Leisure-time physical activity and hyperemesis gravidarum
Is there an association between frequency of pre pregnancy leisure-time physical activity and risk of hyperemesis gravidarum?
Borgny Hedvig Wold
Master of Health Sciences, Institute of Health and Society, Faculty of Medicine
UNIVERSITY OF OSLO
November 2012II
III
Leisure-time physical activity and hyperemesis gravidarum
Is there an association between frequency of pre pregnancy leisure-time physical activity and risk of hyperemesis gravidarum?
© Borgny Hedvig Wold 2012
Title: Leisure-time physical activity and the risk of hyperemesis gravidarum. Is there an association between frequency of pre pregnancy leisure-time physical activity and risk of hyperemesis gravidarum?
Author: Borgny Hedvig Wold http://www.duo.uio.no/
Print: Reprosentralen, Universitetet i Oslo
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Acknowledgements
First of all, I want to express my gratitude to all the contributing women in the The Norwegian Mother and Child Cohort Study (MoBa) study. Each and one of you have contributed to make this large prospective cohort study possible.
Studying to this Master has been very inspiring, and I want to thank skilled and motivating professors, teachers and fellow students at the University of Oslo, Institute of health and society. The way this Master program is built is unique. The Institute integrates the students in the scientific environment, inspiring us to reflection and deeper understanding and providing close relation between research and studies. I would therefore like to thank Professors Vøllestad, Heggen, Mengshoel and the rest of the staff for your enthusiasm and your inspiring lectures. Study advisor Løvenstad at the Institute also deserves many thanks for your patience and help along the way.
I am grateful to my former leader and present supervisor Wenche Nystad and co-supervisor Åse Vikanes at the Norwegian Institute of Public Health (NIPH) for generously tutoring, patience, positive energy and for all the opportunities you have given me. Also a warm thanks to Katrine Owe and Maria Magnus for shearing your wisdom with me. Each and one of my former colleges at the Institute also deserves a warm thanks for including and inspirational work environment, and a special thanks goes to Dominic Hoff for data management, Kjersti Andersen Nerhus, Sachico Watanabe, Jorid Eide, Kari Kveim Lie, Ragnhild Hovengen and Per Magnus. My present colleges at the Norwegian University of Science and Technology also deserves a varm thanks for everyday joy, inspiration and support.
To my dear parents and parents-in-law: thank you for believing in me, for practical help and baby-sitting many times after we moved back to Trondheim. My sister deserves a big hug for cheering me up. Last but not least, my wonderful family Oddmund, Julia and Hanna: You are the keystones of my life. Thank you for endurance, patience and for reminding me about the most important values in life.
The Norwegian Mother and Child Cohort Study was supported by the Norwegian Ministry of Health, NIH/NIEHS (grant no N01-ES-85433), NIH/NINDS (grant no.1 UOI NS 047537-01).
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Preface
When my first Master project on a different topic didn’t work out as planned, Wenche Nystad and Katrine Owe generously let me into their ongoing physical activity project at the NIPH.
The field of physical activity as an exposure on pregnancy outcomes has had increased attention during the last years, and Åse Vikanes, a researcher on hyperemesis gravidarum at NIPH, was very enthusiastic when we suggested a collaboration. Little has been done when it comes to research on lifestyle factors and hyperemesis, so we found it very interesting to do this study.
My first meeting with hyperemesis took place when I was as a young nurse, working at an emergency ward. A pregnant woman became in-patient due to persistent nausea and vomiting.
She was confused, dehydrated and with little ability to communicate, and it was almost understandable to me that anyone could be that sick “merely” because of a pregnancy. When a friend of mine later developed hyperemesis and got sick-leaved at 6th gestational week, I had a better understanding of the condition. Still it was horrifying to see how it profoundly
changed her life. Fortunately she received good treatment at hospital, and several years later she took the chance on a second pregnancy. Today the many months of intrusive nausea and vomiting in both pregnancies are memories, and she enjoys life with her two beautiful children.
As a participant in the MoBa study with my two pregnancies, and also having worked with administration and data collection in the study at NIPH, I am very grateful for the opportunity to use these data in my Master’s degree.
My Master thesis is an epidemiologic study, based on data from the MoBa study. The thesis has two components; an introduction section and a scientific paper. The introduction
describes the background for the thesis and the methodological considerations made in the process. A part of the discussion in the paper hypothesises biological mechanisms. Since this is speculations and not results from analysed data in our study, the possible mechanisms are not described further in the introduction section. The scientific paper is written according to author’s guidelines for British Journal of Obstetrics and Gynecology and will be submitted for publication.
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Abstract
Purpose
Hyperemesis gravidarum (HG) is a severe condition of excessive nausea and vomiting in pregnancy, causing hospitalisation. The aim of this study was to estimate association between pre pregnant frequency of leisure-time physical activity (LTPA) and HG.
Literature review
The prevalence of HG is only about 1% in Norway, but has adverse impact on the affected women’s life. Many factors are associated with HG, but the causes are unknown. A protective effect of LTPA on several pregnancy conditions are described, but the association of LTPA on HG is unexplored.
Methods
This study is based on The Norwegian Mother and Child Cohort Study (MoBa). Data are obtained from questionnaires in gestational week 17 and 30. Study population in this Master thesis consists of 37,407 women. Relative risks for HG according to frequency of LTPA were estimated by binary logistic regression, and crude (cOR) and adjusted (aOR) odds ratios with 95% confidence intervals (CI) were analyzed with SPSS, version 17.
Results
In this study, 372 women (1.0%) reported having HG, and 7.3% of the participants reported LTPA to be low. In contrast 38.3% of the women reported to be physically active “3-5 times per week”. Women with low LTPA had a 50% increased risk of HG compared to those who were physically active 3-5 times per week, aOR= 1.49 (95% CI: 1.06-2.09).
Conclusion
Low LTPA prior to pregnancy is associated with an increased risk of HG, compared to being physically active 3-5 times per week.
VII
Sammendrag
Formål
Hyperemesis gravidarum (HG) er en alvorlig tilstand med sterk kvalme og oppkast som kan føre til sykehusinnleggelse. Målet med studien var å estimere assosiasjonen mellom frekvens av fysisk aktivitet på fritiden (FAPF) før graviditet og hyperemesis gravidarum (HG).
