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Nutritional aspects of behaviour and biology
during pregnancy and postpartum
Anette Lundqvist
Department of Public Health and Clinical Medicine,
Family Medicine
Department of Medical Biosciences, Clinical Chemistry
Department of Clinical Sciences, Obstetrics and
Gynecology
Umeå 2016
Responsible publisher under Swedish law: the Dean of the Medical Faculty
This work is protected by the Swedish Copyright Legislation (Act 1960:729)
ISBN: 978-91-7601-395-3
ISSN: 0346-6612, New Series No. 1771
Omslag:Helen Bäckman
E-version available at http://umu.diva-portal.org/
Printed by: Print & Media, Umeå University
Umeå, Sweden, 2016
Table of Contents
Table of Contents
Abstract
Sammanfattning på svenska
Abbreviations
Definitions used in the thesis
Original papers
Preface
Introduction
Swedish antenatal care
Dietary recommendations
Dietary supplementation
Exposures to avoid or reduce
Weight gain and obesity
Behavioural changes; physical activity and diet
Vitamin D physiology and synthesis
Vitamin D in relation to pregnancy and after birth
Basic regulation of food intake
Steroid hormones, neuroactive steroids and
allopregnanolone
Pregnancy and allopregnanolone
Allopregnanolone and food intake
The GABA system and allopregnanolone
Aims of the thesis
Methods
Study I
Material and methods
Participants
Interviews
Study II - IV
Settings
Sample size
Participants
The questionnaires
Estimation of dietary intake
Blood sampling
Participants - study II
Participants - study III
Participants - study IV
Analysis
Study I
I
I
III
VII
IX
XI
XIII
1
2
3
3
5
6
7
8
9
12
13
13
14
14
15
17
18
19
19
19
20
21
21
21
21
24
24
25
25
27
29
31
31
Statistical analyses study II - IV
Study II
Study III
Study IV
Biochemical analyses study III - IV
Ethical considerations
Ethical reflections
Results
Study I
Study II
Study III
Study IV
Discussion
Methodological considerations
Study I
Study II - IV
Conclusions
Clinical implications and future research
Acknowledgements
References
Original papers
II
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Abstract
Background
A well-balanced nutritious diet is important for the pregnant
woman and the growing fetus, as well as for their future health.
Poor nutrition results from both over-consumption of energyrich foods which can lead to a higher weight gain than is healthy
and under-nutrition of essential nutrients. Food intake is
regulated in complex biological systems by many factors, where
steroid hormone is one factor involved.
The overall aim of this thesis is to describe dietary intake,
vitamin D levels, dietary information and dietary changes, and
to study the relation between allopregnanolone and weight gain
during pregnancy and postpartum.
Methods
Study I was a qualitative study with focus group interviews with
23 pregnant women. The text was analysed with content
analysis. Study II was a quantitative cross-sectional study
conducted in early pregnancy (n=209) with a reference group
(n=206). Self-reported dietary data from a questionnaire was
analysed using descriptive comparative statistics and a cluster
analysis model (Partial Least Squares modelling). Study III had
a quantitative longitudinal design. Vitamin D concentrations
were analysed in 184 women, collected on five occasions during
pregnancy and postpartum. Descriptive comparative statistics
and a linear mixed model were used. Study IV was a
quantitative longitudinal study with 60 women. Concentrations
of allopregnanolone were analysed in gestational week 12 and
35. Descriptive and comparative statistics as well as Spearman’s
correlation (rho) were used to describe the relationship between
weight gain and allopregnanolone concentrations.
Results
The focus group interviews showed that women wanted to know
more about different foods to reduce any risk for their child but
the information about foods was partly up to themselves to find
out. They expressed feelings of insecurity and guilt if they
accidentally ate something “forbidden”. The recommendations
III
were followed as best as possible along with common sense to
deal with diet changes. The main themes were “Finding out by
oneself”, “Getting professional advice when health problems
occur”, “Being uncertain” and “Being responsible with a pinch
of salt”. Some differences in the dietary patterns were found
among the pregnant women compared to references, with less,
vegetables (47 g/day), potatoes/rice/pasta (31 g/day), meat/fish
(24 g/day) and intake of alcohol and tobacco/snuff but a higher
intake of supplements. Both pregnant women and references
had intakes of folate through diet 45% (pregnant) and 22%
(references) lower than current recommendations (500 vs 400
g/day). Vitamin D intake was 34% lower than the
recommendations of 10 mg/day. At least a third of the
participants had insufficient plasma levels below 50 nmol/L of
vitamin D. Season was a strong factor influencing the
longitudinal pattern. Gestational week, season, total energy
intake, dietary intake of vitamin D, and multivitamin
supplementation over the previous 14 days were factors related
to vitamin D levels. A correlation between allopregnanolone
concentrations in gestational week 35 and weight gain in weeks
12–35 was seen (p = 0.016). There was also a correlation
between the increase in allopregnanolone (weeks 12–35) and
weight gain (see above) (p = 0.028).
Conclusions
Dietary recommendations were described as contradictory and
confusing and the dietary advice felt inadequate. The women
faced their diet changes and sought information on their own
but would have wished for more extensive advice from the
midwife. The intake of vitamins essential for pregnancy was
lower than recommended, which is also confirmed by low
plasma levels of vitamin D in at least one third of the pregnant
women. Vitamin D levels peaked in late pregnancy. Aside from
gestational week and season which were related to plasma
levels, intake from foods and supplements also affected the
levels. Reasons for weight gain are complex and depend on
many factors. Allopregnanolone is a factor that was seen to
relate to the weight gain of the studied pregnant women.
IV
Keywords pregnancy, antenatal care, dietary advice,
qualitative, dietary intake, cross-sectional, vitamin D levels,
alloprenanolone, weight gain, longitudinal
V
VI
Sammanfattning på svenska
Bakgrund
En välbalanserad näringsrik kost är viktig för den gravida
kvinnan och det växande fostret, så även för deras framtida
hälsa. En bristfällig kost kan utgöras av både överförbrukning
av energirika livsmedel vilket kan leda till högre viktuppgång än
vad som är hälsosamt och bristande intag av viktiga
näringsämnen. Kostintag regleras av komplexa biologiska
system där flera faktorer är inblandade däribland
steroidhormonet allopregnanolon.
Det övergripande syftet med denna avhandling är att under och
efter graviditet beskriva kostintag, vitamin D-nivåer,
kostinformation och kostförändringar och att studera
allopregnanolons relation till viktökning.
Metod
Studie I var en kvalitativ studie med fokusgruppsintervjuer med
23 gravida kvinnor. Texten analyserades med innehållsanalys.
Studie II var en kvantitativ tvärsnittsstudie som genomfördes i
tidig graviditet (n = 209) och med en grupp icke-gravida
kvinnor (kontrollgrupp) (n=206). Självrapporterade kostdata
från ett frågeformulär analyserades med beskrivande,
jämförande statistik och en klusteranalysmodell (Partial Least
Squares modellering). Studie III hade en kvantitativ
longitudinell design. Vitamin D-koncentrationer analyserades
hos 184 kvinnor, vid fem tillfällen under graviditeten och efter
förlossningen. Beskrivande, jämförande statistik och en linjär
mixad regressionsmodell användes. Studie IV var en kvantitativ
longitudinell studie med 60 kvinnor. Koncentrationerna av
allopregnanolon analyserades vid graviditetsvecka 12 och 35.
Beskrivande och jämförande statistik samt Spearman’s
korrelation användes för att beskriva samband mellan
viktökning och koncentrationer av allopregnanolon.
Resultat
Intervjuerna i studie I visade att kvinnor ville veta mer om olika
typer av mat för att minska en eventuell risk för sina barn men
kostinformation var delvis upp till dem själva att ta reda på. De
VII
uttryckte känslor av osäkerhet och skuld om de råkat äta något
”förbjudet”. Rekommendationerna följdes så väl som möjligt,
tillsammans med sunt förnuft för att hantera kostförändringar.
Huvudteman var ”Söka information på egen hand”, ”Få
professionell rådgivning när problem uppstår”, ”Känna sig
osäker” och ”Ta ansvar med en nypa salt”. I studie II kunde man
se vissa skillnader i kostmönster bland de gravida kvinnorna
jämfört med kontrollgruppen: mindre intag av grönsaker (47
g/dag), potatis/ris/pasta (31 g/dag), kött/fisk (24 g/dag) och
alkohol och tobak/snus och ett högre intag av kosttillskott. Både
gravida kvinnor och kontrollgruppen hade lägre intag av folsyra
via kosten med 45 % (gravida) och 22 % (kontrollgruppen) än
de gällande rekommendationer som är (500 resp 400 g/dag). I
studie III såg man att intaget av vitamin D var 34 % lägre än
rekommendationen på 10 µg/dag. Minst en tredjedel av
deltagarna hade otillräckliga plasma nivåer av vitamin D, under
50 nmol/L. Årstid var en stark faktor som påverkar det
longitudinella mönstret. Graviditetsvecka, säsong, totala
energiintaget, intaget av vitamin D och multivitamintillskott
under de senaste 14 dagarna var faktorer som relaterade till Dvitaminnivåer. I studie IV sågs ett samband mellan
allopregnanolon-koncentrationer vid graviditetsvecka 35 och
viktökning från vecka 12 till 35 (p = 0,016). Det sågs också ett
samband mellan ökningen av allopregnanolon (vecka 12–35)
och viktökningen (se ovan) (p = 0,028).
Slutsatser
Kostrekommendationer beskrevs som motsägelsefulla och
förvirrande och kostråden de fick uppfattades som otillräckliga.
Kvinnorna tog itu med sina kostförändringar och sökte
information på egen hand men hade önskat mer omfattande råd
från barnmorskan. Intaget av vitaminer viktiga för graviditeten
var lägre än rekommendationerna, vilket också bekräftas av
låga plasmanivåer av D-vitamin hos cirka en tredjedel av de
gravida kvinnorna. D-vitaminnivåerna nådde en topp i slutet av
graviditeten. Graviditetsvecka och säsong på året påverkade D
vitaminnivåer, så även intag via mat och kosttillskott. Orsaker
till viktökning är komplexa och beror på många faktorer.
Allopregnanolon är en faktor som sågs relatera till viktökningen
hos de undersökta gravida kvinnorna.
VIII
Abbreviations
BMI
D2
D3
EDTA-plasma
FFQ
FIGO
GABA-A
LC-MS/MS
MI
NFA
NNR
PLS
RIA
SD
VIP
WHO
25(OH)D
Body Mass Index
Ergocalciferol (vitamin D2)
Cholecalciferol (vitamin D3)
Ethylenediaminetetraacetic acid plasma
Food Frequency Questionnaire
International Federation of Gynecology and
Obstetrics
Gamma amino butyric-acid receptor type A
Liquid chromatography-tandem mass
spectrometry
Motivational interviewing
National Food Agency, Sweden
(Livsmedelsverket)
Nordic Nutrition Recommendations
Partial Least Squares analysis
Radioimmunoassay
Standard deviation
The Västerbotten Intervention Programme for
Health Survey
World Health Organization
25- hydroxy vitamin D
IX
X
Definitions used in the thesis
Antenatal care
In this thesis antenatal care means health care during
pregnancy provided in primary health care centres. Antenatal
care is synonymous with prenatal care.
Season
In this thesis season at latitude 63.8° is referred to as winter
16/9–14/4 and summer 15/4–15/9 (1).
WHO’s definition of nutrition
Intake of food necessary for optimal growth, function and
health (2).
WHO’s definition of good and poor nutrition
Good nutrition is a well-balanced diet that provides all essential
nutrients in optimal amounts and proportions, whereas poor
nutrition is a diet that lacks nutrients (either from imbalance or
overall insufficient food intake) or one in which some
components are present in excess (2).
XI
XII
Original papers
I.
Wennberg AL, Lundqvist A, Högberg U,
Sandström H, Hamberg K. Women’s experiences of
dietary advice and dietary changes during
pregnancy. Midwifery. 2013 Sep;29(9):1027–34
II.
Lundqvist A, Johansson I, Wennberg AL, Hultdin
J, Högberg U, Hamberg K, Sandström H. Reported
dietary intake in early pregnant compared to nonpregnant women – a cross-sectional study. BMC
Pregnancy and Childbirth. 2014 14:373
III.
Lundqvist A, Sandström H, Stenlund H,
Johansson I, Hultdin J. Vitamin-D Status During
Pregnancy; a Longitudinal Study in Swedish
Women From Early Pregnancy to Seven Months
Postpartum. [Manuscript accepted]
IV.
