and Figures

Table 1
Mean intellectual and psychological performance for males born
SGA in relation to birth characteristics and adult height. Adjusted
odds ratios (OR) with 95% confidence intervals (CI) of subnormal
intellectual and psychological performance are also given.
Intellectual Performance
Adult height (SDS)
At birth Mean OR (95% CI)
Short <-2 4.30 (1.92) 1.45 (1.21-1.70)
•-2 4.80 (1.93) 1.00*

Light <-2 4.15 (1.95) 1.89 (1.58-2.20)

•-2 4.71 (1.90) 1.11 (0.99-1.22)

Short & Light <-2 3.99 (1.88) 2.01 (1.79-2.23)

•-2 4.58 (1.89) 1.18 (1.06-1.30)
Psychological Performance
Adult height (SDS)
At birth Mean OR
Short <-2 4.48 (1.69) 1.30 (1.04-1.57)
•-2 4.82 (1.79) 1.00*

Light <-2 4.34 (1.68) 1.43 (1.07-2.23)

•-2 4.83 (1.79) 0.98 (0.85-1.10)

Short & Light <-2 4.19 (1.70) 1.74 (1.49-1.98)

•-2 4.72 (1.77) 1.11 (0.98-1.24)

* Reference group, males born short for gestational age with adult
height above –2 SDS

20
Figure 1. Distribution of intellectual performance scores in males
born both short and light for gestational age with final height below or
above –2 SDS.

Percent Born short & light/

Short adult stature
20
Born short & light/
Normal adult stature

10

0
1 2 3 4 5 6 7 8 9
Stanine scores

21
Table 2. Adjusted Odds ratios (OR) with 95% confidence intervals
(CI) of subnormal† performance in different dimensions related to
head circumference at birth and final adult stature among males born
small for gestational age.
N Logical Spatial Theoretical Verbal

Head circumference (SDS)*

<-2 1502 1.33 (1.15-1.55) 1.08 (0.94-1.25) 1.20 (1.04-1.38) 1.19 (1.03-1.38)
§ § §
• -2 5122 1.00 1.00 1.00 1.00§

Height
(SDS)**

<-2 627 1.52 (1.25-1.84) 1.50 (1.25-1.81) 1.37 (1.14-1.65) 1.45 (1.20-1.75)

•-2 5958 1.00§ 1.00§ 1.00§ 1.00§

† Subnormal performance defined as stanine score 1-3.

* Adjusted for Birth length, Birth weight, Gestational age, height and
BMI.
**Adjusted for Birth length, Birth weight, Head circumference,
Gestational age and BMI.
§ Reference group

22
Table 3
Adjusted* odds ratios (OR) with 95% confidence intervals (CI) of
high systolic blood pressure and overweight [body mass index (BMI)
t25 kg/m2] in early adulthood. Males born small-for-gestational –age
(SGA) with normal or short adult stature.

High Systolic High BMI

blood pressure
At birth Adult height (SDS)** OR (95% CI) OR (95% CI)
Short <-2 0.97 (0.70-1.35) 1.65 (1.25-2.19)
•-2*** 1.00 1.00

Light <-2 1.65 (1.13-2.40) 0.82 (0.50-1.32)

•-2*** 1.00 1.00

Short and light <-2 1.41 (1.07-1.86) 1.18 (0.88-1.58)

•-2*** 1.00 1.00

*The risk of high systolic blood pressure adjusted for BMI and
gestational age and the risk of overweight adjusted for gestational age.
**SDS, Standard deviation scores
***Reference group

23
Table 4
Adjusted* odds ratios (OR) and 95% confidence intervals (CI) of high
height-standardized systolic blood pressure, in males born small for
gestational age.

At birth BMI N OR (95% CI)

Short <18.5 210 0.64 (0.42-0.97)
18.5-24.9 2517 1.00**
25.0-29.9 354 1.24 (0.94-1.64)
•30 88 1.89 (1.23-2.90)

Light <18.5 398 0.62 (0.45-0.87)

18.5-24.9 2692 1.00**
25.0-29.9 329 1.26 (0.95-1.69)
•30 77 1.90 (1.22-2.93)

Short and light <18.5 281 0.44 (0.29-0.68)

18.5-24.9 2264 1.00**
25.0-29.9 299 1.30 (0.97-1.75)
•30 79 1.16 (0.71-1.91)

*Adjusted for adult height and gestational age.