Teoretisk forankring
Prevalensen for HG er bare på ca 1% i Norge, men virker til gjengjeld svært negativt inn på livet til de kvinnene som blir rammet. Mange faktorer er assosiert med HG, men årsakene er ukjente. En beskyttende effekt av FAPF er beskrevet for flere svangerskapstilstander, men assosiasjonen av FAPF på HG er ikke utforsket.
Metode
Denne studien er basert på data fra Den norske mor og barnundersøkelsen (MoBa). Dataene er hentet fra spørreskjema som ble utsendt i svangerskapsuke 17 og 30. Studiepopulasjonen til Mastergradsoppgaven består av 37.404 kvinner. Relativ risiko for HG ut fra frekvensen av FAPF ble estimert ved hjelp av binær logistisk regresjon, og ujustert (cOR) og justert (aOR) odds ratio med 95% konfidens intervall ble analysert med SPSS, versjon 17.
Resultater
I denne studien rapporterte 372 (1%) av kvinnene at de hadde HG, og 7,3% av deltakerne rapporterte FAPF som lav. I motsetning rapporterte 38,3% av kvinnene å være fysisk aktive 3-5 ganger per uke. Kvinner med lav FAPF hadde 50% økt risiko for HG sammenlignet med de som var fysisk aktive 3-5 ganger per uke, aOR=1.49 (95%CI:1.06-2.09).
Konklusjon
Lav FAPF før svangerskapet er assosiert med 50% økt risiko for HG sammenlignet med de som er fysisk aktive 3-5 ganger per uke.
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Abbreviations
aOR Adjusted odds ratio
BJOG British Journal of Obstetrics and Gynecology
BMI Body Mass Index. Body weight divided by the square of height (kg/m2)
CI Confidence interval
cOR Crude odds ratio
hCG human Chorionic Gonadotrophin
DAG Directed Acyclic Graph
HG Hyperemesis Gravidarum
ICD International Classification of Disease LTPA Leisure-time physical activity
MBRN Medical Birth Registry of Norway
MoBa The Norwegian Mother and Child Cohort Study NIPH Norwegian Institute of Public Health
NVP Nausea and vomiting in pregnancy
OR Odds ratio
PA Physical activity
Q1 Questionnaire 1 used in MoBa
Q3 Questionnaire 3 used in MoBa
RR Relative risk
WHO World Health Organization
IX Table of Contents
1 Introduction ... 1
1.1 Definitions of hyperemesis gravidarum ... 1
1.2 Pathogenesis and etiology ... 2
1.2.1 Endocrine factors ... 2
1.2.2 Genetics ... 3
1.2.3 Other factors ... 3
1.2.4 Protecting etiological factors ... 3
1.2.5 Etiological risk factors ... 3
1.3 Consequences of hyperemesis gravidarum ... 4
1.3.1 Maternal implications ... 4
1.3.2 The fetus ... 5
1.4 Treatment ... 5
1.5 Leisure-time physical activity ... 6
1.5.1 Definitions ... 6
1.5.2 Effect of leisure-time physical activity ... 7
1.5.3 Socio-demographic factors ... 8
1.5.4 Recommendations for physical activity ... 8
1.6 Why study leisure-time physical activity and hyperemesis gravidarum? ... 8
2 Aim and research question ... 9
3 Methodological considerations ... 10
3.1 Design ... 10
3.2 Ethics ... 10
3.3 Analytic model ... 11
3.4 Variables ... 12
3.5 Statistical analysis ... 14
3.6 Measurement errors and bias ... 14
3.6.1 Random errors ... 14
3.6.2 Systematic errors ... 14
3.6.3 Confounding ... 17
3.7 Study sample ... 17
4 Extended result ... 18
5 Conclusion ... 19
X
6 References ... 20 7 Paper ... 25 Appendix ... 45
1
1 Introduction
Women suffer from a variety of symptoms during pregnancy. One of the most common symptoms is nausea and vomiting in pregnancy (NVP) which up to 80% of all pregnant women experiences to some extent (1). In contrast, hyperemesis gravidarum (HG) is rare and severe (2). Due to the severity of the symptoms, HG has a substantial impact on the quality of life for the affected women (3). The etiology of HG is still unknown despite many years of research (1), and thus we lack the knowledge on how to prevent the disease. There is some evidence that lifestyle plays a role, and physical activity is such a factor known to reduce or prevent disease in general, and to be associated with pregnancy-related conditions such as preeclampsia and gestational diabetes mellitus (4-6).
1.1 Definitions of hyperemesis gravidarum
Nausea and vomiting in pregnancy seems to have been a plague for women through several millenniums (7) and is apparently described as early as 4000 years ago in a papyrus as a part of the Petrie collection in Egypt (8). The explanations of NVP and HG has changed over the years (9), and O’Brien and Newton (7) describes three different eras of beliefs, in their review from 1991:
The Early Somatic Era started in antiquity and lasted till about 1929, and two etiological theories developed; one that NVP had its origin in “reflexes”, associated with pregnancies and caused by neurological connection or displacements of abdominal organs and the uterus. The second theory suggested “some toxins” like undigested food, sperm, the fetus, etc to be the cause of NVP. The Intrapsychic Era challenged the somatic theories and is described from 1930 – 1981. Etiological theories postulated psychological distress, neurosis, a strong
psychogenic basis and hysteria. The hysteria was explained by the pregnant women’s disgust towards her husband and the fetus, associated with a hysterical personality and lower
intelligence (8). The Biochemical and Sociological Stress Era from 1981 to present, has had a renaissance of the original hypothesis regarding reflexative, toxic or neurotic character, although refined into the setting and knowledge of today. The “toxin” is no longer thought to be causative, but biochemical changes suggested to generate symptoms. Immunological, metabolically, hormonal, situational stress and associated factors are debated today (7) and a summary of the present pathogenesis and etiology will be described in paragraph 1.2.