Lundvist A, Bäckström T, Sandström H. Weight
gain relates to allopregnanolone levels during
pregnancy – a longitudinal study. [Manuscript]
Paper I is reprinted with permission from Midwifery, DOI.
10.1186/s12884-014-0373-3.
Paper II is reprinted with permission from BMC Med.Central
XIII
XIV
Preface
Preface
During my work as a midwife, my interest in issues of healthimproving factors has deepened. I experienced that food intake
was marginal in conversation in antenatal care in the 1990s.
The dietary recommendations in the early 1990s were not easy
to interpret, with various risks to handle, and therefore quite
complex for the pregnant women to follow. I remember the
concrete advice I was given during my pregnancies; “eat as
usual and cook in a cast-iron pot”, which was easy for me to
follow.
The interest in vitamins and food intake during pregnancy
ended up in a master’s thesis in nursing. My colleague
AnnaLena Wennberg and I were introduced to Herbert
Sandström. He was also interested and has extensive knowledge
in these fields. Herbert suggested that we should make plans for
a longitudinal study during pregnancy (on folic acid). We were
presented to other researchers with interest and knowledge in
the subject. They joined our group and we started to make plans
for our new project. The project developed and took its present
form over time. We worked on preparations for the data
collection which started in autumn 2006. Combined with the
project I worked at the Department of Obstetrics and
Gynaecology, and in the beginning of the 2000s in primary care.
In 2012 I finally registered as a PhD student at Family
Medicine.
1
Introduction
Introduction
Maternal lifestyle and nutritional factors before and during
pregnancy can influence pregnancy outcomes which affect the
child in the longer term (3). Barker et al (4) showed in the 1990s
that the environment in the uterus is important for the child’s
health in future life. Later studies have shown that epigenetic
changes can lead to non-communicable diseases transmitted to
the next generation (5,6). Healthy eating habits should also be
maintained after birth and during lactation. The body needs to
be rebuilt for lactation to optimize milk production and to
regain weight after pregnancy.
The diet should meet the nutrient requirements of
macronutrients (carbohydrates, protein, fat) as well as a variety
of micronutrients such as minerals and multiple vitamins. The
energy need in adults (18–30 years) is approximately 2000–
2500 kcal/day depending a bit of the current physical activity
level. The mother should also avoid toxins and contaminants.
An unbalanced diet can occur from over-consumption of nonnutritive energy-rich foods and/or under-consumption of
nutrient-dense foods (3,7–9).
The requirements for most minerals and vitamins increase
during pregnancy and lactation; for some vitamins, especially
folate, requirements are increased in the preconception period
(10–15).
A pregnancy normally presupposes weight gain due to the
growing fetus, placenta, amniotic fluid, maternal tissue and
increased maternal fat stores. Well-nourished women with a
mean weight gain of 12 kg have additional energy requirements
of 90, 287, 466 kcal/day for the first, second and third trimester
respectively (17). That corresponds roughly to a piece of fruit in
months 1–3; a hearty snack and a fruit in months 4–6; two
hearty snacks and a fruit in months 7–9 (16). During exclusive
lactation there is an increase of energy requirements of about
454 kcal/day (17).
2
Introduction
Swedish antenatal care
Swedish antenatal care is free of charge, financed by public
health care. Each county council or region is responsible for
women’s antenatal care. The antenatal clinics are organized in
public or private sector as well as in hospital settings. The
majority are placed in primary health care centres with a
midwife as the primary caregiver. Specialist prenatal care is
provided mainly through hospital clinics. There is a long
tradition in Sweden of health prevention during pregnancy and
the participation rate among pregnant women is high, around
99%.
The tasks for Swedish midwives are to promote health, prevent
and detect health risks, contribute to good sexual and
reproductive health, and minimize risk to and morbidity of
women and children during pregnancy, childbirth and infancy.
Pregnant women, sometimes with their partner, visit a midwife
8–10 times, starting in early pregnancy with a follow-up visit 6–
12 weeks postpartum. Midwives take up a comprehensive
history about somatic diseases and conditions. They provide
counselling and advice based on the anamneses of psychosocial
profile, lifestyle habits that include diet, physical activity, and
use of alcohol, tobacco, drugs, mental health, and dietary
intake, including calculating BMI. Physical and laboratory
examinations are implemented, for example measurements of
weight, blood pressure and laboratory tests, registrations of
uterine growth and screening to detect maternal and fetal
complications. In the postpartum visit both physical
examinations and laboratory test are performed. Experiences of
pregnancy, delivery and lactation are also in focus in the health
consultations as well as sexual life issues and contraception
(18).
Dietary recommendations
Nordic Nutrition Recommendations (NNR) are aimed at the
general population and are a basis for national recommendations (11). A balanced Nordic diet is recommended
because it contains a lot of vegetables, fruit and berries, nuts
and seeds, peas and beans, whole grain, seafood, selected types
3
Introduction
of fish, vegetable oils and low-fat dairy products (11). This
Mediterranean diet gives high amounts of most micronutrients,
for example a relatively high content of folate (19) zinc and
several vitamins (20). Even if a healthy diet limits the need for
supplementation, there are still some nutrients that need
attention and may require supplementation. Iron, iodine, folate,
vitamin B12, calcium and vitamin D are nutrients where
deficiencies are common worldwide (3).
Iron is vital for all organs; for example forming the oxygenbinding part of haemoglobin that transports oxygen from the
lungs to the tissues. Iron requirements are increased during
pregnancy progress due to haemoglobin synthesis and transport
to the fetus as well as iron losses during labour. A reduced
concentration of Hb means anaemia, and the limit during
pregnancy is set at 110 g/L (21,22). Deficiency has been
associated with pre-term birth and low birth weight (23,24).
Obese pregnant women are at a higher risk of iron deficiency
compared to women with a normal weight measuring lower
maternal iron stores (25). The NNR recommendations are
about 15–18 mg depending on deposits and current iron values,
during breastfeeding 15 mg is recommended (22).
Supplementation is common during pregnancy. Anaemia is a
widespread problem in many countries and puts mothers at
several risks, with postpartum haemorrhage as one example (3).
Dietary sources are blood-based foods, meat, fish, whole grain
cereals, spinach, and some fruits (22). The concentration of iron
in human milk is low but with a high bioavailability (12) which
ensures that a full-term, healthy, breastfed or formula-fed
infant needs no outside supply during the first 4–6 months
(26,27).
Folate (vitamin B9) is a water-soluble vitamin that is abundant
in liver, vegetables, especially in beans, green leafy vegetables,
berries, fruit, and root vegetables (16). The vitamin is heat
sensitive and losses in the cooking process are common (29).
The synthetic form of folate is called folic acid, which is more
stable and found in supplements and in fortified foods. Folate is
needed in the formation of new cells, especially in rapidly
growing cells and the formation of red blood cells. The vitamin
is also necessary for the processes of ribonucleic acid (RNA) and
4
Introduction
deoxyribonucleic acid (DNA) synthesis (30). Some medications
(Folic Acid Antagonists) affect the body’s ability to absorb or
metabolise folic acid which increases the risk of having a child
with neural tube defects (31). Adequate levels of folate are
required already before conception to protect against neural
tube defects due to the fact that the neural tube closes very early
in the pregnancy, around weeks 3–4. The vitamin also prevents
megaloblastic anaemia during pregnancy (32). In several
countries, certain foods are fortified with folic acid, but not in
Sweden. Recommendations from the Swedish National Food
Agency (NFA) are applicable to Sweden and recommendations
during pregnancy and lactation are based on the NNR. NFA
(33) recommends supplements with 400 µg folic acid/day to all
women planning a pregnancy and continuing during the first
trimester. The recommended intake of folate is 500 µg/day
during pregnancy and breastfeeding due to fast-growing tissues
(22,34). Folate in human milk varies over the lactation period
(35) and the highest concentrations are found 3–6 months after
birth (36).
NFA in Sweden has adapted and summarized the advice from
the NNR about eating habits and dietary guidelines for
pregnancy and lactation (16,37). Midwives are the primary
caregivers in antenatal care, to whom NFA refers as the
profession to give women detailed dietary advice. The advice is
consistent with that of the NNR above, with a varied diet, at
least 500 g of fruit and vegetables per day with a daily intake of
500 mL low-fat dairy products such as milk or yoghurt. Fish,
shellfish (2–3 times per week) and vegetable oils are good
sources of unsaturated fat. For some fish species there are
restrictions for consumption, with a recommendation to eat a
maximum 2–3 times per year due to dioxins, PCB and mercury.
Meat, chicken, eggs, beans, lentils or peas are recommended as
well as bread and potatoes, rice, pasta, bulgur wheat, preferably
wholegrain. Water is recommended for meals and when thirsty.
The recommendation is also to reduce the intake of refined
sugar products such as cakes, sweets and soft drinks (16,20).
5
Introduction
Dietary supplementation
Recommendations from the NFA are that anyone who might
become pregnant is advised to take 400 micrograms of folic
acid each day until gestational week 12, to prevent neural tube
defects (16,33,38) as mentioned before. Vitamin B12 and
vitamin D in supplements or fortified products are advised for
vegans. Vitamin D supplements are recommended to veiled
women and women who do not eat fortified foods (39).
Generally, dietary supplements and herbal products should be
treated with caution and some products should be completely
avoided, e.g. ginseng (40).
Exposures to avoid or reduce
Alcohol: Although there are studies suggesting that light
drinking during pregnancy is not linked to developmental
problems in mid-childhood (41,42), the recommendation in
Sweden is to abstain completely from alcohol. Spontaneous
abortion, prenatal and postnatal growth restriction and
neurological birth defects have been associated with alcohol
exposure (43).
The restrictions during lactation allow for the ingestion of small
amounts of alcohol, even though alcohol itself has no positive
effects on lactation. According to current research, there is no
medical risk with a moderate amount of alcohol during
lactation, i.e., 1–2 glasses of wine (1 standard glass of wine=12 g
alcohol=12–15 cl) or its equivalent 1–2 times a week. The
amount of alcohol that is transferred to the child with the milk
is small and not considered harmful (44–46).
Caffeine: Contradictory results in literature make it difficult
for health professionals to advise pregnant women on caffeine
during pregnancy. The intake of caffeine is restricted to 300 mg
per day. This is equal to either three cups of coffee (1.5 dL/cup)
or six cups of black tea (16). The risk of unfavourable birth
outcomes has been highlighted in studies (47,48) but the latest
Cochrane Review found insufficient evidence to confirm or
disprove the effectiveness of caffeine avoidance on birthweight
6
Introduction
or other pregnancy outcomes due to the quality of the included
studies (49).
Mercury in large quantities can damage the brain and nervous
system. Mercury can be passed to the baby through the
mother’s placenta and breast milk. It is a metal which
accumulates in fish such as perch, pike, walleye and burbot.
Large predatory fish contain higher levels per gram, and thus
fresh tuna, swordfish, large halibut, shark and ray should be
avoided. Canned tuna belong to a different species from tuna
sold fresh and do not contain high levels of mercury (28).
Dioxin and PCBs affect the development of the brain and
nervous system, which can cause behavioural disorders. They
can also affect the immune system and endocrine systems as
well as reproduction. These are organic pollutants that have
become widespread in the environment. The recommendation
is to avoid herring and wild salmon and trout from around the
Baltic Sea and the Gulf of Bothnia. This also applies to wild
salmon, trout and whitefish from Vänern and Vättern. For
women of childbearing age, it is especially important to
minimize the intake of these toxins as they are transferred to
the fetus and breastfed infants through the placenta and breast
milk (50,51).
The bacteria Listeriosis monocytogenes is present
everywhere in nature. Listeriosis is also found in food stored a
long time in the refrigerator and then eaten without being
heated, for example, vacuum-packed smoked and pickled fish,
soft cheeses and sliced cold cuts. The Listeriosis bacteria die
when foods are heated to over + 70 °C. Pregnant women may
get flu-like symptoms or be symptom-free. During the infection,
transmission to the fetus may in the worst cases lead to
miscarriage or a severely sick child (52).
The parasite Toxoplasma gondii has the cat as its host and
excretes the parasite in the feces. Other animals, such as lamb
or pigs, can be infected and became a source of infection for us
humans as cat feces is. Contaminated soil, vegetables and
berries are also potential sources of infection. The parasite can
spread through the placenta to the fetus and cause miscarriage,
7
Introduction
birth defects or congenital infection. The parasite dies when
heated to at least 65 °C or deep frozen at –18 °C for at least
three days (16,53).