** Reference group

24
Figure 2. Effect of relative catch-up growth (%) on the offspring’s
birth length among mothers born short for gestational age.
-.1

-.2
Mean birth length (SDS) in the offspring

-.3

-.4

-.5

-.6

-.7

-.8

-.9
0 50 100 150 200

Relative catch-up growth (%) in the mother

25
DISCUSSION

Summary
The main interest of this thesis was to study the effect of catch-up
growth and final height in young adults born small for gestational age.
The data show that around 10% of the infants born SGA did not catch-
up in height and ended up with a short adult stature. The results
indicate that catch-up growth was associated with reduced risk of
subnormal intellectual and psychological performance in males and
with reduced risk of overweight in both males and females. The
results do not support the hypothesis that catch-up growth in height is
associated with increased risk of high blood pressure. In females born
SGA, short adult stature was associated with increased risk of giving
birth to a short for gestational age child, compared to females with
normal adult stature.

Methodological discussion

Cohort studies
Cohort studies are observational studies in which a group of
individuals exposed and unexposed to a risk factor or a disease are
followed over time and incidences of diseases in the groups is studied.
One of the major advantages with this type of studies compared to
others, such as case control studies, is the opportunity to study several
outcomes rather than just one. Another advantage is the opportunity to
study exposure before any outcomes have occurred, which reduces the
risk of bias. We used cohorts of individuals born SGA and compared
the outcomes between the individuals with and without catch-up
26
growth/short adult stature. All information was taken from the Birth
Register and Conscript Register, and we were able to study several
outcome variables. However, we were limited to information included
in different registers. For example, we did not have any information of
paternal height and socioeconomic status of the parents, which might
have influenced our results.

Internal validity (Chance , Bias, Confounding)

As bias or systematic errors can not be adjusted for in the analyzes, it
is important to minimize them in the design of the study. All data from
the Birth Register were collected prospectively which practically
eliminates the risk of recall bias. At conscription, the test of
intellectual performance was computer-based. Thus, we had no
reasons to suspect misclassifications of the test results, due to final
height, neither did we have reason to believe that possible
misclassifications of the test results and medical examinations should
differ with regard to birth characteristics.

Exclusion criteria
There was a rather high proportion of congenital malformations in the
studied cohorts. We chose to exclude all infants from the Birth
Register with diagnoses in the International Classification of Diseases
(ICD), 8th revision (ICD-8 covering the years 1968-1986) codes
740.99 to779.99, the 9th revision (ICD-9, 1987-1996) codes 740A to
759X and the10th revision (ICD-10, 1998 and forward) codes Q00
toQ99.9, to make sure that all individuals having a malformation with
a possible impact on height were excluded. Thus, we also excluded
minor malformations including congenital malformations of skin, hair
and nails, which could explain the high number of malformations.
However, there was a higher number of individuals born SGA
compared to those born not SGA excluded due to congenital
malformations. We have reasons to believe that some of the results
might be underestimated due to the exclusion criteria.

27
Young cohorts
The studied cohorts consisted of rather young individuals. The males
were aged 18-24 and females 16-26 years. Thus, some individuals
might thus not have reached their final height. The relationship
between size at birth and risks of high adult blood pressure and
overweight might have been even more interesting to study if the
males had been older. In papers III and IV, body mass index (BMI)
was defined according to the standard set by the World Health
Organization [50]. The BMI increases with age during adulthood and
the risk of overweight might have been underestimated due to young
age [51].

Confounding occurs when an association between an exposure and an

outcome is affected by another exposure. The confounder is
independently associated with the exposures and the outcome. We
tried to minimize influence of possible from confounding factors by
studying cohorts that were relatively homogeneous, consisting of non-
malformed female and male singletons born to mothers with
citizenship in Nordic countries. Still, we had limited information on
socioeconomic factors, which in other countries are known to
influence the risk of giving birth to SGA infants, final height, and
education at least in other countries [50]. However, the Swedish
society is rather homogenous, and existing socio-economic differences
are relatively small. Among Swedish children between 6 month and
5.5 years, Lindgren et al [52] have shown a negligible social class
difference in height, weight and head circumference between the
upper class and middle class. A 0.5 cm difference in height was found,
when compared to height of children from the working class in
preschool years, in favor of the upper class, but no difference in
weight. Other studies have shown differences in intellectual
performance between those born small and those born appropriate for
gestational age, even after adjustment for socioeconomic factors [53,
54].