2
The relationship between NVP and HG is not known, and it is unclear whether they are different diseases or if they represent gradients of the same phenomenon (1). Since the understanding and characterisation of HG has varied through the times, differences in coding and definitions of the condition has existed, complicating the comparison between studies. In order to study a homogenous group I have chosen to focus on HG in my thesis.
The definition of HG in this thesis is defined as excessive nausea and vomiting starting for the first time before the end of the 22nd week of gestation, causing metabolic disturbances at such severity that it requires hospital admission (8, 10).
In Norway, the prevalence of HG varies between 0.8 – 3.2% depending on country of birth (2), yet with most studies reporting an incidence of 0.5-1.0% (1, 11, 12).
1.2 Pathogenesis and etiology
HG seems to be a complex disease, and several factors are known to be associated.
Psychosomatic perspectives on HG exist in the literature of today, but will not be taken into considerations in this thesis. First, I have chosen to present the pathogenesis related to HG, then the etiological factors grouped as either protective or risk factors for HG.
1.2.1 Endocrine factors
High levels of human Chorionic Gonadotropin (hCG) is thought to contribute to the development of HG (1, 13, 14). hCG hits its highest point at the same time as HG has its highest incidence (1), and hCG conditions such as multiple and molar pregnancies are also known to have a higher HG incidence. Still, this does not explain why only a small number of pregnant women experiences HG (13) and why some women don’t have NVP despite
elevated hCG (14).
Estrogen is also suggested to play a major role in the development of HG (13), and higher incidence of HG has been found in several conditions associated with high estrogen level, such as higher BMI and young maternal age (1).
Other endocrine factors described to be associated with HG are progesterone, TSH,
adrenocorticotropic hormone (ACTH), cortisol, growth hormone, prolactin and leptin (1, 13, 14).
3 1.2.2 Genetics
Recent research has reported that hyperemesis seems to be inherited from mothers to daughters (15) and Zhang et al (16) found a high familial clustering of HG, implying
substantial support for a genetic contributing factor. A study by Trogstad et al (17) using data from MBRN showed that a second pregnancy had about 15% increased risk of HG if HG occurred in the first pregnancy. For women who did not have HG in the first pregnancy, the risk of having HG in the second pregnancy was only 0.7%.
1.2.3 Other factors
Other pathogenic factors have also been described to be associated with HG, amongst them chronic infection with helicobacter pylori (14) and over activation of the immune system (1).
1.2.4 Protecting etiological factors
Maternal smoking habits both before and during pregnancy are described to reduce the risk of HG (9, 18, 19). This has also previously been found in MoBa data by Vikanes et al (20) where occasional smoking and daily smoking seemed to reduce the risk by 35% - 55%, respectively. The lower level of estrogen and hCG found in smokers are suggested to explain the protective effect of smoking (21).
Few studies have reported level of education, but Klebanoff et al found a maternal
educational level of twelve years or more to have 26% lower risk for HG compared to women with less education (22). In line with this, MoBa data has previous shown a higher percentage of hyperemesis among women with low maternal educational level (20, 23).
Diet pre pregnancy has shown a protective effect regarding allium (onion) vegetables, fish, seafood and a moderate intake of drinking water (23).
1.2.5 Etiological risk factors
Young maternal age and primiparity are both associated with a higher risk of HG (9, 11, 24).
Increased levels of estrogen are thought to be the cause of HG amongst young pregnant women (9). In contrast, older maternal age is associated as a protective factor, possibly explained by a cumulative experience in dealing with higher estrogen levels (9).
4
Body Mass Index (BMI) is associated with HG, but different studies have shown conflicting results. An increased risk of HG has been found within obese women (9, 22). Vikanes et al (20) previously found an association of BMI in MoBa, where both underweight (BMI < 18.5 kg/m2) and overweight (BMI > 25.0 kg/m2) were significantly associated with a risk for HG, although the associations were not significant among smokers (20). One Swedish study found low BMI to be a risk factor for HG, whereas high BMI seemed to protect against HG (25).
Other factors reported to be associated with an increased risk of hyperemesis are female fetal gender (11), multiple gestations (11, 19), interval between pregnancies (17), ethnic
differences (2) and maternal hyperthyroid disorders, pre-existing diabetes and
gastrointestinal disorders (19). Also a diet containing a high daily consumption of total fat, primarily saturated fat, is found to increase the risk of HG (18), but in contrast, Haugen et al (23) found no association between fat intake and HG in a subsample of MoBa data.
1.3 Consequences of hyperemesis gravidarum
1.3.1 Maternal implications
HG usually starts between the 4th and 10th week of gestation and reaches its end by 20th gestational week (24), but for about 10% of these women the condition will last throughout pregnancy (1).
Because of its severe character, HG is the second most common reason for hospitalisation among women with live births (26). The diagnosis of HG is based on characteristic symptoms and exclusion of other conditions that may cause the same clinical picture, such as
appendicitis, urine tract infections and pancreatitis (24). Severe HG with pernicious nausea and vomiting often causes hypovolemia and dehydration; weight loss, rising pulse rate, falling blood pressure, dry and furry tongue, loss of skin elasticity and ketotic breath (12). Vitamin deficiencies can occur due to lack of vitamin B1, B6, B12 and vitamin K (24).Laboratory analysis shows ketonemia, ketonuria, electrolyte and vitamin imbalance and potential hepatic and renal damage amongst other findings (8, 24).
O’Brien and Naber (3) studied how NVP and HG affected the quality of life, where 34% of the women reported that the symptoms were so severe that they had to give up on their daily routine in some way. The worst aspect for the HG patients was the pervasiveness and severity
5 of the nausea and vomiting, and to become a person in need of constant support. A mother of three children told this about her vomiting situation:
“That’s all I did all day long. This time I would actually say, I thought I was going to die. I told my husband I would rather die than continue to live like this”.
A study of nausea and vomiting in pregnancy, not HG, has shown NVP to be very intense and measured to be of similar intensity to the nausea patients experiences when they undergo cancer chemotherapy (27). It is likely that women with HG might have similar experiences, and a relative recent study showed that some women chose to end their pregnancy due to the adverse experiences with HG (28).
In addition to the implications for the women and their families, the economic costs for the society are calculated to be of a considerable size due to healthcare expenses and lost productivity (29).