Weight gain and obesity
Weight gain during pregnancy differs substantially between
women. The proportion of overweight or obese (BMI ≥25)
women at enrolment in Swedish antenatal health care increased
from 25% in 1992 to 38% 2012. In 2013 25% of all pregnant
women in maternal care were overweight and 13% were obese
(54). The guidelines from the US Institute of Medicine are the
most accepted in Europe and are also used in Sweden. The
guideline recommend women with a normal BMI at enrolment
(BMI 18.5–25) a 11.5–16.0 kg gestational weight gain; in women
with overweight (BMI 25–30) lower weight gain is
recommended (7.5–11.5 kg) and in obese women (BMI ≥30) 5–
9 kg (55).
The term overeating can be used when energy intake exceeds
the body’s energy expenditure which leads to excess body
weight and obesity in the long run (56). Factors such as
increasing meal size and passing meals during the day are also
linked to obesity (57). Excessive weight gain during pregnancy
entails a risk of complications for both mother and child. For
example metabolic complications such as gestational diabetes,
hypertension, thromboembolism, implications for infant growth
and adiposity are reported. Further complications are the
increasing frequency of caesarean delivery and higher birth and
placenta weight. Asphyxia-related outcomes in term infants are
found as well as longer stay in hospital (58–62). Furthermore,
lactation rates seem to be lower among obese women and early
termination, which is not favourable for the mother or the child
(63).
Behavioural changes; physical activity and diet
A pregnancy is a major life event that constitutes a strong motivator for women to embrace a healthier lifestyle. Motivational
interviewing (MI) is a method that is used in Swedish antenatal
8
Introduction
care to promote motivation and behavioural change related to
lifestyle factors. The idea is to support patients in their efforts to
change an unhealthy lifestyle habit. The method has been
influenced by Prochaska and DiClemente’s theoretical model
(64) and developed by Miller and Rollnick (65). The National
Board of Health and Welfare has described the guidelines and
educational requirements for MI (66).
Physical exercise is beneficial and safe for pregnant women (67)
and has also been associated with lower weight gain. According
to a meta-analysis the effect of physical exercise was lower than
the effect of dietary interventions (68). Recently it was reported
that women with a high gestational weight gain are more likely
to have problems in managing weight retention and reaching
normal weight in the postpartum period (69). Physical activities
are recommended for at least 30 minutes daily to achieve and
maintain a healthy weight (16,37). NNR for adults, including
pregnant women are specified depending on the type of physical
activity and its intensity. At least 150 minutes of moderateintensive physical activity per week is applicable (11).
A link between Mediterranean diet and less increase in BMI
during pregnancy has been observed by Silva-del Valle et al
(70), and women with high adherence gained less weight and
were more likely to be within the recommended BMI range
from the Institute of Medicine. Adherence to a Mediterraneanlike diet has also been suggested to be beneficial for fetal growth
(71). Pregnancies with low adherence was associated with lower
birth and placenta weight (72) and increased risk for the child
to have hyperinsulinemia at birth (73). Both under- and overnutrition can contribute to the development of gestational
diabetes and also epigenetic changes that may contribute to
future diabetes type 1 and 2 according to a review by Nielsen et
al (74). In a study from Sweden the mean gestational weight
gain was significantly reduced by 1 kg (p= 0.029) by weight
interventions and education compared to a standard care group
(75). Phelan et al (76) showed that behavioural lifestyle
interventions reduced gestational weight gain in women with
normal weight. The interventions also prevented weight
retention postpartum in normal weight, overweight and obese
women. The opposite result has also been seen, that eating
9
Introduction
patterns are difficult to influence with small changes in
women’s dietary intake (77). An Australian study showed that
adherence to current dietary guidelines was low, and even
though women perceived that they had a healthy diet, they
could not meet recommendations for fruit, dairy products and
other core food products (78).
Vitamin D physiology and synthesis
Vitamin D receptors are present in our body’s organs, in tissues
and cells as well as in the placenta-decidua during pregnancy.
Vitamin D is essential for the regulation of calcium and
phosphorus homeostasis and is involved in many biological
processes, such as cell proliferation and differentiation in target
tissue (79,80).
There are two variants of vitamin D: cholecalciferol (vitamin D3)
and ergocalciferol (vitamin D2). One source is exposure to
sunlight. With the help of the sun’s UVB (ultraviolet B
radiation; wavelengths 290–315 nm) rays, 7-dehydrocholesterol
in the skin is converted to vitamin D3 (81). Another source of
vitamin D3 is through food intake, fatty fish, eggs, enriched
dairy products and supplements. Vitamin D2 is also found in
mushrooms and some supplements (39). Vitamin D3 and
vitamin D2 are then hydroxylated in the liver to calcidiol
25(OH)D2 and 25(OH)D3. Renal handling continues the
regulated conversion to the biologically active steroid hormone
calcitriol (1,25(OH)2D3). Calcitriol synthesis is influenced by
levels of calcium, phosphate, and parathyroid hormone, and it
works together with parathyroid hormone to maintain calcium
and phosphorus homeostasis (81,82). A brief description of
vitamin D synthesis is shown below (Figure 1).
10
Introduction
Figure 1. A brief description of vitamin D metabolism.
The synthesis of vitamin D in the skin is affected by many
factors where amount of and exposure to sunlight, skin type,
latitude and season have a strong influence on the amount of
vitamin D that is synthesized (83). In the Umeå area (latitude
63.8°N), sun exposure is sufficient for vitamin D3 synthesis
from around the middle of April to the middle of September,
most of this period in the hours around noon. In the remaining
seven months synthesis is impossible (1).
11
Introduction
Vitamin D in relation to pregnancy and after birth
The importance of vitamin D during pregnancy has been
highlighted in recent years. The need for both calcium and
vitamin D is increased during pregnancy for fetal growth and
development, and during lactation due to growth of the newborns, especially for skeletal growth and mineralization. During
pregnancy the body adapts by changing the metabolism with
increased synthesis of calcitriol (1,25(OH)2D) simultaneous
with changes in hormones, e.g., prolactin, placental lactogen,
calcitonin, and estrogen (84). The fetus accumulates about 30 g
calcium, mainly in late pregnancy. The maternal intestine and
kidneys facilitate maximum absorption and excretion of calcium
and phosphates to meet this need (81,82).
Many studies, meta-analyses and reviews have indicated
vitamin D deficiency and adverse health outcomes in pregnant
women and new-born around the world. An increased risk of
gestational diabetes, pre-eclampsia, preterm birth, small for
gestational age and risk of reduced bone mineral content has
been reported, related to deficiency of vitamin D (85–89).
Contradictory results found no association with preterm birth
have also been reported (90). The definition of deficiency is
debated and no consensus seems to prevail about the optimal
level. Vitamin D status is estimated by measuring the total
concentration of 25(OH)D levels in serum or plasma, which is
the sum of D2 and D3. The level of 25(OH)D is influenced by
changes in synthesis or intake of vitamin D, otherwise the levels
are stable (91). The Institute of Medicine has issued
recommendations with a decision limit of serum concentrations
of at least 50 nmol/L, which are adopted in this thesis (92,93).
Regarding lactation, vitamin D content in human milk is low
and the infant stores of vitamin D are limited, with depletion
around 8 weeks of age (84). Nevertheless lactation contributes
about 200 mg/day calcium to the newborn child through breast
milk (94).
12
Introduction
Basic regulation of food intake
Food intake and appetite are strictly regulated by a complex
control system. In the human body there is an interaction
between the gut, brain, adipose tissue together with major
organs to control the food intake for maintenance of the body’s
energy metabolism. The nervous system is used to communicate
these interactions together with several hormones, peptides and
neurosteroids that both stimulate and inhibit the appetite (95).
In the hypothalamus several nuclei influence food intake by
regulating circulating hormones and neuronal activity to nuclei
in the brainstem (95,96).
Regulation of food intake is also controlled by two
complementary units: the homeostatic and the pleasure
(hedonic) systems. The homeostatic system controls energy
intake when energy stores are depleted. The pleasure signals act
by reward regulation and can, for example, increase the desire
to eat tasty food or use a drug. Cognitive and emotional factors
can take precedence over the homeostatic metabolic system and
cause an unbalanced state of energy (97,98).
In this thesis I will mainly focus on pregnancy and the relation
to Gamma-butyric-acid-A (GABA-A) receptor-modulating
steroids, especially allopregnanolone as this steroid increases
substantially during pregnancy.
Steroid hormones and neuroactive steroids like
allopregnanolone
During pregnancy large amounts of progesterone are produced
by the placenta. A metabolite of progesterone, allopregnanolone, is also produced by the placenta and increases in
serum parallel with progesterone. Allopregnanolone is also
produced by the fetus and the concentrations are higher in the
fetus than in the mother. During pregnancy the allopregnanolone levels increase considerably, up to 100 times
higher than in non-pregnant women (99,100). Besides being
synthesized in the placenta, allopregnanolone is synthesized in
the maternal brain, adrenal and ovary, and is also high in the
fetus circulation and brain (101–104).
13
Introduction
Steroids are synthesized from cholesterol and metabolized to
different types, progesterone being one primary type (105).
Neuroactive steroids are small lipid-soluble molecules active in
the central nervous system. They easily pass the cell membranes
and blood-brain barrier and bind to receptors to exert their
effect (106). Allopregnanolone binds to and acts as a potent
positive modulator of the GABA-A receptor (107,108). It is now
known that the GABA system and thereby allopregnanolone is
central in the regulation of satiation and appetite. Activation of
the GABA-A receptors in the regulation centres for food intake
leads to overeating and in time to weight gain and obesity. In
non-pregnant women one example is that allopregnanolone
levels fluctuate during the menstrual cycle (109,110) and mean
physiological values in healthy women are 0.3–1.9 nmol/L in
the follicular phase and 1.1–3.7 in the luteal phase (111–113).
Several studies have shown an increased energy intake during
the luteal phase of the menstrual cycle and cravings have also
been reported (114,115).
Pregnancy and allopregnanolone
Allopregnanolone has many functions related to maternal
neuroendocrine stress responses. During pregnancy the levels
of the sex steroids estradiol and progesterone and its metabolite
allopregnanolone
increase.
Progesterone
secretion
is
established and maintained during pregnancy. Allopregnanolone is important to maintain many of the necessary
adaptations in the woman’s body during pregnancy. One is to
protect the fetus from maternal stress hormones and
unfavourable birth outcomes; another is to secure fetal growth
and brain development (116).
Allopregnanolone and food intake
Steroid hormones such as allopregnanolone are, as mentioned
earlier, highly involved in food regulation and satiety among
other effects in the body (117). In conjunction, hunger, satiety
hormones (e.g. ghrelin, leptin) and steroids regulate the
nutritional signals with initiation, frequency and size of meals
(118–120).
14
Introduction
Allopregnanolone is well-studied and higher levels have been
measured in overweight and obese humans compared to
normal-weight girls, men and women (121,122). Turkmen et al
found that uncontrolled eating is significantly related to
allopregnanolone levels in women with polycystic ovary
syndrome (123). The results of a new thesis show that
allopregnanolone can act at different levels of feeding and can
thus be involved in weight gain (124). The energy intake in
rodents increased under the influence of allopregnanolone;
both amount eaten and lengths of eating increase with
increasing allopregnanolone. In addition, when a choice of food
was possible, energy-rich foods were preferred. The increased
weight gain was correlated to intake of energy-rich foods (125–
127).
The GABA system and allopregnanolone
GABA is the main inhibitory neurotransmitter in the central
nervous system. GABA-A receptors contain subunits forming a
chloride channel. When GABA activates, chloride ions pass and
hyperpolarization of the post-synaptic cell membrane follows.
Allopregnanolone modulates and influences the channel’s
opening time (116). This means that, depending on the
concentrations of allopregnanolone, the receptor either
activates for a prolonged opening time and the GABA inhibitory
effect enhances (128). GABA activates different subtypes of
receptors (A, B, C), GABA-A is affected by modulators such as
allopregnanolone, but also by barbiturates and benzodiazepines
(107,129). The subtypes of the GABA-A receptors related to food
intake regulation are found in the hypothalamus, around the
arcuate nucleus, the key node for energy regulation (117).