Random error
In large cohort studies it is essential to have a high proportion of
follow ups, to avoid bias and random error. We used the Swedish

28
Birth Register which includes information on all individuals born in
Sweden from 1973 and onwards. The male cohort consisted of more
than 250 000 males and the female cohort more than 43 000 subjects,
which permitted powerful comparisons between different subgroups
of SGA born individuals. In the analyzes of the male cohorts (Papers
I-III) we had access to information on the vast majority of males
included in the original birth cohort. Conscription was until the end of
the 1990ties mandatory and enforced by law. Only 2.4 % in each birth
cohort were not conscripted. In the female cohort we had information
about virtually all females born in Sweden 1973-83 who gave birth to
there first child between 1989 and 1999.

External validity (Generalizability)

Not conscripted males

In papers I-III, we defined our study population as single born males

without congenital malformations who survived until their 18th
birthday, and whose mothers had Nordic citizenship. The proportion
of the study population that was conscripted varied from 86.8 % to
92.2 %, dependent on birth year and included years of conscription.
Compared with conscripted males (0.3%), there was a higher
proportion of very preterm born boys among not conscripted males
(0.5%). Similarly, the proportion of short for gestational age boys was
2.5% among conscripted boys and 3.1% among not conscripted boys,
while corresponding proportions of light for gestational age were
2.7% and 3.6%, respectively. Thus, the proportion of preterm and
SGA born males in the analyzed population was lower than in the
general population. Unfortunately, we were not able to analyze
outcome variables for non conscripted males. It could be speculated,
though, that those with severe growth retardation or disabilities will
not be conscripted. This might have lead to an underestimation of the
risks associated with being born preterm or small-for-gestational-age.

29
Female birth characteristics, final height and offspring birth
characteristic
In papers IV and V, we used information on female birth
characteristics (1973-83) to study the effect on final height and BMI
(paper IV) and offspring’s birth characteristics (paper V). As
information on outcome measures was collected at the women’s first
delivery (1989-99), all women had given birth at a relatively young
age (16-26 years, and 92% between 18-26 years)
Younger women are known to have increased risk of giving birth to
SGA infants [24]. This might lead to a higher proportion of SGA
infants, compared to the rest of the population. Whether mothers born
SGA give birth at younger age compared to females born appropriate
for gestational age is to our knowledge not known.

Causation
The present studies were mainly analytical, and we have analyzed
associations between risk factors and outcome. Conclusions on
mechanisms behind the associations were not drawn, since these
cannot be determined from this kind of studies. Thus, we were not
claiming to have established causality between exposure and outcome.

General considerations

Birth length
Birth length is seldom used in the literature as a predictor of risk
associated with being born SGA. Compared to measurement of birth
weight, birth length measurements have been claimed less reliable.
The possible errors in birth length measurements, though, are non-
differential with regards to final height and other outcomes later in
life. In accordance with previous investigations [5, 55], we found that
birth length is a strong predictor of final height. Deviance in birth
length may indicate the timing and etiology of growth disturbance
during fetal life [12, 21].

30
In the study of females, those born short for gestational age had an
almost five-fold increased risk of short adult stature and those born
light a doubled risk. This is in accordance with a previous report on
males born SGA [5]. The linear relationship between birth length and
adult stature among females was also very similar to the results shown
in males [5]. Another Swedish study [55] has shown somewhat
different figures. However, in that study, the numbers of crude
estimates corresponds to the crude estimates shown in paper IV. Birth
length was associated with a five-fold increased risk whereas birth
weight was associated with a two-fold increased risk. Thus, despite
the fact that birth length is more difficult to measure than birth weight,
birth length is a better predictor of final height. Birth weight could
therefore be used as an estimate of birth length when this measure is
not available.

SGA subgroups
In the present studies, infants born SGA were classified into three
subgroups- born short, born light, or born both short and light- as
suggested by Albertsson-Wikland [4]. Growth restricted infants are
often classified into two subgroups, born with symmetrical or
asymmetrical growth restriction [56]. That infants are born
symmetrically (short and light) growth restricted may reflect a genetic
constitution with a growth disturbance during the first trimester.
Infants born asymmetrically growth restricted (only light for
gestational age) are considered to have a growth disturbance during
the third trimester. The last group is believed to have a severe growth
restriction due to extrinsic factors, and catch-up growth in height is
often seen. Catch-up growth among infants with proportional growth
restriction is less common. Some of these infants are genetically
small, whereas others are growth restricted due to intrinsic factors
such as fetal infections, toxic effects, or genetic diseases [10]. Infants
born only short-for-gestational-age is a less studied subgroup of
individuals born SGA. It could be hypothesized that short-for-
gestational-age infants have a growth disturbance in the second
trimester, and are thus less growth restricted than infants born both
short and light.