1.3.2 The fetus
For the fetus, HG is associated with adverse pregnancy outcomes, especially if the condition is left untreated, and Veenendaal et al (30) showed in a systematic review that HG is
significantly associated with low birth weight, small for gestational age and prematurity.
There was no difference in Apgar score, congenital anomalies or perinatal death, comparing HG pregnancies to control pregnancies. Two case-control studies have suggested long term effects in offspring after severe HG to be associated with testicular cancer (30) and leukaemia (31).
1.4 Treatment
Treatment of HG is of importance due to the severity of the deficiency conditions (24), and the mortality rate is now very low because of adequate treatment with fluid and electrolyte replacement (12, 24).
When women with HG are admitted to hospital, the given treatment is intravenous fluid replacement, electrolyte and vitamin correction, antihistamine and antiemetic drugs. If nothing works and the condition is very severe, steroid medication can be given (32).
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1.5 Leisure-time physical activity
Modern society and stationary jobs has contributed to a reduced need for physical expenditure in our daily tasks, and thus a good physical condition is no longer as necessary for the human being (33). Generally, physical activity is recognized as an important life style component (34), well-known to reduce the risk of several diseases (35). A sedentary lifestyle can cause increased morbidity (4), and physical inactivity has proven to be as great a risk factor for disease as smoking, cholesterol and high blood pressure (36).
This paragraph will provide a brief understanding of definitions, effects, socio-demographic factors and recommendations. Finally I will summarize why I find it important to study leisure-time physical activity and hyperemesis gravidarum.
1.5.1 Definitions
Physical activity and its subcategories are widely used concepts, and they are often mixed or used synonymously despite different meanings (37). In order to provide a common
understanding of the different terms, the definitions of physical activity, leisure-time physical activity (LTPA), exercise and physical fitness are defined under. The concept LTPA is used in the analysis of this Master thesis, but the term physical activity is also used when referring to the concept in a more general setting. Exercise and physical fitness is not studied in the thesis, but is defined to show the differences between the terms.
Physical activity
Physical activity is defined as “any bodily movement produced by skeletal muscles that results in energy expenditure”. We are physically active in order to maintain life, but the amount varies from person to person and also over time for a specific person (38). There exists no standardised definition of the term physical inactivity (39), but a suggested
definition is a condition of minimal energy expenditure beyond resting or baseline metabolic rate (37).
Subcategories of physical activity are leisure-time physical activity (LTPA) and exercise.
Leisure-time physical activity
7 LTPA includes all kinds of activities one participates in during free time, and is chosen on the basis of personal interest and needs (40). Examples of LTPA are walking, dancing,
swimming, biking, hiking, gardening and exercise programs (38)
Exercise and Physical fitness
Exercise is defined as an activity that is planned, structured and repetitive. The intension is to maintain or progress in one or more components of physical fitness (38).
Physical fitness are attributes people have or achieve, and refers to the ability to do daily tasks with vitality, attentiveness and enough energy to meet everyday tasks without fatigue (38).
1.5.2 Effect of leisure-time physical activity
The effect of physical activity and LTPA can be described by frequency, duration and
intensity. Frequency is how often LTPA is performed, and can be measured by the number of days or sessions made during a certain set of time. The duration is how long the LTPA lasts, measured in minutes or hours, and intensity expresses the amount of physical effort needed to do the LTPA. These three factors are the major keys to the overall dose and effect of physical activity, but also type of activity is an aspect (4).
Leisure-time physical activity and maternal pregnancy conditions
The benefit of physical activity and risks for diseases caused by inactivity has been strongly supported in epidemiological studies for the past decades (33, 35). A lot of research has been done on exercise in athletes or in relation to well-known conditions such as heart disease and diabetes (41), but in recent years science has also provided new knowledge on how physical activity affects the health of pregnant women. A review from 2007 showed a protective effect of leisure time physical activity on pregnancy conditions such as gestational diabetes mellitus and pre-eclampsi (42), although with conflicting results for pre-eclampsia (5, 43, 44). A recent publication from Mudd et al (6) summarises evidence from USA, Canada and
Scandinavia, providing supportive, positive effects of LTPA and exercise during pregnancy on outcomes such as gestational diabetes, hypertensive disorders and excessive gestational weight gain. To my knowledge no studies have been performed on LPTA and HG.
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1.5.3 Socio-demographic factors
Educational level, age, parity, pre pregnancy BMI and smoking are factors found to be associated with physical activity both in the US and in Norway. The factors also shows a socio-demographic gradient (45, 46).
1.5.4 Recommendations for physical activity
In Norway the general recommendations for physical activity suggests that everybody should be physically active for at least 30 minutes per day, preferable all days of the week. The intensity should be moderate, and an additional health gain can be achieved by increasing the daily amount or intensity. The Norwegian guidelines are based on the American
recommendations, and are common for adults in general as well as for pregnant women (4).
1.6 Why study leisure-time physical activity and hyperemesis gravidarum?
Although HG is a rare disease, it is the second most common reason for admittance to hospital among pregnant women with live births (26). Further more, HG is reported to be associated with adverse pregnancy outcomes, such as prematurity, small for gestational age and low birth weight (30). Treatment is based on symptom relief and correction of vitamin-, fluid- and electrolyte deficiency, but left untreated HG can cause maternal death and severe morbidity (12). HG has a negative impact on the women’s quality of life and is of substantial cost for the society (3, 29). Many etiological factors, and some lifestyle factors, have been associated with HG, but the causes are still unknown (1, 18, 20, 23, 24). In general, physical activity is a recognized life style factor known to have beneficial effects on many diseases, and also adverse consequences of inactivity is recognised (36, 41). A protective effect of leisure time physical activity on maternal health is described (6, 42), but as far as I know the impact of LTPA on HG has not been explored yet. Earlier research on physical activity in MoBa has mainly focused on exercise, and strolling has usually been excluded due its low energy expenditure (47). In this study I wanted to use the term LTPA to include strolling, which is a common activity and thus of importance from a public health perspective (4). On this background I found it important to study whether a life style factor such as LTPA was associated with the risk of HG.
9
2 Aim and research question
Our aim is to study whether pre pregnant LTPA is associated with the risk of developing HG.