The rationale
A well-balanced diet and healthy weight gain in the mother
provides good conditions for the well-being of both the mother
and the growing baby (3). A poor diet and sedentary lifestyle
may cause illness. Especially obesity and excessive weight gain
entails a risk for complications associated with pregnancy,
delivery and infancy. Eating habits can be difficult to change,
therefore, it is advantageous to adopt and maintain good habits
15
Introduction
already before pregnancy but in antenatal care from early
pregnancy. Based on the above facts, it is interesting to further
explore more about the complexity of being pregnant in relation
to nutritional aspects; to adapt daily lives to restrictions in areas
such as food intake and weight gain while physical and
psychological changes occur. Studies on dietary intakes,
including vitamins, during pregnancy are sparsely studied in a
Swedish context. Variations of allopregnanolone levels and its
relationship to weight gain are above all studied in rodents.
There also are few longitudinal studies on vitamin D levels
among pregnant women in sub-Arctic areas. Nevertheless, it is
therefore important to increase knowledge and understanding
about women’s nutrition in the context of being pregnant and
becoming a mother.
16
Aims
Aims of the thesis
The overall aim of this thesis is to describe dietary intake,
vitamin D-levels, dietary information and dietary changes, and
to study the relation between allopregnanolone and weight gain
during pregnancy and postpartum.
The specific aims of the four papers in the thesis were:
Paper I
To describe women’s attitudes to and experiences
of dietary information and advice as well as dietary
management during pregnancy.
Paper II
To compare dietary patterns of early pregnant
women with non-pregnant women in the county of
Västerbotten, Northern Sweden.
Paper III To longitudinally assess vitamin D status during
pregnancy and postpartum, and to identify factors
associated with vitamin D status, including intake
and seasonal variations, in pregnant women in
northern Sweden (latitude 63.8°N).
Paper IV To examine whether allopregnanolone levels relate
to weight gain during pregnancy in a group of
pregnant women.
17
Methods
Methods
The studies in this thesis are based on qualitative and
quantitative methods to examine the research field from
different angles and with different scientific approaches.
Table I. Material and methods used in the studies comprising
this thesis.
Paper
I
II
III
IV
Design
Qualitative
design
Crosssectional
cohort study
Longitudinal
cohort study
Longitudinal
cohort study
Participants
Pregnant
women
(n=23)
Pregnant
women
(n=209).
Reference
women
(n=206)
Women
pregnant
and
postpartum
(n=184)
Pregnant
women
(n=59)
Data
collection
Focus
groups (n=6)
FFQ and
excerption of
data from
medical
records
Blood
sampling
FFQ
Excerption
of data from
medical
records
Blood
sampling
Weight
measures
Excerption
of data from
medical
records
Biochemical
analysis
–
–
25(OH)
vitamin D
Allopregnanolone
Inclusion
period, year
2007
2006–2009
2006–2009
2006–2009
Analyses
Content
analysis:
domains,
subthemes,
themes
Descriptive,
comparative
statistics,
partial least
squares
analysis
(PLS)
Descriptive
comparative
statistics,
linear mixed
model
Descriptive
nonparametric
statistics
18
Methods
Study I
Material and methods
Focus groups are well established and commonly used for data
collection in health care research. In focus groups, interactions
between participants are an important element when talking
about experiences, beliefs and views concerning a specific
phenomenon or topic chosen by the researcher. The moderator
leads the discussion according to an interview guide with
questions/areas related to the selected phenomenon. Follow-up
questions are used to clarify and deepen the conversation. The
process promotes and stimulates both depth and breadth in the
discussion. Various individual experiences, new thoughts and
ideas are generated and expressed among active participants,
and unanticipated issues may be brought up (130,131).
Participants
We contacted midwives at five antenatal clinics in primary care
and asked them to distribute written information about the
study in their ongoing antenatal classes. The health care centres
were located in small (n=2), midsize (n=1), and urban towns
(n=3). All women were first-time pregnant except for one
woman who had had a stillbirth. We visited their classes and
gave further information combined with an invitation to
participate in a focus group interview. The interviews were
conducted in a room at the health care centre. In total 27
women agreed to participate but four of them did not show up
at time of the session. Each woman participated in only one of
the six focus groups, so the study included 23 women in total.
Characteristics of the participating women are shown in Table
2. None of the women reported that they smoked.
19
Methods
Table 2. Characteristics of the participants in study I.
Characteristics (n=23)
Age (median (range))
Cohabitating/Single living (n)
Urban/Rural residence (n)
29 (19–41)
21/2
16/7
Highest education:
University (n)
High school (n)
Compulsory school (n)
16
5
2
No dietary preferences (n)
Lacto-vegetarian (n)
21
2
Interviews
In 2007, we conducted six focus group interviews at the health
care centres. AnnaLena Wennberg, the first author, and I acted
as either moderator or observer in all the interviews. We
designed and used an interview guide with open-ended
questions covering the research aim. We wanted to get more
knowledge about sources of dietary information that women
experienced, as well as how they experienced and handled the
advice. The participating women had met previously through
parental education classes and they were thus acquainted with
each other before the interview. The interviews were audiorecorded, lasted about 45 minutes and were transcribed
verbatim. The initial questions were followed by exploratory
and follow-up questions such as “please tell more“, “what are
your thoughts about that?”, “please explain how you reacted
and felt”. It was easy to start a fruitful discussion in the groups.
The conversation flowed and the participants’ different
experiences and opinions were ventilated. Participants who
were more reticent could be drawn into the conversation
through the follow-up questions and the discussion thereby
deepened.
20
Methods
Studies II–IV
Settings
All studies are based in Swedish primary care in Västerbotten
County Council.
Sample size
The recruitment of the cohort proceeded from a power
calculation based on Koebnick et al in a study of 39 pregnant
women from first to third trimester (132). Using Koebnick’s
data for vitamins B12 and folate and homocysteine with
differences between first and third trimesters showed that we
would have a statistical power of at least 80% if 200 women
were included.
Participants
The enrolment and attendance for the cohort is described in
Figure 2. The population in study II is based on the cohort on
the first sampling occasion (weeks 10–12). In study III
participants who provided blood samples on 3–5 occasions are
included. Study IV is based on a stratified sample of
participants (described later in this chapter) from the cohort on
the first and third sampling occasions.
We included 226 pregnant women from five health care centres
representing a socio-economic and geographical cross-sectional
sample. Women at their first visit to the antenatal clinics during
the recruitment period were offered information on the study by
the midwives. Women who expressed an interest in
participating were given verbal and written information, and
were invited to participate. The exclusion criteria’s were: major
medical conditions, being unable to attend the ordinary
antenatal programme, and insufficient competence in the
Swedish language. All data were collected in connection with
ordinary antenatal visits except for the last occasion, when the
women booked an appointment at the health care centres.
There were no differences in the available social parameters
between the dropouts and those with three or more sampling
21
Methods
occasions. In addition to the dropouts, 27 questionnaires
scattered over the study period were not collected and six blood
samples were not provided. The enrolment process was handled
by the midwives and we had no face-to-face contact with the
participants during the study period.
22
Methods
Pregnant women consecutively
recruited at enrolment in
antenatal care (n=226)
Dropout reasons:
occasion 1 (n=34)
occasion 2 (n=8)
moved, abortionmiscarriage, no
reason given
184 women
attended on 3–5
occasions
scattered over
the study period:
126 on five
occasions
40 on four
occasions
18 on three
occasions
1st
Gestational week 10–12. Sampling
(n=224)
2nd
Gestational week 19–21. Sampling
(n=191)
3rd
Gestational week 34–36. Sampling
(n=174)
4th
Postpartum week 9–12 Sampling
(n=160)
2006–2009
Blood sampling
(n=894)
Anthropometry
questionnaire
including FFQ
(n=868)
Data from
medical
records
5th
Postpartum week 28–30 Sampling
(n=145)
Figure 2. Enrolment and attendance of pregnant women in the
cohort
23
Methods
The questionnaires
The self-reported questionnaire was the same as used in the
Västerbotten Intervention Programme (VIP) for health survey,
including a food frequency questionnaire (FFQ) of 66-items.
Questions about socioeconomics, psychosocial conditions,
marital status, and level of education, self-rated health,
personal health history, family history, and quality of life (SF36)
were also included. The questionnaire also covered social
network and support, working conditions, physical activity,
alcohol consumption, tobacco use, and dietary supplement use.
Body weight (light clothing) and height (no shoes) were
measured at the same time as blood samples were collected. The
pregnant women were informed to answer the questions about
the last 14 days. All data both from questionnaires and blood
samples were administered and stored in Northern Sweden
Biobanks in Umeå.
Estimation of dietary intake
In the FFQ, the women reported their consumption frequencies
on a nine-level scale from 0 (never) to 8 (4 times/day or more).
The FFQ included eight questions about the frequency of
consumption of various types of fats; nine on milk and other
dairy products; seven about bread and cereals, six about fruit,
greens and root vegetables; six questions on soft drinks and
sugar-containing snacks; and five questions on spirits, wine and
beer consumption were included in a list of beverages. Twenty
of the remaining 25 questions recorded intake of potato, rice,
pasta, meat and fish, and five were on varied items, such as salty
snacks, coffee, tea and water.
The participating women indicated their average portion of
potato/pasta/rice, vegetables, and meat/fish by looking at four
colour photographs illustrating four plates with increasing
portion sizes of potatoes, vegetables, and meat. The reported
consumption frequencies were converted to number of intakes
per day. The content of energy and nutrients was calculated by
multiplying daily intake frequency by the portion content
according to the specific nutrient in the database provided by
the NFA (Uppsala, Sweden) (133).
24
Methods
Blood sampling
Blood samples were collected after 15 minutes’ seated rest. The
participants were asked to fast and 97.8% of them had at least 8
hours of fasting before blood sampling, the remaining had 4–8
hours of fasting. Peripheral venous blood was drawn, with no
stasis used, into vacuum tubes, one containing EDTA, one with
heparin and one serum tube suitable for trace metal analysis,
total volume 25 mL. Plasma or serum was obtained by
centrifugation at 1500 g for 15 minutes. Plasma and serum were
aliquoted in smaller plastic tubes. Aliquots of buffy coat as well
as erythrocyte fractions were also collected. All samples were
stored frozen at –80 °C until analysis. Sampling procedures
were handled in accordance with VIP routines (134).
Participants – Study II
Participating women were recruited as described previously. A
reference group of 206 women was nested from the current VIP
(135). A flow diagram of the study population is presented in
Figure 3.
Pregnant women
recruited at
enrolment in
antenatal care
(n=226)
Not fulfilling FFQ
quality criteria
(n=17)
Study group
(n=209)
Reference group
(n=206)
Figure 3. Participants in study II.
25
Västerbotten
Intervention
Program (VIP)
Methods
FFQ data were used to estimate dietary intake. VIP invites all
40-, 50-, and 60-year-old inhabitants in Västerbotten County to
a health screening; 30-year-olds are invited in some
municipalities. The references were selected and had
participated in VIP during the same recruitment period as the
pregnant women. We included all 30-year-old women from the
Umeå area together with an equal-sized 40-year-old group of
women (n=206). The reference women completed the same
FFQ as the pregnant women but they reported their food intake
during the last year while the pregnant women reported their
intake during the previous two weeks. Characteristics of the
participating women are shown in Table 3.
26
Methods
Table 3. Characteristics of the participants in study II.
Pregnant
women (n=209)
Reference
women (n=206)
Age (years):
Mean, Standard deviation (SD)
Median, min - max
30.4 (4.2)
30.0 (21–42)
35.0 (5.0)
37.0 (30–40)
Married or cohabitating (n)
/single living (%)
206/3
(98.6/1.4)
170/35*
(82.9/17.1*)
Nullipara/Multipara (n, %)
131/78 (62.7/37.3)
—
Singleton/twin pregnancy (n)
206 / 3
—
University degree (n, %)
126 (60.3)
99 (48.3)
High school/Compulsory
school (n, %)
83 (39.7)
106 (51.7)
Born in Sweden/other origin
(n)
197/12
Not available
Starting BMI
(kg/m2 (mean (SD))
BMI groups (n, %)
< 24.9
25–29.9
≥ 30.0
24.2 (4.8)
—
144 (68.9)
47 (22.5)
17 (8.1)
127 (61.7)
50 (24.3)
29 (14.1)
1/2
13/26
Smokers/snuff users (n)
*stated as unmarried.
Participants – Study III
Study III included 184 women recruited as described
previously. They participated in three to five sampling occasions
during the study period. The number of blood samplings varied
depending on the different participation at each sampling
occasion, for example; a participant who provided three blood
samples could have provided them in week 12, week 21 and 12
weeks postpartum. EDTA-plasma was used to analyse
concentrations of vitamin D and FFQ for dietary intake. A flow
27
Methods
diagram of the study population is presented in Figure 4
followed by characteristics (Table 4).