31
Catch-up growth
Catch-up growth was defined as being born short for gestational age
according to the Swedish growth curves [17], and being above –2 SDS
in height as adult. Infants born light did not by definition necessarily
have a true catch-up growth to attain an adult height above –2 SDS,
but still they had an increased risk of short adult stature. When
individual catch-up growth was analyzed as a continuous variable in
papers I and III, similar results as analyzing the dichotomized catch-
up variable were found. In paper V, the term relative catch-up growth
was introduced to separate the effect of delta catch-up from final
stature. Delta catch-up growth is simply the difference between adult
height in SDS and birth length SDS and gives no information about
the severity of gestational growth restriction. An individual might
have had a large catch-up, but still end up with short adult stature.
Relative catch-up growth measures the effect of catch-up growth in
percentage, where 0% indicates no catch-up growth in height and
100% represents catch up to normal final height (i.e., final height =0
SDS = population mean).

Findings

Intellectual performance
In paper I it was shown that preterm birth, small head circumference,
and SGA were independently associated with increased risk of
subnormal performance in both the intellectual and the psychological
tests. It has been demonstrated that infants born preterm have an
increased risk of neurodevelopmental disturbances, especially if they
are also SGA [57-59]. The effect of catch-up growth on intellectual
performance on infants born SGA, though, has to our knowledge not
been studied previously. Among males born SGA, lack of catch-up
growth was associated with a substantially increased risk of
subnormal performance in both the intellectual and psychological
tests. When we further analyzed the different dimensions of the test of

32
intellectual performance (paper II), we found that being born SGA
was associated with subnormal performance in all four subtests.
Within the subgroups of males born SGA, being born with a small
head circumference or ending up with a short adult stature was
associated with further increased risk of subnormal performance.

Low birth weight for gestational age was associated with an increased
risk of subnormal intellectual performance, which is in accordance
with some [57, 59-64], but not all [65-67], previous studies. The vast
majority of these studies were done on small cohorts on young
children age 6 months to 13 years [57, 59-62, 67]. Studies on Danish
conscripts (4300 males) [63] do support the result whereas a study
from Norway on young males age 18 do not. The Norwegian study
was done on 105 conscripted males with birth weight below 2500g
[65]. Intelligence testing was done on 71 of the males and the mean
did not differ form the national average. For the first time we were
able in the present work to perform large, population based studies on
young adults. Independent of weight, we found that birth length is of
importance for intellectual and psychological capacity. The different
dimensions of intellectual performance were almost equally affected.

Head circumference
Head circumference was analyzed as a predictor of intellectual
performance in papers I and II. Unfortunately, there was no
information about head circumference at conscription and we did not
have the possibility to study “catch-up growth” of the head. Head
circumference at birth was found to be negatively associated with
increased risk of subnormal intellectual and psychological
performance, which is in accordance with previous studies, where a
small head at birth has been reported to be associated with low
intellectual performance [68] and minor neurological dysfunction
[57]. Among those with small head circumference, the risk of
subnormal intellectual performance was most pronounced in the
logical dimension.

The highest proportion of infants with small head circumference was

found among those born both short and light. Still, even after
adjustment for birth weight and birth length, a small head
33
circumference was independently associated with increased risk of
subnormal performance.

Blood pressure
In paper III, low birth weight for gestational age was associated with a
slightly increased risk of a high systolic blood pressure. The
association remained essentially unchanged after adjustment for final
height, BMI, birth length and gestational age. However, short adult
stature, but especially high BMI in young adulthood were found to be
better predictors of high systolic blood pressure than birth
characteristics. An inverse relationship between birth weight and
systolic blood pressure has been presented and replicated in several
studies [43, 69, 70]. Some studies indicate that the inverse relationship
between birth weight and systolic blood pressure is true only if the
individual attains overweight [44, 71-78]. Other investigators have
claimed that the correlation persists even after adjustment for BMI
[79, 80]. Holland et al found that BMI and birth weight were
independently associated with high blood pressure in a study on 1356
males and 1359 females age 36. Low birth weight was defined as ”
2500 g, i.e. a mixture of SGA and prematurely born. However,
overweight was found to be a stronger risk factor associated with high
systolic blood pressure than low birth weight. Blake et al found
similar results in a study on 2057 children age 3 to 6 years. In paper
III, overweight among males born light for gestational age was
associated with increased risk of high systolic blood pressure, whereas
no such association was found among males born both short and light.
Previous reports have been performed on rather small cohorts (580 –
3000 individuals), except the study done by Seidman et at [71] which
includes 32 580 young adults and his data support the results in our
population-based study presented in paper III.