The research question was thus formulated like this:
“Is there an association between frequency of pre pregnancy leisure-time physical activity and the risk of hyperemesis gravidarum?”
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3 Methodological considerations
3.1 Design
Data in this thesis was obtained from the Norwegian Mother and Child Cohort Study (MoBa), conducted by Norwegian Institute of Public Health. MoBa is nationwide longitudinal
prospective pregnancy cohort, and over 108.000 pregnancies were recruited during a period from 1999-2008. The study is described further in the attached paper.
A cohort study is a central design in epidemiology and appropriate when observing a group of people over time to see who develops disease and who do not, concerning a given exposure (48). Our study gathers information from several time points; 3 months prior to pregnancy, up to approximately gestational week 25. Physical activity as the exposure variable is asked retrospective, three months prior to pregnancy. Hyperemesis as the outcome variable is collected at present and retrospective time between 17th and 30th gestational week. The described longitudinal timeframe makes it possible for the exposure to take place before the outcome.
There are also other advantages with this design. A large sample size enables us to study rare exposures and outcomes, and a precise association estimate is achievable because of narrow confidence intervals. A large cohort also minimizes biases, which will be discussed in later paragraphs.
3.2 Ethics
The Helsinki declaration for ethical principles in medical research is and has been followed during the MoBa data collection, implicating that all participants have given their informed consent. They can withdraw their consent from MoBa at any time, without stating a reason.
The study was approved by the Norwegian Data Inspectorate and the Regional Ethics Committee for Medical Research.
Data used in this thesis are anonymous, meaning that the data file don’t contain variables that could theoretically lead to identification of the participants in any way. Using MoBa data for this purpose is not considered to have any ethical disadvantages for the participants.
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3.3 Analytic model
As an analytic model I have used the concept of Directed Acyclic Graph (DAG). The exposure, outcome and related covariates are applied in a simplified model, see Figure 2 below. Drawing DAGs can illustrate and provide an understanding on how the different variables are associated to each other. The concept of this causal modelling is extensive.
There are several rules and guidelines to follow for setting up and analyzing a DAG, and it is beyond the scope of this thesis to study and to describe this deeply. References used and providing a thoroughly presentation are (49, 50).
Very briefly, in this thesis a goal with DAG was to get an overview over variables of interest, to be able to control for variables in paths causing confounding and thereby to assess the effect of LTPA on HG. The confounders were chosen on basis of a priori knowledge; known from the literature to affect both exposure and outcome. On this background I cannot adjust for variables occurring later in time than pre pregnancy LTPA, e.g. maternal pregnancy BMI since this factor cannot affect LTPA occurring before pregnancy.
The possible biological interactions between the variables are complex and partly unknown, so a simplified DAG was necessary. The arrows are pointing towards the expected causal direction. By following certain rules and listing up the different paths between the variables in the figure, we can find out whether it is a causal or non-causal path. Non-causal paths are thought to be transmitting bias, and these paths can be closed by controlling. In this case, the variables considered to be confounders were controlled for in the analysis.
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3.4 Variables
A description of the main exposure (LTPA) and the main outcome (HG) is given in the paper, and also HG is described further in 3.5.2.
Height and weight
From Q1 we included self-reported pre pregnancy height and weight, which we used to calculate body mass index (BMI = weight (kg)/height (m)2). The questionnaire asked that the
13 women used their antenatal card for data in which their height and pre pregnant weight were registered at the first pregnancy consultation. Height was measured in centimeter (cm).
Minimum value recorded was 123.0 cm, maximum 198.0 cm. Mean weight was 168.1 cm (±
5.98). Weight was measured in kilos (kg), minimum was 32 kg, maximum 160 kg. The curve had a fairly normal distribution with a slightly positive skew. Mean weight 67.2 kg, median 65.0 kg, (± 12.5). I chose to use the weight data as normally distributed data since they was to be recoded to BMI. The height and weight data did not have any outliers considered to be abnormal, so cut-offs was not used.
BMI
BMI (kg/m2) had a minimum value of 12.5, maximum 59.5, mean 23.8 (±4.2). BMI was further analyzed as a categorical variable according to WHO’s classification (<18.5, 18.5- 24.9, 25.0-29.9 and ≥30.0) (51).
Smoking habits
Smoking habits pre pregnancy were obtained from Q1, and was a sum-score of the pre pregnancy question about smoking (see Appendix, Q1, question 94 and 96). The questions were categorized as nonsmoker, occasional smoker and daily smoker.
Maternal education
Maternal education was a sum-score of question 50 in Q1; finished and ongoing education.
Length of education was categorized in years (< 12 years, 12 years, 13-16 years and ≥ 16 years.
Maternal age
Data on maternal age was obtained from the MBRN. Mean age was 28.4 (±4.4), with the youngest woman entered as 14 years old, and the oldest woman was 46 years old. The curve was normally distributed, and categorized as <20, 20-24, 25-29, 30-34 and ≥ 35 years old.
The reason why I chose to have so many groups was because both young and older maternal age was known a priori to be associated with hyperemesis. Seen retrospectively I could have managed with fewer groups.
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3.5 Statistical analysis
In the early analysis phase, histogram was used to assess whether the data were normally distributed. Missing data was excluded from the analysis. LTPA and HG are categorical variables, and HG was dichotomised. In order to study how well the predictor variable LTPA explained the dependent variable HG binary logistic regression was performed, and the relative risk of HG according to LTPA was approximated by calculating odds ratio. The significance level was set at 5% (95% confidence interval).
The attached paper explains how the variables are categorised. Respondents with physical activity frequency of 3-5 times per week was used as reference group, because the cumulative 50% was 4.7 times per week. All studied associations were adjusted for maternal education, maternal age, maternal pre pregnancy smoking and maternal pre pregnancy BMI. According to the rules from the MoBa Scientific Management Group, the effects of confounders or covariates are not allowed to be published.
3.6 Measurement errors and bias
3.6.1 Random errors
In epidemiology, the best way to avoid random error is by increase the size of the study population. Also, the exposure and confounders occurred prior to pregnancy and might reduce random errors. MoBa has a large sample size providing precise estimates and narrow
confidence intervals.