Pregnant women
recruited at
enrolment in
antenatal care
(n=226)
Not fulfilling inclusion criteria
<3 sampling occasions (n=42)
Women included
in the study
(n=184)
1st
sampling
occasion in
gestational
week 12
(n=145)
2nd
sampling
occasion in
gestational
week 22
(n=179)
3rd
sampling
occasion in
gestational
week 35
(n=174)
Figure 4. Participants included in study III.
28
4th
sampling
occasion in
postpartum
week 12
(n=155)
5th
sampling
occasion in
postpartum
week 29
(n=145)
Methods
Table 4. Characteristics of the participants in study III.
Characteristics (n=184)
Mean (SD)
Age (21–42 years)
31 (4.4)
Proportions
(%)
Born in Sweden
93.5
Married or cohabitant
98.7
University education
59.4
Nullipara/multipara
62.2/37.8
Singleton/twin pregnancy
97.8/2.2
Gestational length (weeks)
39.4 (1.7)
Starting BMI (kg/m2)
Reported total energy
(kcal/day) (mean (SD))1
24.1 (3.8)
1,629 (476)
1Energy
intake was increased by 25% to adjust for underreporting due to the short FFQ as
described in study II (136).
Participants – Study IV
For study IV a sample of 60 pregnant women was included from
the larger cohort of 226 women. The women were stratified on
the basis of weight gain and they were divided into two weight
gain groups based on the median value of 11 kg: <11 kg (n=29),
≥11 kg (n=30). EDTA-plasma was used to analyse
allopregnanolone from gestational week 12 and 35. The internal
loss is represented by three women who did not provide blood
sample in week 35 which means that 56 blood samples are
analysed in week 35. The aim in the recruitment was to have a
spread in the weight increase during pregnancy and to cover the
weight gain area. A flow diagram of the study population is
presented in Figure 5 followed by characteristics (Table 5).
29
Methods
Pregnant women
recruited at
enrolment in
antenatal care
(n=226)
Recruitment of 60 women
with weight gain under
(n=30) and over (n=30) 11
kg
No blood samples on
both occasions (n=1)
No blood samples at
week 35 (n=3)
Women included in the
study (n=59)
Weight gain group < 11 kg
from week 12 – 35 (n=29)
Weight gain group ≥ 11 kg
from week 12 – 35 (n=30)
Figure 5. Participants included in study IV.
30
Methods
Table 5. Characteristics of the participants in study IV.
Characteristics
(n=59)
Age (years)
Married or cohabitant (%)
Born in Sweden (%)
University education (%)
Birth weight (g)
Placenta weight (g)
Median
(min–max)
32.0 (21–39)
98.3
91.5
66.1
3550 (2445–4640)
575 (340–890)
Weight total (kg)
Gestational week 12
Gestational week 35
66.0 (47–120)
78.0 (56–127)
BMI total (kg/m2)
Gestational week 12
Gestational week 35
23.7 (18–41)
28.0 (22–43)
Starting weight (kg) week 12
Weight group < 11 kg
Weight group ≥ 11 kg
66.0 (47–120)
65.5 (50–86)
Follow-up weight (kg) week 35
Weight group < 11 kg
Weight group ≥ 11 kg
72.0 (56–127)
79.5 (62–103)
Analysis
Study I
Qualitative content analyses focuses on the subject and the
material to analyse both manifest and latent content. The
analysis deals with interpretation but the interpretations vary in
depth and level of abstraction. Differences between and
similarities within codes and categories are sought (137, 138).
The transcribed text (verbatim) was analysed according to
procedures described by Graneheim and Lundman (137). First
31
Methods
we listened to the recordings for comparison with the text mass
to perceive any non-verbal expressions or signs that could be
applied to the text, e.g. laughs and breaks. Notes had also been
written down during the interviews by the observer, which were
also available for completion. The interviews were read several
times to get an idea of the whole picture, such as a general
perception of what has emerged, and we compared and
discussed this in our research group. The text was then divided
into meaning units according to the aim. A meaning unit is
words, sentences or paragraphs with content and context
related to one another close to the text (137). The next step was
to shorten the meaning units, to condense but keep the core.
Then the meaning units were labelled into codes, with the whole
context in mind. Various codes were compared based on
similarities and differences individually and then we compared
and discussed them together with the research group. Codes
were then labelled and linked to domains based on the subject
areas. According to Graneheim and Lundman (137), a domain
sheds light on a specific topic of content with marginal
interpretation from parts of the text. The codes were further
abstracted by content, creating 11 subthemes and four themes.
The themes answers the question “How?” and have a thread of
an underlying meaning from meaning units to subthemes with a
higher level of interpretation (137). The whole process of
abstraction from codes to subthemes and themes was reflected
on and discussed recurrently in the research group until
agreement was reached. In this process we went back to the text
several times to check that we had understood and interpreted
correctly so nothing contradictory had emerged on the path to
the themes that were found. The analysis process on one of the
themes, “Being responsible but with a pinch of salt”, is seen in
Table 6.
My contribution
I am the second author of this paper. I participated in the
planning, design of the study and collection of data. I also
participated actively in the analysis process and critical revision
of the manuscript.
32
Methods
Table 6. An example of the analysis process from meaning unit to subthemes and theme.
Condensed meaning units
Codes
Subthemes
Theme
“more careful with vegetables, fruit almost manic”, “observant out in cafés,
what’s in the sandwich?”, “I buy Swedish products”, “I eat self-caught trout”,
“know the origin and the handling feels healthy”
--------------------------------------------------------------------------------------------“there is much to watch out for if you want”, “but it depends on how much one
absorbs”, “I have used my common sense”, “mother said, ‘In my time there
was no rule like that – use your common sense.’”
-------------------------------------------------------------------------------------------“I eat as I used to”, “eat almost as usual”
--------------------------------------------------------------------------------------------“I watch out and eat nothing inappropriate”, “I keep away from what’s
forbidden”, “it is not so awkward for me...”
-------------------------------------------------------------------------------------------“I take it with a pinch of salt...have avoided to some extent”
-------------------------------------------------------------------------------------------“sometimes can’t do any harm”, “I make exceptions sometimes with ham”,
“small deviations in general … follow the advice later”
-------------------------------------------------------------------------------------------“I put it aside during Christmas”, “I let loose on the Christmas
table...otherwise not been eating anything”
-------------------------------------------------------------------------------------------“take a small slice because it’s tasty”, “if weight gain is normal you can indulge
in things”
-------------------------------------------------------------------------------------------“the body tells you and gives signals about what it wants”, “my taste has
changed”, “I fancy snacks”, “I’m hungry for milk products”, I had a need for
juices, fruit and vegetables“
More observant of what is eaten. Want to know food
content
Checking food
content
--------------------------------------------------------------Much to concern about. Choose what you bother
about. Use common sense. Relate to the past
--------------------Using common
sense
Being
responsible
but with a
pinch of
salt
-------------------------------------------------------------Eat as usual
-------------------------------------------------------------No fuss for me
-------------------------------------------------------------Take with a pinch of salt
-------------------------------------------------------------Make a few exceptions
--------------------Making
exceptions
-------------------------------------------------------------Put aside on grand occasions (Christmas)
-------------------------------------------------------------Want to enjoy good food
-------------------------------------------------------------The body tells you what it wants
33
-----------------Following body
signals
Methods
Statistical analyses in studies II–IV
IBM SPSS Statistics version 20/22 (IBM Corporation, New
York, NY, USA) was used for all calculations in studies II–IV.
Study II
Multivariate PLS modelling was used to search for clustering of
subjects and to identify factors associated with being a pregnant
or reference women. PLS handles all variables, including those
that co-vary, simultaneously, after auto scaling to unit variance
and transformation of non-normally distributed variables, and
creates a pooled point estimate for each woman. The method
searches for structures between the x-swarm (here diet and
some subject characteristics) and the outcomes (here being a
pregnant or reference women) (139). Detailed information on
variables in the independent (x-data) matrix are presented in
Paper II.
Dietary variables were estimated amounts eaten per day and
presented as mean with 95% confidence intervals. For alcohol
median and range (minimum-maximum) was set. Categorical
variables were presented in percentages. To test for differences
between groups we used Student’s t-test and a Mann Whitney U
test for alcohol. For categorical variables we used Pearson Chisquare test; when there were five or lower in each cell Fisher’s
exact test was used. Mean values between all pregnant and
reference women were adjusted for BMI, education, smoking
and age group in a generalized linear model. Macronutrients
(fat, protein, carbohydrates) are presented as energy percent
(E%). E% means the proportion of macronutrients provided as
percentages of the total energy intake. The level of significance
was set at 0.01, two-sided.
Study III
A failure analysis was made of the 42 women who provided ≤ 2
samples which showed only marginal/no differences in
characteristics. Levels of vitamin D were also analysed in those
women who had a miscarriage, abortion or missed abortion and
34
Methods
the mean value was 60.5 nmol/L compare to 57.7 nmol/L in the
184 women participating in the study.
Mean value and standard deviations are presented for
continuous variables. Categorical variables are presented as
percentages. To compare mean values of different variables with
vitamin D levels at each sampling occasion we used Student’s ttest. To investigate correlations between BMI and vitamin D
levels at each sampling occasion Spearman’s correlation
coefficient (rs) was used. A linear mixed model was used for
both univariate and multivariate analyses to test relationships
between vitamin D concentrations in plasma and different
factors. The vitamin D levels were not linear, for each pregnancy
week the levels slightly increased. Therefore a square term of
gestational week was used in the linear mixed model. The level
of significance was set at 0.05, two-sided.
Study IV
Non-parametric statistics were used. Continuous variables were
presented with median and range (minimum and maximum).
Categorical variables were presented with percentage.
Correlations by Spearman’s coefficient (rs) were used to test
relationships between the weight gained (wk 12–35) and the
allopregnanolone increase (wk 12–35) and between
allopregnanolone concentrations at the end of pregnancy and
the weight gained (wk 12–35). The participants were divided
into weight gain group low (<11 kg) or high (≥11 kg). The
differences in distribution between weight increase,
allopregnanolone, birth and placenta weight at each sampling
occasion (e.g., wk 12, 35) were tested with a Mann Whitney U
test. The level of significance was set at 0.05, two-sided.
Biochemical analyses studies III–IV
In study III, concentrations of 25(OH)-vitamin D in EDTAplasma were analysed with liquid chromatography-tandem
mass spectrometry (LC-MS/MS). The method allows for the
separation of D2 and D3 forms of 25(OH)-vitamin D.
35
Methods
In study IV, allopregnanolone in EDTA-plasma was analysed
using Radio-Immuno Assay (RIA) technique, previously
described in detail by Timby et al (113). To quantify the plasma
samples, 0.4 mL was extracted with diethyl ether (Merck KGaA,
Darmstadt, Germany). Purification and separation of
allopregnanolone from cross-reacting steroids was done with
celite chromatography. Allopregnanolone was measured by RIA
using a polyclonal rabbit antiserum raised against 3 α-hydroxy20-oxo-5α-pregnan-11-yl-carboxymethyl ether coupled to
bovine serum albumin, provided by RH Purdy (The Scripps
Research Institute, La Jolla, CA, USA) (140). The sensitivity of
the assay was 25 pg. The intra-assay coefficient of variation was
6.5%, and the inter-assay coefficient of variation for the
allopregnanolone assay was 8.5%.
Ethical considerations
The study was approved by the Regional Ethical Review Board
at Umeå University, Sweden (Dno 04-171 M).
The ethical application included permission from the Data
Inspectorate regarding data storage and handling of sensitive
data. In study I we collected informed oral approval before the
interviews were booked and information was given about
protection of confidentiality due to the recorded interviews. For
studies II–IV, information was given both orally and in writing
about the whole procedure, confidentiality, data handling and
the assurance that participants could withdraw at any time.
Written consent was collected at the start in early pregnancy
and also for each sampling occasion according to Biobanks
routines.
Ethical reflections
Different ethical considerations were brought up when planning
and collecting the data. One reflection concerns participation; it
is possible that the women found it difficult to decline
participation as the midwife also performed routine medical
care. The ability to say no without any negative consequences
was clearly expressed in the oral and written information. We
36
Methods
talked about that issue with the midwives before starting so they
would be aware of different reactions. Neither I nor the other
researcher were involved in the care of the women, which
reduced the risk of dependence on the researcher. I have also
thought of the questionnaire, which is quite extensive and could
be perceived as a privacy violation, but we heard no such views.