Some studies have shown that catch-up growth in height might lead to
raised blood pressure [3, 39], whereas others claim the opposite [40].
It has also recently been demonstrated that catch-up growth in SGA
children induced by growth hormone treatment does not influence
blood pressure negatively [42]. Among boys born short for gestational
age, catch-up growth was not associated with a higher risk of high
systolic blood pressure, compared with those without catch-up growth
34
(paper III). In contrast to previous studies [2], among males born with
birth weight below -2 SDS, those who ended up with a short adult
stature did actually have a higher risk of high systolic blood pressure,
compared to males with adult height within normal.

Overweight
Since BMI in young adulthood was found to be a better predictor of
systolic blood pressure than birth characteristics, we wanted to study
risk factors for BMI. There have been reports of association between
being born large for gestational age and high BMI in adulthood [81].
It has also been shown that both men and women born SGA have an
increased mean BMI gain but a lower mean height gain during
puberty compared with those born appropriate for gestational age [6].
Sas et al [42] have shown that SGA children with growth hormone
induced catch-up growth did not attain BMI above the population
mean. The influence of spontaneous catch-up growth in height on risk
of obesity among those born SGA has to our knowledge not
previously been studied. In both the male (paper III) and female
(paper IV) cohorts, being born short for gestational age with a failure
to catch-up in height was associated with increased risk of being
overweight in early adulthood.

Intergeneration
Several studies have shown intergenerational effects of being born
small for gestational age. Only a few have focused on birth length.
Still, intergenerational effect of being born short for gestational age
has previously been shown [82] in a study on 215 females. This
finding was confirmed in the study on our cohort of 1 363 short for
gestational age females presented in paper V. We were able to show
an almost linear association between maternal and offspring’s birth
length. Associations between the mother’s and her offspring’s birth
weight have been shown in some [83, 84] but not all [85] previous
studies. Among females born short for gestational age, a short adult
stature was associated with increased risk of giving birth to a short
infant. We found that both final height and catch-up growth in height
influenced infants’ birth length. Still, females born short for

35
gestational age with normal adult stature generally gave birth to
shorter infants, than females born appropriate for gestational age.

36
Conclusions

x In males born SGA, spontaneous catch-up growth in height is

associated with reduced risk of subnormal intellectual and
psychological performance.
x Lack of catch-up growth among males born SGA, resulting in
short adult height is especially associated with risk of
subnormal logical performance.
x Catch –up growth is not associated with increased risk of high
systolic blood pressure among males born SGA.
x Spontaneous catch-up growth in height is associated with
reduced risk of overweight in both males and females born
SGA.
x In females, short birth length is the most important of birth
factors for prediction of short adult stature.
x Females born short for gestational age have, especially if they
end up with short adult stature, increased risk of giving birth to
short infants.

37
Acknowledgements

I would like to express my gratitude to:

Professor Torsten Tuvemo, my principle supervisor, for never-ending

enthusiasm, for encouragement, for your generosity with time and for
always being positive to all my ideas.

Professor Sven Cnattingius my supervisor in epidemiological studies,

for all your support and good ideas and advices.

Björn Jonsson, PhD, my supervisor in statistics, who taught my

everything I know about statistics and SPSS, for your generosity with
time and patience for all my questions

Professor Uwe Ewald, for always listening to my problems, for

sharing your expert knowledge in neonatology, for constructive
criticism and for visiting V at the hospital.

Anna-Karin Berg, for sharing your private life, for supports and
making the time at the lab enjoyable

All friends at forskningslab Gun, Hong, Janne, Kerstin, Asma, Barbro,

Elisabeth, Anna and Maria, for interesting discussions and friendship.
Barbro Westerberg, Inga Andersson, Karin Wennqvist for support and
assistance with practical matters.

My colleagues at the clinic, especially Anders Forslund for friendship

and lunches.

My sisters Birgitta and Eva and their families Per, Lova, Agnes,
Ellinor and Thomas and X, for always being there, friendship and
love.

38
My friends, Pernilla my role model in research, for all your
encouragement and for making me buy an overlook, Karin W and
Helena for being good friends, Martin S, Ylva and Lasse, Oskar and
Caroline, Anna and Andreas, Henrik and Karin, Lisa and Calle for
dinners and taking care of Robert.

My parents Margareta and Erik for love, support and never-ending

encouragement, and my parents and family in law Christina and Per-
Göran Bodén, Anna and Johan Torén and Anna and Henrik Bodén
with families.

Robert, my husband and best friend. For your tolerance and love and
for wanting to have children with me. Valter our son, I love you.

39
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