3.6.2 Systematic errors
Bias is caused by errors in the design and the way the study is performed (48). In this study all data was collected in forehand, and the way I can address bias is to see them and to interpret the findings.
Selection bias
Selection bias happens when exposed and unexposed persons are selected in such a way that an association is observed when in reality exposure and disease are not associated (48). MoBa
15 was not specifically designed to study associations between physical activity and HG, and this might reduce the potential for selection bias, e.g. in the meaning that not only women
interested in physical activity joined the study.
In the latest version of the MoBa data file, the response rate was 38%, and the low
participating rate was associated with differences between participating and non-participating women (52). The MoBa participants seems to differ from the target population in Norway with regards to age, smoking habits, marital status and a socioeconomic gradient that can influence the prevalence estimate (52, 53). Vikanes has shown that immigrant women are underrepresented in MoBa (54).
Owe (47) found that MoBa participants who didn’t answer the questions on recreational exercise were more prone to be smokers, less educated and be overweight pre pregnancy. Still it is not considered likely to be a selection of participants into the study because of physical activity measurement questions (47), and although the prevalence of physical activity may not be accurate, association measures in MoBa are thought to be valid (53).
Missing analysis was not done in this thesis, but is likely to be of similar character as described above, although this study uses a later version of the data set.
The prevalence of hyperemesis in this study was estimated to be 1%. Using data from MBRN, Vikanes found the overall prevalence of hyperemesis in Norway to be 0.89% (2), showing a slightly higher prevalence of HG in our data. Inclusion took place in 18th gestational week at the ultrasound examination, and one can speculate that if women with the most severe HG were not able to participate it would affect the prevalence. Since this study didn’t have a lower prevalence than the general prevalence of HG in Norway, this assumption does not seem likely.
On this background selection bias might have affected the prevalence estimates in this study.
Nevertheless, it is anticipated that although the prevalence of exposure and outcome might differ from the Norwegian population the associated estimates can still be valid (53).
Information bias
Information bias may appear from the way information is obtained from the participants.
Recall bias might happen when the participants have to report phenomenon back in time (48).
16
In a cohort study recall bias is reduced due to the longitudinal design. Some of the questions in Q1 and Q3 go back three months prior to reporting.
Outcome variable: In our data, hyperemesis was defined as prolonged nausea and vomiting in pregnancy that required hospitalization before the 25th week of pregnancy, as reported in Q3, question 26 and 27 combined. All participants were asked which gestational week they were hospitalised as a consequence of “long-term nausea and vomiting”. The highest option of gestational week was “21-24” for HG. Although there is discrepancy with a few gestational weeks between the HG-definition by Fairweather and WHO (8, 10) and our data,
misclassification is not considered likely. Also, short interval time between the questionnaire and the hospitalisation makes recall bias less likely. This is more thoroughly addressed by Vikanes et al (20).
Exposure variable: The description of self-reported leisure-time physical activity before pregnancy, the questions and categorisation is given in the paper.
Assessment of LTPA: Many different methods exist for measuring physical activity, such as diaries, motion sensors and doubly labelled water (DLW) technique. In epidemiologic studies with large sample size, questionnaire is the most practical assessment method (33, 35). The questionnaire should have high reproducibility (the ability to replication) and high validity (estimating the correct level of activity) (35). The physical activity questions in MoBa have been validated by Brantsæter et al (55) where the questions used to measure regular exercise in pregnant women was found to be valid. A direct comparison to this study cannot be done as the validation study used physical activity data at 15th gestational week, whereas physical activity data in this study is asked retrospect. Further, women with HG were excluded from the validation study.
My study does not have data on duration, type or intensity level or a total measure of LTPA including gardening etc, possibly leading to an underestimating of physical activity. An attempt to calculate intensity based on the different categories of physical activity was considered in this thesis. However, data on intensity derived from the questionnaire were considered to be poor. A lack of information from other ascribing intensity factors such as velocity, surface and steep hills makes intensity assessment from the questionnaire
complicated (56). Further, the questionnaire didn’t have good enough information to capture a total measure of LTPA.
17 The nature of self reported data from questionnaires might lead to imprecise information of activity level, and measurement needs to be accurate to prevent wrong estimates (56). Still, the most frequently used and easiest way to measure physical activity in large
epidemiological studies are by using questionnaires (33, 35). Misclassification and information bias cannot be ruled out.
3.6.3 Confounding
Confounding is one of the most central problems in observational epidemiologic studies, and overlooking it can result in observing a true association thinking there is a causal inference when in fact there is not. For a variable to be a confounder it must be a known risk factor for an outcome and also be associated with the exposure but not a result of the exposure (48).
In this study confounders was chosen on basis of a prior knowledge. I have controlled for the known risk factors for HG and associated factors for LTPA that was available in the data set, and the analytic model is shown in paragraph 3.3. Unmeasured variables such as genetics and diet may leave a residual confounding that cannot be excluded.
3.7 Study sample
The study sample consists of nulliparous women with singletons. With these selection criteria the sample was found to be more homogenous. Primiparity has been associated with HG (9) and also previous experience with HG may have such an impact on a woman’s life that she could choose to end a second pregnancy or not to welcome another (28). Further, women with children at home are likely to have less available time for exercise and other physical activity compared to nulliparous women (57). Singleton pregnancies were chosen because multiple gestations are at higher risk of developing hyperemesis and to have other pregnancy
complications (19). An alternative would have been to include multiparous women, and instead controlled for this variable in the analysis.
18
4 Extended result
The results of the study are presented in the paper.
Presented here is a table that is referred to in the paper, but not shown:
Due to the low number of women reporting no LTPA, the category “never” was merged with those reporting LTPA “1-3 times per week”, and regression analysis was performed in table 2 in the paper. By splitting the group reporting low LTPA into “never” and “1-3 times per month”, the most sedentary group turned out to have the highest risk of HG; aOR=2.84 (95%
CI 1.42 – 5.72).