However, what came to our attention was that it was
comprehensive, which could be perceived as a hassle. I would
also like to bring up the food registration as a risk for concern
about women’s own composition of the diet. The midwives
received certain nutritional training from the researchers so
they could be aware and be prepared for participants’ questions
about diet. A small but still important reflection is about blood
sampling and fasting, which can feel painful and tough if one
has morning sickness. The staff offered women juice to drink
and biscuits after sampling. Waiting times at the blood samples
and other practical inconveniences were also the reason for
some women to dropout after 1–2 occasions as we were told. All
blood samples were frozen and stored until analysis. Any
deficiencies such as low haemoglobin levels would be
discovered in blood tests by the antenatal base program.
37
Results
Results
Study I
Table 7 briefly presents the themes.
Table 7. A summary of findings in study I.
Domains
Dietary information
gain
Reactions to dietary
information
Dietary management
Subthemes
Having private talks
Reading by oneself
Getting guidance for
deviances
Getting guidance for
symptoms
Being confused
Feelings of fear and
guilt
Being monitored
Checking food content
Following body signals
Using common sense
Making exceptions
Themes
Finding out by oneself
Getting professional
advice when health
problems occur
Being uncertain
Being responsible with
a pinch of salt
The themes “Finding out by oneself” and “Getting professional
advice when health problems occur” were interpreted from the
women’s described experiences.
Finding out by oneself:
“You read through these booklets you get from the midwife, but
especially about diet, I think there is very little written in the
material you get. So it’s mostly on the Internet you find
something.”
Getting professional advice when health problems occur:
“My levels of iron began to decline and I heard (from the
midwife) that I should eat liver paté and black pudding.”
The women were interested and wanted information and
support about healthy food for themselves and for the child.
They were also concerned about risks and closely followed the
recommendations. However, they experienced that dietary
38
Results
information was partly up to them to find out by searching in
the media, talking with friends and relatives. They were given
some booklets by the midwife but not enough to interpret and
show how to handle their everyday food choices. When
deficiencies or symptoms occurred advice was given by the
midwife. The women experienced different reactions related to
the information or advice according to the theme “Being
uncertain”.
Being uncertain:
“You should eat this fish but not that one, which leads you to
avoid all fish so you don’t risk eating the wrong kind, but then
you don’t get enough Omega 3… so it’s a bit confusing.”
They described positive and negative experiences of feeling
watched over by other people, for example what they were
eating. Feelings of fear and guilt arose when eating something
they should not have, related to the risk of harming the baby.
Situations that could cause emotions of confusion were when
dietary advice felt contradictory or different in various contexts
and they didn’t know how to find out what is the right thing to
do.
This theme deals with women’s ways of managing the dietary
advice about what to eat and what to avoid due to health risks.
Being responsible with a pinch of salt
“Well, it’s like this; I have handled it with a pinch of salt,
because I really don’t bother to find out about everything; at
the same time, I pay attention, of course, and don’t eat
anything inappropriate.”
The women talked about being stricter by following the advice
particularly in the early phase of pregnancy with a more easygoing style in late pregnancy. Minor exceptions from
recommendations were regarded as acceptable and mentioned
in all groups, on special occasions like Christmas. They also
talked about knowing the origin of the food, organic or
homemade food. To listen to and follow your body signals was a
way to make the right food choices; the body give signs about
what they wanted to eat and preferred not to eat. Most women
39
Results
said that they wanted to use their common sense in decisions
about food choices, selecting among the large flow of information to make their own sensible decisions.
Study II
When we compared the dietary pattern of the pregnant women
to the reference women, the pregnant group differed to some
extent, which is illustrated in the PLS analysis (Figure 6).
Clustering of participants is displayed in a score loading plot
with t[1] and t[2]on the x- and y-axis. The two axes are
significant components used for the projection, t[1] and t[2]
with the optimal separation of the variables in the model. The
differences in dietary intake between the two groups are
quantified and stated in percentages and adjusted mean values,
is presented in Table 8. Both groups reported a lower intake
from foods of folate and vitamin D compared to the NNR (Table
9) (11). Pregnant women had lower intake of alcohol and use of
tobacco/snuff than reference women.
40
Results
Figure 6. Clustering of dietary patterns for pregnant and
reference women, a) <35-year-old and b) ≥35-year-old women.
Table 8. Dietary intake compared between groups of women.
Multivitamin (%)
Multimineral (%)
Iron supplement (%)
Vegetables (g/day)
Potatoes/rice/pasta
(g/day)
Meat/fish (g/day)
Iron by food (mg/day)
Folate intake by food
(µg/day)
Vitamin D intake by food
(µg/day)
Early pregnant
women
42.6
17.2
11.0
97.7
167.1
Reference women
14.1
4.4
5.8
144.7
197.9
103.3
13.0
276.5
127.0
14.5
312.8
6.6
6.6
Study III
Mean levels of vitamin D increased by gestational length at each
sampling occasion, 55.2, 60.2, 64.6, 54.2, 53.5 nmol/L, with the
highest levels observed in late pregnancy. The distribution in
categories showed that a least a third of the women had
insufficient plasma levels of vitamin D (<50 nmol/L) during the
study period (37.2, 38.0, 33.3, 38.0, 42.0%).
Box plots in Figure 7 visualize how median values are
distributed over the study period, a) plasma concentrations of
25(OH)D, b) self-reported estimated dietary intake of vitamin
D by foods. Vitamin D concentrations show a greater variation
than dietary intake, which shows a more stable pattern.
41
Results
a)
b)
Figure 7. Box plots showing total plasma concentration and
estimated dietary intake of vitamin D on sampling occasions 1–
5.
42
Results
The linear mixed model analyses showed that gestational week,
season, total energy intake, dietary intake of vitamin D, and
multivitamin supplementation over the previous 14 days were
factors related to vitamin D levels of the participating women.
The individual patterns show that seasonal variation influenced
the baseline values and longitudinal patterns of vitamin D levels
during and after pregnancy.
Figure 8 visualizes how median values of plasma concentrations
of 25(OH)D are distributed over the study period divided by
season i.e., a) winter and b) summer. This figure shows the
impact of summer season with substantially higher vitamin D
levels at each sampling occasion.
Figure 9 visualizes how median values from dietary intake of
vitamin D by foods are distributed over the study period divided
by season i.e., a) winter and b) summer. The estimated intake
by foods is quite stable, although we can notice a slight
increased intake on some occasions during the study period.
43
Results
a) Winter season 16/9–14/4
b) Summer season 15/4–15/9
Figure 8. Box plots showing total plasma concentration of
vitamin D on sampling occasions 1–5 divided by season.
44
Results
a) Winter season 16/9–14/4
b) Summer season 15/4–15/9
Figure 9. Box plots showing estimated dietary intake of
vitamin D by foods on sampling occasions 1–5 divided by
season.
45
Results
Study IV
The differences in distribution showed that the group of women
who gained ≥11 kg during pregnancy showed significantly
higher plasma concentrations of allopregnanolone (nmol/L) in
the 35th gestational week compared to the woman who gained <
11 kg (61.7 vs 45.4, p=0.006). Spearman’s ρ (rho) showed a
correlation coefficient of 0.288, (p=0.028), indicating a positive
relationship between the weight increase and the allopregnanolone increase. The correlation coefficient of 0.320,
(p=0.016), also indicating a positive relationship by correlation
analysis between allopregnanolone in the 35th gestational week
and weight increase.
Figure 10 shows that the increase in allopregnanolone (nmol/L)
from week 12–35 was significantly larger with a weight gain of ≥
11 kg compared women with a weight gain of <11 kg (median
36.5 vs 50.9, p=0.011).
46
Results
a)
b)
Figure 10. a) illustrates the increase of allopregnanolone
between the two weight groups and b) illustrates the weight
increase between the two weight groups. Median increase 6 and
14 kg respectively in groups low and high weight increase.
47
Discussion
Discussion
The overall aim of this thesis is to describe dietary intake,
vitamin D levels, dietary information and dietary changes, and
to study the relation between allopregnanolone and weight gain
during pregnancy and postpartum.
This thesis shows that pregnant women found dietary
recommendations confusing and difficult to interpret and deal
with. Pregnant women showed a desire for increased knowledge
about suitable safe food and there were demands for more
support from midwives on this issue. In early pregnancy, intake
by foods rich in iron was on the low side, folate and vitamin D
intake seemed to be insufficient compared to recommendations.
Dietary patterns of pregnant women reflected a lower intake of
vegetables, meat/fish, potatoes/rice/pasta, alcohol, and
tobacco/snuff compared to reference women. This was also
confirmed by low serum levels of vitamin D (<50 nmol/L) in at
least a third of the participants. Vitamin D levels increased to a
peak in late pregnancy and we found several factors that related
to levels of vitamin D, with season being the strongest. Finally,
we also found that higher weight gain was related to higher
allopregnanolone levels. Allopregnanolone seems to be a factor
involved in the complex mechanisms of weight increase.
In study I women described their experiences of gaining control
over food content, by closely following the list of “approved”
food and checking the food content when shopping or when
eating in restaurants. Even at dinners with friends and among
the family they were quite thorough with what they ate and
conscious exceptions were occasional, as for example at
Christmas. The reason for their concern was the risk of harming
the child that was also expressed. This is in agreement with
Lupton et al, who stated that women are expected to deliver a
healthy baby by monitoring and regulating their own actions
with the goal of creating a safe environment in the uterus in
which nothing harmful can happen. However, risk thinking can
take over and create feelings of pressure and anxiety (141),
which seems to correspond with our findings even though our
women described ways to handle it.
48
Discussion
The findings about the lack of dietary advice in study I are
supported by Lucas et al (142) who concluded in a systematic
literature review that women generally do not receive adequate
nutrition education during pregnancy. Routinely having
assistance to facilitate informed decision is also questionable.
The reason for that could be speculated about but according to
Arrish et al (143) nutrition education content in midwifery
programmes is inadequate, which leads to a lack of knowledge
in midwives regarding nutrition requirements. Wennberg et al
interviewed midwives who talked about their lack of knowledge
on nutritional issues in the care of pregnant women in need of
counselling. Midwives also had difficulties controlling or
evaluating sources of information on the Internet in their
ambition to support women to interpret various health
information (144). Another explanation could be unclear
guidelines on what should be communicated and how. In 2007,
the WHO published standards for maternal and new-born care
to secure nutritional education for pregnant women (145), and
recently a guide for pregnancy, childbirth, postpartum and newborn care has been published by the WHO for further
implementation in antenatal care (146). In a Swedish context
antenatal guidelines recommend midwives to give dietary
advice in early pregnancy but how the education should be
given is not further specified (18).
Tradition, social environment and cultural beliefs are factors
that influence eating habits. Food and its consumption culture
is one of the most important factors associated with the unique
culture of various ethnic groups or nations (quote from Nam et
al) (147). Knudsen et al (148) found age differences and regional
differences for alcohol consumption as well as for lactation
plans and food intake. Emmet et al (149) found differences in
nutrient intake and dietary pattern associated with maternal
educational level, smoking habits, and economic aspects.
There are conflicting results in studies due to improved diet
during pregnancy and lactation. Wennberg et al used a food
index to compare the healthiness of reported food habits.
During pregnancy women reported relatively unchanged food
habits with a lack of nutritious diet. Those who reported a
healthy food index at the beginning of pregnancy reported
49
Discussion
healthy eating throughout pregnancy. After birth generally
poorer diet content was reported, with less fruit and vegetables
(150). Findings by Smedley et al (151) showed a positive trend
towards a better diet and decreased fast food intake during
pregnancy.
I believe that becoming a parent should imply opportunities to
reflect on food-related issues with health care professionals who
are knowledgeable and inspire confidence. Larsson found in a
cross-sectional study that the Internet is a well-used source
among Swedish pregnant women. The women in their study
sought information on different issues related to pregnancy.
The women seldom discussed the information with their
midwives, however. The author suggests that midwives should
take the opportunity to discuss information with the women
during antenatal visits, and this is in line with the needs among
the women in study I who expressed uncertainty about
nutrition issues and a need for more knowledge (152). Having
midwives as a guide to good nutrition is important for parents
to help them to make informed choices. It should be easy for
parents to find out which food is beneficial and feel confident
about it. In a focus group study by Wise et al (153), pregnant
adults expressed their views about the development of a
nutrition intervention. A modern and youth-focused way of
education was advocated that motivates and encourages
behavioural changes. Methods of learning were video formats,
peer discussion and hands-on cooking with active participation
cooking. Education should be an expert-focused, competencybased and interactive display with simple, comfortable and
affordable cooking.
