Risk Estimation and Prediction of Preeclampsia, IUGR, and Thrombosis in Pregnancy

From the Department of Obstetrics and Gynecology,
University of Lund, Malmö University Hospital
Risk Estimation and Prediction
of Preeclampsia, IUGR, and
Thrombosis in Pregnancy
Pelle Lindqvist

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© Pelle Lindqvist
Printed in Sweden
Team Offset & Media, Malmö 1999
ISBN: 91-628-3859-8

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Abstract
3
Abstract
The aim of this thesis was to improve background knowledge for making a
reliable medical evaluation at the first visit of a woman in her 13th gestational
week, to the antenatal clinic. We have focused on the prediction and the risk
estimation of preeclampsia, intra-uterine growth restriction (IUGR), and
thrombosis.
The thesis is based on five studies, in which we have evaluated biochemical
analyzes, genetic tests, anamnestic information, and statistics (based on data in
the from medical files and at the Swedish Medical Birth and Hospital Discharge
Registers).
A high maternal urine chorionic gonadotropin level in early pregnancy was
associated with a 3-fold increased risk of preeclampsia, vis-à-vis low values,
while low epidermal growth factor levels were associated with IUGR
pregnancies.
Maternal smoking was associated with an increased and consumption
dependent risk of thrombosis (Odds ratio (OR)=1.24; 95% Confidence interval
(CI) 1.02-1.51). Moderate smoking was associated with lower incidence of
preeclampsia associated with preterm birth in both study series (OR=0.1; CI
0.01-0.7, and OR=0.6; CI 0.5-0.8, respectively).
Apart from a 1.1% risk of thrombosis, APC resistance was not associated with
preeclampsia, IUGR, or spontaneous abortion. However, the carriers of APC
resistance had fewer profuse hemorrhages at delivery (3.7% vs. 7.9%), which
might have given them an evolutionary advantage, explaining the high
prevalence (10.7%). The natural incidence of pregnancy-associated thrombosis
was 13/10,000, evenly divided between ante- and postpartum periods. APC
resistance was associated with an 8-fold increased risk of thrombosis.
Overweight, heredity of thrombosis, and cesarean delivery were all associated
with a roughly 5-fold increased risk of thrombosis. Preeclampsia was associated
with a 3-fold increased risk of thrombosis, postpartum.

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List of Papers
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LIST OF PAPERS
This thesis is based on the following papers which will be referred to in the text
by their roman numerals:
I.
Lindqvist P, Grennert L, Maršál K. Epidermal growth factor in maternal
urine – a predictor of intrauterine growth restriction. Early Human
Development 1999; 56: 127-135.
II. Lindqvist PG, Maršál K. Moderate smoking during pregnancy is associated
with reduced occurrence of preeclampsia. Acta Obstetricia et Gynecologica
Scandinavica 1999; 78: 693-97.
III. Lindqvist PG, Svensson P, Dahlbäck B, Maršál K. Factor V:Q506 mutation
(activated protein C resistance) associated with reduced intrapartum blood
loss – a possible evolutionary selection mechanism. Thrombosis and
Haemostasis 1998;79:69-73.
IV. Lindqvist PG, Svensson P, Maršál K, Grennert L, Luterkort M, Dahlbäck B.
Activated protein C (FV:Q506) and pregnancy. Thrombosis and
Haemostasis 1999; 81: 532-7.
V. Lindqvist P, Dahlbäck B, Maršál K. Thrombotic risk during pregnancy, a
population study. Obstetrics and Gynecology 1999; 94: 595-99.

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Contents
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CONTENTS
ABBREVIATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Prevention of preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Prediction of preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Intra-uterine growth restriction (IUGR) . . . . . . . . . . . . . . . . . . . . . . . . 19
Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Antenatal identification of IUGR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Prediction of IUGR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Basis of present studies on prediction of IUGR and preeclampsia . . . 22
Epidermal growth factor (EGF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Human chorionic gonadotropin (HCG) . . . . . . . . . . . . . . . . . . . . . . . . . 22
APC resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Hemostasis during pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Blood coagulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Anticoagulant system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
The protein C anticoagulant system . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Hereditary thrombophilias in the protein C system . . . . . . . . . . . . . . . . 24
APC resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Thrombosis and thrombosis incidence . . . . . . . . . . . . . . . . . . . . . . . . . . 27
SUBJECTS AND METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
A prospective study on the prediction of preeclampsia and IUGR
(Paper I) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Two retrospective series of women with preeclampsia (Paper II) . . . . . 28
A retrospective study of APC resistance in women with a history of
preeclampsia and/or IUGR (Paper III) . . . . . . . . . . . . . . . . . . . . 30
A prospective study of APC resistance and pregnancy (Paper IV) . . . . 31
A national retrospective case-control study of pregnant women with
thrombosis (Paper V). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

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Contents
Data Sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Methodological considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Diagnosis of preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Study size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Power estimations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Determination of increased or decreased risk . . . . . . . . . . . . . . . . . . . . 35
Risk estimation and design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Prediction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Reliability of smoking information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Non-differential vs. differential bias of smoking information . . . . . . . . 36
Statistics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Differences between groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Calculation of risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Correlation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Calculation of selection advantage . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Statistical package . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
Prediction of preeclampsia and /or IUGR . . . . . . . . . . . . . . . . . . . . . . . 38
Association of EGF and HCG in maternal urine with preeclampsia and
/or IUGR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
Association of APC resistance with preeclampsia and IUGR . . . . . . . . 39
Risk of pregnancy complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Smoking habits and risk of preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . 39
Risk of fetal loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
Association of fetal loss and APC resistance . . . . . . . . . . . . . . . . . . . . . 42
Homozygous individuals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
Risk of pregnancy-associated thromboembolism . . . . . . . . . . . . . . . . . 43
Incidence of thrombosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
APC resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Heredity and overweight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Homozygous individuals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
Risk of bleeding complications associated with delivery . . . . . . . . . . . 48
Blood loss and APC resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Prediction of preeclampsia and /or IUGR . . . . . . . . . . . . . . . . . . . . . . . 51
Prediction of preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Prediction and prevention of IUGR . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Adverse outcome and APC resistance . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Intra-uterine growth restriction (IUGR) . . . . . . . . . . . . . . . . . . . . . . . . 52

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Contents
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Spontaneous abortions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Stillbirth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Abruptio placentae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Adverse outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Bleeding complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Thrombosis and pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Thrombosis incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Risk estimation of thrombosis during pregnancy . . . . . . . . . . . . . . . . . 56
Heredity and overweight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Cesarean delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Parity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Hereditary thrombophilias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
APC resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Prophylaxis during pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Information to APC-resistant women . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Smoking during pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Smoking and preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Smoking and IUGR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Smoking and thrombosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Blood loss and evolutionary selection advantage . . . . . . . . . . . . . . . . . 63
The clinical impact of anemia and profuse blood loss during delivery in
ancient times - a historical background . . . . . . . . . . . . . . . . . . . 63
Selection advantage from sickle cell anemia . . . . . . . . . . . . . . . . . . . . . 64
APC resistance and evolutionary selection advantage . . . . . . . . . . . . . 65
Fictitious example of selection advantage of APC resistance . . . . . . . . 65
Present situation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
SUMMARY and CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
SWEDISH SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Svensk sammanfattning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Inledning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Graviditetshormon och 'epidermal growth factor' . . . . . . . . . . . . . . . . 81
APC-resistens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Publikation I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
Publikation II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

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Contents
Publikation III . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
Publikation IV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Publikation V . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Evolutionär fördel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Slutsats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
ACKNOWLEDGMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85

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