Table 1. Crude (cOR) and adjusted odds ratios (aOR) for developing hyperemesis gravidarum by frequency of leisure-time physical activity pre pregnancy among women (n=37,407) in MoBa
Leisure-time physical activity pre pregnancy
Number of women (%)
Hyperemesis gravidarum
Cases (%) cOR (95% CI) aOR (95% CI)*
Never 249 (0.7) 9 (3.6) 3.82 (1.93-7.60) 2.84 (1.42-5.72) 1-3 times/month 2464 (6.6) 39 (1.6) 1.64 (1.15-2.35) 1.35 (0.94-1.94) 1-2 times/week 6115 (16.3) 54 (0.9) 0.91 (0.66-1.25) 0.83 (0.60-1.14) 3-5 times/week
(ref) 14314 (38.3) 139 (1.0) 1 1
≥ 6 times/week 14265 (38.1) 131 (0.9) 0.95 (0.74-1.20) 0.97 (0.76-1.24)
* The model is adjusted by maternal age, pre pregnancy body mass index, education and pre pregnancy smoking.
19
5 Conclusion
A large sample size can give a statistically significant finding with narrow confidence intervals. This is not necessarily the same as clinical relevance. The result from this study cannot be understood as an advice for women with HG, as leisure-time physical activity was studied before, and not during, pregnancy. From a public health perspective the finding is a support for the general recommendation of being physically active. It thus seems important for women in fertile age to become physically active as a prevention advice for HG.
As far as we know, this is the first study to investigate the association between frequency of leisure-time physical activity and hyperemesis. The limitations of the study must be taken into consideration, but this study shows that women in MoBa who have no or low LTPA prior to pregnancy seems to have an increased risk of HG compared to women with LTPA 3 to 5 times per week. Future studies are needed to confirm these findings. More research is also needed to investigate the effect of intensity and duration of physical activity on HG, and to address potential biological mechanisms.
20
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7 Paper
Pre-pregnancy leisure-time physical activity and the risk of hyperemesis gravidarum: A prospective Cohort of Norwegian Women
Wold BH1, Vikanes ÅV2, Magnus, M3, Owe KM4, Nystad W3
1 Faculty of Medicine, Department of Public Health and General Practice, Norwegian University of Science and Technology, Trondheim, Norway
2Department of Genes and Environment, Norwegian Institute of Public Health, Oslo, Norway
3Department of Chronic Diseases, Norwegian Institute of Public Health, Oslo, Norway
4Division for information and documentation, Statistics Norway, Oslo, Norway
Corresponding author:
Borgny Hedvig Wold, Norwegian University of Science and Technology, Faculty of
Medicine, Department of Public Health and General Practice, Pb 8905, NO-7489 Trondheim, Norway
E-mail address: [email protected] Phone: 004773598882
Word count:
Abstract: 250 words Main text: 4568 words Tables: 2
Figure: 1
Running title: Pre-pregnancy leisure-time physical activity and hyperemesis gravidarum
26
ABSTRACT
Objective: To estimate association between frequency of pre pregnancy leisure-time physical activity (LTPA) and hyperemesis gravidarum (HG).
Design: Population based cohort study.
Setting: Nationwide pregnancy data, Norway.
Sample: 37,407 primiparous, singleton pregnancies in The Norwegian Mother and Child Cohort Study (MoBa) inclusion period 1999-2008.
Methods: Data on HG, LTPA, body mass index, maternal age, education and smoking habits were all obtained from questionnaires. Relative risks for HG according to level of LTPA were estimated by multiple regressions. Crude (cOR) and adjusted (aOR) odds ratios with 95%
confidence intervals (CI) were calculated.
Main Outcome Measures: Self reported HG defined as prolonged nausea and vomiting in pregnancy that required hospitalization before the 25th week of pregnancy.
Results: 372 women (1.0%) reported having HG, and 7.3% of the participants reported LTPA to be “never” or “1-3 times per month”, defined as “low” LTPA. In contrast 38.3% of the women reported to be physically active “3-5 times per week”. Participants with low LTPA had 50% increased risk of HG compared to those who were physically active 3-5 times per week, aOR= 1.49 (95% CI: 1.06-2.09).
Conclusions: Low LTPA prior to pregnancy was associated with a 50% increase in risk of HG, compared to those being physically active 3-5 times per week. Our findings suggest potential health profit by moving from being sedentary to being physically active.
Keywords: The Norwegian Mother and Child Cohort Study, MoBa, hyperemesis gravidarum, leisure-time physical activity, pregnancy.
27 Introduction
Hyperemesis gravidarum (HG) involves excessive nausea and vomiting starting before the 22nd week of gestation (1). The prevalence of HG in Norway varies between 0.8 – 3.2%
according to country of birth (2) and due to dehydration and vitamin deficiencies it is the second most common reason for hospitalization among women who had a live birth, (3).
Today the mortality rate is very low, but still HG is associated with adverse pregnancy outcomes, such as having a child with low birth weight, small for gestational age and preterm birth (4).
Previous research has suggested that genetic factors are involved in the development of HG (5, 6). Still, the impact of genes and other risk factors are unclear. An increased risk of HG has also been associated with nulliparity, adolescents, multiple gestations and female fetuses (7, 8). Although the underlying mechanisms for HG remains unknown and no known advice for prevention can thus be given, it is from a public health perspective interesting to know whether life style factors influence the risk of HG. Smoking is found to decrease the risk of HG by up to 50% (9-11). Likewise, body mass index (BMI) is found to be associated with HG (8, 9), where women with low BMI (< 18.5 kg/m2) or high BMI (≥ 25 kg/m2) have between 40% to 100% increase in risk of HG compared to those with normal with BMI (BMI between 18.5 kg/m2 and 24.9 kg/m2). Adherence to a healthy diet may also be associated with HG (12, 13). A case control study found a higher intake of total fat to increase the risk of HG (12), and in a sub sample of MoBa a diet including fish and allium vegetables were described to have a protective effect (13). Other life style factors such as the impact of physical activity on the risk of HG, have not yet been studied.