The low alcohol and tobacco/snuff usage found in study II can
be interpreted as adherence to current recommendations. The
sufficient intake of calcium could be explained by food habits
and taste depending on what you like to eat or drink, which was
also expressed in the study by Wise et al (153). Branum et al
found in a US study the lowest folate levels in the first trimester
and the use of folic acid or iron-containing supplements in 55–
60% of women in early pregnancy. In addition to supplements,
the American food supply had been enriched with folic acid
since 1997 (154). Both studies II and III reflect an inadequate
50
Discussion
intake of foods with important vitamins such as folate and
vitamin D. In early pregnancy (study II) intake of multivitamins
was reported in less than 50% of the pregnant women. This
supports the idea of a need for more knowledge and
understanding among health care professionals and coming
parents to prevent insufficient levels in important stages of fetal
development. When divided by season, we found a low but quite
stable intake of vitamin D by foods over the year, which
suggests that the nutritional content is roughly unchanged
among the participants. The intake among participants is
comparable with Jensen et al (155), who suggest supplements
for pregnant women to improve health. Plasma concentration in
study III, on the other hand, was significantly higher during the
summer season as expected and in line with other Swedish
studies (156,157). Some dairy products in Sweden such as milk
and margarine are fortified with vitamin D. A global summary
of maternal and new-borns vitamin D status found a European
maternal prevalence of low vitamin D levels in 57% with <50
nmol/L. For new-borns the prevalence was 73% and the
concentrations between mother and child were highly
correlated (86).
The iron balance requires stores of approximately 500 mg iron
in the beginning of pregnancy, according to NNR (22). In late
pregnancy an increasing amount of iron is transferred to the
fetus. This means that an additional amount of iron is required
usually in late pregnancy in order not to develop iron deficiency
or even to suffer from iron deficiency anemia (24). Study II
reflected an iron intake by food on the low side. In a Swedish
context, severe anemia during pregnancy with related
complications is fortunately uncommon. The reasons for this
are many, including social welfare, good public health and
access to proper antenatal care.
Results consistent with ours, as reported in a review by
Blumfield et al (158), found low intake of micronutrients in
developed countries. This is also supported by Emmet et al
(149). It is difficult to ensure adequate intake of folate and
vitamin D only from the diet depending on differences in intake
of food and exposure to sunlight. Vegetables, including beans,
fruit, berries, green leaves, liver, dairy products and fat fishes
51
Discussion
are rich in folate and vitamin D, but consumption of these food
groups varies a lot between pregnant women in different
countries.
In a Nordic perspective, we have quite good access to and
opportunities for necessary nutritional intake as well as
following food and lifestyle recommendations. Sweden is
considered to have a generally high level of knowledge with
respect to acquiring, understanding and using health
information. This is often referred to as health literacy and
facilitates the potential to make informed health decisions
(159). The women in study I had what I consider to be a high
educational level which they also used to make choices about
food content. Although variations occur among countries,
Lupatelli et al (160) conducted a multinational Internet-based
study on pregnant women which showed an association
between low health literacy and poor adherence to prescribed
medication. The International Adult Literacy Service (161)
reported that in Sweden about 10% of the adult population were
at the elementary level of health literacy. According to
Mårtensson and Hensing, a person with generally good health
literacy can, in some situations, have this literacy lowered due
to stress or unease (159). A pregnancy could be an example of
such a situation when certain requirements are made on one’s
lifestyle and changes to adapt to. The women in study I talked
about being watched over by others in the selection of different
foods. That also included their desire to find enough
information about suitable food, to feel safe and make the right
choices. There are many considerations that have to be made
which can cause pressure on the women. Too rapid a flow of
information can lead to a poorer ability to use health
information received. One example is recent research which
presents and considered as the “truth” but the next day is
replaced by another “truth” (159). Feelings of uncertainty and
confusion about what is right may come up and put one’s health
literacy out of order. These are feelings that women expressed
in study I. They also spoke of a need to reflect and discuss
difficulties about food choices, also suggested by Mårtensson
and Hensing as a tool to deal with worries (159). Areas of
concern could be, for example, whether to eat fish or not, take
supplements or not, carefully weighing benefits versus risks. In
52
Discussion
the debate, pregnant women can end up confused about what is
best, as they don’t want to take any risks for the baby’s sake.
There are some target groups who are generally recommended
to take extra supplements such as vegans and veiled women.
The low levels of vitamin D we found among the pregnant
women raise the question of how to achieve a sufficient vitamin
D for women throughout the year.
In study IV we found that allopregnanolone levels were
associated with weight increase in pregnancy. What use can
health care professionals have for these findings? I hope it will
give a greater understanding for women’s feelings of cravings
and taste for different food. Pregnant women in study I wished
more comprehensive information about food issues and how to
deal with food changes which the findings in study IV can
hopefully contribute to. Healthcare professionals who meet
pregnant women can confirm women’s need for increased food
intake with knowledge of physiological processes and at the
same time point out the importance of good food choices.
According to an interview study by Wennberg et al, midwives
find situations very challenging when women are obese, have
eating disorders or practise other diets such as vegan. Midwives
then used strategies to convey their message to the women
(162).
According to Atkinson, overeating is a result of increased
appetite and lack of satiety which can lead to development of
obesity (163). Experiences from earlier studies highlight that
allopregnanolone can inhibit satiety neurons by modulating the
GABA-A receptors and thereby regulate food intake (98,107).
We can only speculate but not declare any causal explanation
for our findings of any increased food intake in the study group,
as this remains to be investigated. It is essential for infant
growth that mothers increase their food intake during
pregnancy. Allopregnanolone levels are normally increased
during pregnancy due to synthesis by the fetus and in the
placenta (101,102), with a possible influence on the feeling of
satiety. Allopregnanolone, like other steroids, has favourable
protecting effects for the fetus (116) but it could also be one
mechanism that ensures sufficient food intake when the body
needs it. A problem nowadays is that many people eat too much
53
Discussion
energy-rich food, but may lack essential nutrients. In the richer
part of the world we have access to a lot of tasty energy-rich
food which may not have an optimal content of nutrients
needed during pregnancy and lactation.
As mentioned above, weight gain is individual and
recommendations are based on pre-pregnancy BMI. However,
excessive weight gain and obesity are established as risk factors
for medical complications. Risks relates to weight before
conception, weight gain during pregnancy and maternal glucose
metabolism during pregnancy and lactation (164). A recently
published Swedish study shows that the risk of stillbirth
increases linearly with increasing weight (165). Compared to
two stillbirths/1000 pregnancies among women with stable
BMI, the number of stillbirths is estimated at three/1000
pregnancies among women who increase their BMI by 2–4 BMI
units. Adjustment was made for factors associated with
increased risk of fetal death, such as smoking, low education,
mother born abroad (165). In the post-pregnancy period it is
important to return to the body’s normal state, rebuild body
stores and return to pre-pregnancy weight. Davis et al found
that short intervals between pregnancies as well as excessive
weight gain are risk factors for lasting maternal obesity (166).
Weight loss reduces the risk of remaining overweight. To reduce
weight gain and prevent adverse outcomes, lifestyle
interventions with counselling combined with weight control
programmes are suggested by Phelan et al (76,167).
Methodological considerations
I have some reflections about the project that I want to
highlight. This project required an extensive planning before
the data collecting could be started and furthermore during the
collection period. Our project also required a lot of skills and
patience by all involved to complete the study in a credible way.
We informed and educated the midwives and laboratory
personnel at the participating health care centres. A lot of
information and clarifying of routines was developed. All links
in the chain had to work from data collection and further
reading of the questionnaire and handling of specimens for
properly handling in accordance with established procedures.
54
Discussion
The midwives showed great commitment, which was also
needed to deal with study procedures. Midwives and
researchers had continuous contact with each other to reconcile
how everything worked during the study period.
My pre-understanding as a midwife has naturally followed me
throughout the project. It is unavoidable but important to be
aware of this. During the interviews it was something I kept in
mind when listening to what the women expressed and how
they talked about a current issue. Staying open for unexpected
thoughts and views was important, but I cannot rule out that
my prior understanding affected this negatively or positively in
some way. I could easily understand what situations the women
talked about and it was easy to put follow-up questions.
An inductive approach is used in qualitative methods in which
conclusions are drawn from observations and narrated
experiences. Qualitative methods are often used in complex
issues where the researcher intends to understand a
phenomenon (138). In quantitative research a hypotheticaldeductive approach is used to test assumptions, i.e., hypotheses.
When we discuss the validity of both qualitative and
quantitative studies we use different concepts, but the purpose
is to evaluate the extent to which the studies have reached a
trustworthy conclusion (168).
Study I
The reason that study I was made was that we first did a pilot
study on 20 volunteer women to test our questionnaires. When
we made the follow-up call for evaluation, almost all women
commented that the questionnaire did not cover all issues about
diet. There were more things that they liked to talk about that
felt relevant for them, for example snacks between meals,
questions about dietary and practical consequences in daily life.
The focus group interviews were made in 2007 but, as we know,
conditions continuously change over time and have naturally
changed since then. Guidelines for antenatal care and dietary
recommendations are updated. The result should be interpreted
with that in mind. However, increased access to information
55
Discussion
through the Internet can contribute to continuing confusion
about how to manage diet changes in the best way. Various
discussions about nutrition from different countries can be
questioned by the pregnant women themselves.
Data were collected together with the first author and we
alternated roles of being moderator and assistant at the
interviews. We also filled in for each other when needed in
order to cover all the information we were aiming for.
Participants in each group were acquainted with each other,
which might have made it easier for them to speak freely with
one another (131).
There are some limits I would like to point out. In the written
aim “attitudes” were included. In hindsight, it was an
unfortunate way to express the women’s experiences, which it
was our aim to study. However, it can be difficult to tell whether
an experience cannot include an opinion on the subject. Also,
the last sentence in paper I says: “Therefore, this study
increases the knowledge about effective, preventive antenatal
care”, a statement which I think may be far-reaching. Further, I
can ask myself afterwards why we overruled the role of the
partner and did not go further into this issue. We noticed that
few women talked about their partner, which surprised us.
There is also a limited discussion about how to achieve
trustworthiness in the paper. On the discussion about
transferability to other contexts or other groups of people,
Hamberg et al state that it is up to the reader to decide whether
the results are transferable (169).
The transferability; of our results to a broader multicultural
context has to be assessed with care since only Swedishspeaking women, born in Sweden, were interviewed. On the
other hand, wanting the best for your child and not taking risks,
having thorough information to handle diet changes can be
assumed to be fundamental to all pregnant women.
Credibility highlights how well the procedure (data collection
and analyses) captures the research focus. We wanted to shed
light on the research question of pregnant women’s experiences
56
Discussion
of receiving dietary information and handling food changes. It
was a task for my co-researcher and me to inspire confidence,
ask as much or as many open questions to follow up and deepen
the discussion. The participating women knew that we were
midwives, and even though we were not working in antenatal
care at that time it might have prevented them from speaking
freely. Credibility also means how well similarities and
dissimilarities have been judged during the interpreting process
and that all relevant data are included. The recurrent
discussions in our research group to find an agreement
improved the credibility.
Dependability; the degree of changes that happen over time
during the data collection or analyse process can make a study
unstable. Open dialogues with co-researchers are ways to
handle questions of dependability (137), and we did indeed
discuss this. We read the previous interviews to see whether
certain areas needed more light, we discussed that and if
needed put more specific questions in the next interview.
Studies II–IV
Both internal and external validity are discussed in this section.
Internal validity refers to the extent to which a study’s results
reflect the true situation of the study population (168).
External validity refers to the extent to which a study’s results
are applicable to other populations (168).
The FFQ in relation to studies II–III;
A shortened version of the original FFQ (66 vs 84 items) was
used since that is the available instrument used in the VIP. To
balance the inevitable increment of underreporting, energy and
nutrient intakes were adjusted by +25% to facilitate
comparisons
(in
relation
to
other
studies
and
recommendations) with what would have been obtained with
the longer version.
The FFQ instrument in general
57
Discussion
The VIP-FFQ has been frequently used for many years and a
longer version with 84 questions has also been validated against
different biomarkers and nutrients (170–172), which ensured a
reliable interpretation of estimated nutrients. The VIP
questionnaire is mainly focused on risk factors for diabetes and
cardiovascular disease and not specially developed for pregnant
women. The FFQ is not particularly designed to record certain
vitamin intake, but rather to take monitor overall dietary intake.
On the other hand, the FFQ contains all food groups for the
general population, which includes pregnant women. A selfreported FFQ has limitations associated with recording of diet
in general and the use of FFQ especially. Errors may occur
depending on the precision of the information that the women
reported and also instrument errors (173).
To what extent is the study group comparable with the
reference group in study II?
To search for similarity between the study group and the reference group in study II, the data were collected within the same
age span, in the same time period and geographical region and
with the same questionnaire in both groups. The difference is
that the reference women attended a health check-up and the
pregnant women visited antenatal care. Further, the references
answered by reflecting their diet intake in the last year and the
study group the last 14 days to give an idea of the current
dietary intake during pregnancy. It still cannot be ruled out that
some degree of recall of the pregnant women’s previous
circumstances has been biased as regards intake of healthy and
unhealthy food, alcohol and tobacco. Recall bias has been found
in the VIP cohort as a source of error (174). Both groups
participated voluntarily and their decision to participate was
probably motivated by similar concerns since the VIP also
carries out research which is well known in Västerbotten. I
believe that this difference did not affect the outcome
significantly.
The ambition was to invite a sufficient number of participants
in the cohort, representing a socio-economic and geographical
cross-sectional sample, based on a power calculation. A
potential selection bias may be present in study II as 60% of the
pregnant women had a university degree compared to 48% for
58
Discussion
the references. That may be a result of a skewed selection of
antenatal clinics or women declining participation, which they
are fully entitled to do, and also a consequence of a consecutive
recruitment method. A failure analysis was conducted in study
III in order to draw fair conclusions. In study II, by presenting
the characteristics of both pregnant women and references the
reader can also assess the generalizability of the data/results
(168).
The representativeness both within and outside the respective
population
In study II participants were divided into two age groups (<35
and ≥35-year-old women) to illustrate any differences in food
habits depending on age in both groups. The overall differences
in evaluated nutrient intake between references and pregnant
women were not so great. One explanation is that women were
in an early phase of pregnancy when adaptation to pregnancy
changes are in progress. It is also possible that food habits
during this stage of life do not change so much and continue
almost as usual. Exceptions, such as differences in intake of
alcohol, tobacco/snuff and supplements show that the need for
immediate situation-specific adaptations is observed. The size
of the cohort is considered sufficient for the results to be
transferable to other populations living under similar
conditions. The study group in study IV was quite small. A
strength was that we were able to demonstrate significant
correlations even though a larger study group would have been
preferable. Information on food intake was not included in the
study, which could have been a possible explanatory factor for
allopregnanolone.
The project design was to follow each woman individually with
repeated sampling for approximately 1.5 years, monitor changes
in dietary intake, plasma vitamin D levels and allopregnanolone
levels in plasma. There were quite a few pregnant women who
ended their participation in general; some dropouts were inevitable as a result of moving or having a miscarriage.
Variations by dietary intake have been reported, and blood
levels were measured in all seasons of the year, which is a
strength. The study group was ethnically homogenous, which
limits bias due to skin pigmentation and clothing habits which
59
Discussion
could have affected the levels of vitamin D for example.
Reliability: the repeated measurements of vitamin D indicated
a steady intake over the year, which can be seen as a credible
result. The allopregnanolone levels in our sample followed the
same increased level as in other comparable studies (99,100)
which supports the reliability of the measurements and results.
I believe that the results in study III could be transferred to
pregnant women living in similar environments. In study IV it is
likely that weight increase relates to increased allopregnanolone
levels in pregnant women in other populations as well.
Standardization and controlling for confounding variables
Potential confounding variables were statistically adjusted for in
study II and study III by regression models. In study II, the
divided age groups were standardized as mentioned above, to
adjust for differences in food habits by age and because of the
imbalance in the different groups. Energy was standardized to
specify E% by macronutrients. Other nutrients were
standardized by residuals from regression which is a form of
energy standard that explains how much of a nutrient is ingested in relation to all energy intake, described in detail by Willett
(173). The use of residuals was intended to circumvent potential
errors from underreporting or overreporting, as underreporting
has been found due to the instrument in smoking, low
education and high BMI (175). In study IV there was no control
for confounding variables as this was a descriptive study and
the purpose was not to explain any factors that cause either
weight gain or allopregnanonlone concentrations.
The biochemical analyses
In study III the method used to analyse levels of vitamin D2, D3
and total vitamin D level (25(OH)D) is regarded as the gold
standard LC-MS/MS (Perkin Elmer, Waltham, MA, USA). The
current method reduces the problems usually found with
immunological methods. The analytical reliability was ensured
by external controls from DEQAS.
In study IV, Radio Immuno Assay (RIA) for the measurement of
allopregnanolone was used, described and referred to in the
method section. RIA has been validated versus GC-MS/MS (gas
60
Discussion
chromatography tandem mass spectrometry) and LC-MS/MS
(liquid chromatography tandem mass spectrometry) (99).
61
Conclusions
Conclusions
I. Pregnant women were eager to know about healthy diet to
reduce the risks of eating something”forbidden”. They searched
for information by themselves and could manage dietary
changes quite well. They described dietary recommendations as
confusing as they felt inadequate and contradictory and would
have wished for more comprehensive advice from the midwife.
II. Early pregnant women had a different dietary pattern to
some extent, with more supplements, less alcohol and
tobacco/snuff compared to reference women. Intakes of folate
and vitamin D by food were low compared to recommendations
and intake of iron was on the low side.
III. Vitamin D levels peak in late pregnancy but levels were
<50 nmol/L in at least a third of the participants. Aside from
gestational week and season which were related to plasma
levels, intake from foods and supplements also affected the
levels.
IV. Allopregnanolone was associated with weight gain during
pregnancy.
Clinical implications and future research
The findings in this thesis suggests that midwives in primary
care have an important role to support and educate pregnant
women about healthy eating habits and to improve dietary
intake.
Obesity and excessive weight gain during pregnancy is an
increasing problem. Further studies are needed to describe the
role of allopregnanolone during pregnancy and the postnatal
period.
62
Conclusions
Based on this thesis I have some suggestions for future
research:
–
–
–
–
Longitudinal studies on dietary intake during pregnancy
and postpartum period including subgroups in a
multicultural context.
Exploring the role of allopregnanolone, its significance
and consequences during pregnancy including
measurement of food intake.
Investigate experiences from a family perspective of the
pregnant woman, with respect to dietary intake as well as
eating habits.
Exploring fetal outcome in relation to maternal dietary
parameters.
63
Acknowledgements
Acknowledgements
Jag vill rikta ett varmt och hjärtligt tack till alla som på olika
sätt bidragit med stöd och uppmuntran så att jag kunnat
slutföra denna avhandling. Det är några personer jag särskilt
vill tacka:
De kvinnor som deltagit i projektet, tagit prover och
fyllt i enkäter vid flera tillfällen under så lång tid, ni är
enastående.
Barnmorskor och laboratoriepersonal på MHV: ni
trodde på vår idé och tog er an projektet. Fixade och trixade
med datainsamling, vilket jag är innerligt tacksam för. Ett
särskilt tack till Lena Ekström och Karin Vincent-Wård på
MHV Tegs hälsocentral, ni gjorde ett jättejobb med extra
rekrytering av deltagare.
AnnaLena Wennberg, kollega och vän, tack för allt! Tänk att
vi gick igång med det här projektet och att vi med stort tålamod
slutförde det, det gjorde vi bra.
Mina kunniga och entusiastiska handledare som funnits till för
mig under denna tid:
Herbert Sandström, min huvudhandledare
Tack för allt ditt stöd och för att du alltid tagit dig tid för mig.
Du har alltid varit närvarande, engagerad med uppmuntran och
inspiration. Under tidens gång har du på ett tydligt sätt låtit mig
ta ökat ansvar. Du har med lugn hand styrt mig framåt. Du har
smidigt hanterat när jag ”spottat ur mig vissa besvärjelser”. Jag
har så många gånger känt mig tacksam som råkade på just dig
en gång i tiden.
Katarina Hamberg, min bihandledare
Du har delat med av din stora kunskap och dina smarta idéer.
Du har öppnat mina ögon för hur olika man kan välja att göra
och se på saker och ting i vetenskapliga sammanhang. Slutfasen
var periodvis intensiv men du bidrog med klarsynthet och med
nya öppna tankar.
64
Acknowledgements
Johan Hultdin, min bihandledare
För ditt goda stöd och dina fiffiga lösningsförslag. Din
kreativitet och inställning har varit till excellent hjälp, så även
din datakunskap. Du fick mig också att komma igång med
kappan på allvar när jag gått och gruvat för att starta. Det var
kanske inte fullt så enkelt som du sa, men kul har det varit.
Torbjörn Bäckström, min bihandledare
Med din stora expertis och erfarenhet har projektet och jag
utvecklats. Generöst har du delat med dig av dina tankar,
erfarenheter och lärdomar. Har dessutom fått lära mig mycket
matnyttigt om allopregnanolon och smittats av din entusiasm.
Mina medförfattare:
Ingegerd Johansson, tusen tack för att du gav dig in i
projektet och tålmodigt delat med dig av ditt stora kunnande,
goda omdöme, erfarenhet och idéer.
Ulf Högberg, att du hängde på oss från början har betytt
mycket, din kunskap, klokskap och erfarenhet har kommit väl
till pass.
Hans Stenlund, för trevligt samarbete. Du är verkligen
fenomenal på att lära ut statistik, tackar ödmjukast för all hjälp
och stöd.
Patrik Wennberg, Eva Fhärm, Agneta Hörnell,
Margareta Persson, Sigrid Nyberg och Roger Karlsson
som granskat projektet vid olika tillfällen från antagning till
mitt- och kappa seminariet och sist men inte minst på
fördisputationen.
Anna Backeström, min rumskompis för trevligt sällskap och
givande samtal.
Helen Ingvarsson för att du så väl beskrivit vissa MHVspecifika delar och haft bra synpunkter till kappan.
Alla administratörer och doktorander på allmänmedicin för
trevligt sällskap, skratt och roliga samtal; Marie
65
Acknowledgements
Hammarstedt, Maria Boström, Lotta Mörtsell och
Karin Hedlund tack även för ert administrativa stöd.
”Grupp fyra” vid Nationella forskarskolan i allmänmedicin för
trevliga och givande sammankomster.
Åsa Ågren, John Hutilainen, Sören Holmgren, Kerstin
Enquist Olsson och övriga gänget på enheten för
Biobanksforskning och Biobanken Norr, som lärde upp mig
kring era rutiner och bistod med all upptänklig hjälp. Sören
och John ett särskilt tack till er praktiska vägledning kring
datahanteringen.
Håkan Jacobsson och personalen vid klinisk kemi,
laboratoriemedicin som på ett bra sätt styrde upp D vitamin
analyserna.
Umeå Neurosteroid Research Center; Elisabeth
Zingmark och Di Zhu för gott stöd och hjälp med analyserna
av allopregnanolon.
Alan Crozier för språkgranskning av min kappa.
Mina härliga och positiva arbetskamrater på Vård och
Kvalité.
Unni Nordström och Sara Larsson särskilt tack för er
omtanke och uppmuntrande hejarop. Catrine Jacobsson och
Sonya Hörnqvist Bylund för goda konstruktiva råd för och
hjälp med korrekturläsning.
Kerstin Lagervall min chef. Jag uppskattar dig mycket, en
chef att lita på med klokhet och generositet. Tack för allt ditt
stöd.
Släkt och goda vänner som med uppmuntrande attityd fått
mig att koppla av och njuta av trevlig samvaro, skratt och goda
middagar.
Min familj: Ulf mitt hjärta, livskamrat och bästa vän. Maria,
Sara och Erik, mina älskade underbara barn som tveklöst trott
på mig och hållit efter mig på olika sätt. Vad vore min engelska
66
Acknowledgements
om jag inte fått nöta på och tränat mina föredrag på er? Ni har
bistått med goda råd och lyssnat tappert. Britt min kära
svärmor, du har stor en del i detta. Tack för allt ert stöd, er
närvaro och kärlek.
Till sist vill jag rikta ett tack till Västerbottens Läns Landsting
och Umeå universitet som bidragit finansiellt till min
doktorandutbildning.
67
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