Physical activity is a life style factor, known to be associated with a protective effect on a variety of diseases, such as cardiovascular disease, diabetes 2 and breast cancer (14-17), and
28
physical inactivity has shown to be as great a risk factor for disease as smoking and high level of cholesterol and blood pressure (18). The impact of physical activity on pregnancy-related conditions have received increased attention in recent years (19-21). Leisure-time physical activity (LTPA) is a subcategory of physical activity and includes all kinds of activities one participates in during free time, chosen on individual basis, and includes activities such as walking, dancing, swimming, biking, hiking, gardening and exercise programs (22, 23). A review from 2007 indicated that LTPA may be associated with gestational diabetes mellitus, pre-eclampsia and preterm delivery (19). A recent paper from Mudd et al (24) summarises evidence from epidemiological research in the US, Canada and Scandinavia, and beneficial effect of pregnancy LTPA is found for included pregnancy outcomes such as: gestational diabetes mellitus, hypertensive disorders, excessive gestational weight gain, birth weight, timing of delivery and child body composition.
The Norwegian Mother and Child Cohort Study (MoBa) is a nationwide birth cohort
comprising high quality data with unique possibility to explore whether life style factors prior to pregnancy influences the risk of HG. The aim of this study was to explore whether LTPA, measured as level of frequency prior to pregnancy was associated with HG.
Methods
This study is based in data from MoBa, a prospective population-based pregnancy cohort conducted by the Norwegian Institute of Public Health. Participants were recruited from all over Norway from 1999-2008, and 38.7% of invited women consented to participate. The cohort now includes 109,000 children, 91,000 mothers and 71,700 fathers. Follow up is conducted by questionnaires at regular intervals and by linkage to national health registries.
The current study is based on version V of the quality-assured data files released for research in 2011. Written informed consent was obtained from all participants upon recruitment. The
29 study was approved by The Regional Committee for Medical Research Ethics in South- Eastern Norway.
Pregnant women were recruited through a postal invitation at 17 weeks of gestation after having signed up for a routine ultrasound examination at their local hospital. 50 of 52 hospitals in Norway participated in the study. The MoBa study is described in detail elsewhere (25).
This study population included MoBa participants who had answered Questionnaire 1 (Q1) completed at gestational week 17 and Questionnaire 3 (Q3) completed at gestational week 30, comprising items of background factors, exposures and maternal health both before and during pregnancy (http://www.fhi.no/moba). The data was linked to mothers age from the Medical Birth Registry of Norway (MBRN), and resulted in 108,264 participants. We included only primiparous women with singletons, leaving 46,424 women. Further, we excluded from consideration women who had not answered both questionnaires (n=5,091) and women who responded to the first version of Q1 where the questions on physical activity were formulated differently than the later versions (n=1,707). After further excluding
participants with missing data on one or more variables in the analysis (n=2,219), the final sample comprised 37,407 women (figure 1).
Variables
The main outcome is hyperemesis gravidarum (HG), defined as prolonged nausea and vomiting in pregnancy that required hospitalization before the 25th week of pregnancy, as reported in Q3. The information was self reported and HG was categorised as “no” and “yes”.
30
The main exposure variable was self-reported frequency level of leisure-time physical activity (LTPA) before pregnancy. In Q1, the women were asked how often they performed the following 14 activities during the last three months before pregnancy: walking, brisk walking, running (jogging or orienteering), bicycling, training in training centres/weight training, prenatal aerobics classes, low impact aerobic classes, high impact aerobics classes, dancing (swing, rock, folkdance), skiing, ball games, swimming, horseback riding, and other. For each activity, the participants could report frequency according to these categories: “never”, “one to three times per month”, “once a week”, “twice a week” and “three or more times a week”.
The frequency of each category was calculated in order to get the total frequency of the physical activity. Due to the low number of women reporting no LTPA, the category was merged with those reporting LTPA “1-3 times per week”. Hence, the following four
categories of LTPA were used in the analysis: “Never or 1-3 times per month”, “1-2 times per week”, “3-5 times per week”, “6 or more times per week”. Respondents with LTPA frequency of 3-5 times per week was used as reference category.
Covariates known to be associated with pre pregnancy levels of LTPA and HG, were included as potential confounders. Based on literature search and by a simplified directed acyclic graph (DAG) as an analytic model; maternal age at delivery, self reported pre pregnancy height and weight, smoking habits before pregnancy and maternal length of education were included. Maternal age was categorised as <20, 20-24, 25-29, 30-34 and ≥ 35 years old, body mass index (BMI: weight in kg/height in m2) was categorised as: underweight
<18.5kg/m2, normal weight 18.5-24.9kg/m2, pre obese 25.0-29.9kg/m2 and obese ≥30.0kg/m2) (26). Length of education in years was defined in four categories (< 12 years, 12 years, 13-16 years and ≥ 16 years). Pre pregnancy smoking was categorised as non smoker, occasional smoker and daily smoker.
31 Statistical analysis
First we described maternal characteristics by pre pregnant frequency of LTPA. All covariates was analysed as categorical variables We used binary logistics regression analysis to estimate the associations between frequency of pre pregnancy LTPA and HG, presenting crude (cOR) and adjusted odds ratio (aOR) with 95% confidence intervals (CI). Confounder control was obtained through the adjusted odds ratios. Data were analysed with the Statistical Package for the Social Sciences, version 17 (SPSS Inc, Chicago, IL).
Results
372 women or 1.0% reported having HG. Table 1 shows maternal characteristics by frequency level of pre pregnant LTPA. 7.3% of the women reported low LTPA, 16.3%
reported LTPA 1-2 times per week, whereas 38.3% and 38.1% reported LTPA 3-5 times per week and >= 6 times per week, respectively. Women reporting low LTPA were younger, less educated, had higher BMI and were more likely to smoke compared to those who were physically more active. The cumulative 50% of LTPA was 4.7 times per week (data not shown).
Table 2 shows the association between the frequency level of LTPA and HG. Women who reported low level of LTPA had an increased risk of HG (cOR=1.84, 95% CI 1.32-2.56) compared to women reporting being physically active 3-5 times per week. When adjusting for potential confounders, the risk of HG for those with low LTPA decreased to aOR 1.49 (95%
CI 1.06-2.09). By splitting the group reporting low LTPA into “never” and “1-3 times per month”, as reported initially, the most sedentary group had the highest risk of HG; aOR=2.84 (95% CI 1.42 – 5.72) (data not shown).
Discussion