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Pre-eclampsia – Possible to Predict?: A Biochemical and Epidemiological Study of Pre-eclampsia
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pre-eclampsia is a major cause of maternal and perinatal morbidity and mortality worldwide. A predictor of pre-eclampsia would enable intervention, close surveillance and timely delivery, and thereby reduce the negative consequences of the disorder.

The overall aim of this thesis was to study potential predictors of pre-eclampsia by biochemical and epidemiological methods.

Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2) are regulators of angiogenesis, which is important for placental development. In a prospective and longitudinal study of a low-risk population the Ang-1/Ang-2 ratio was evaluated. The Ang-1/Ang-2 ratio increased during pregnancy in all women but at gestational week 25 and 28 the ratios were significantly lower in women who later developed pre-eclampsia. The relevance of Histidine-rich glycoprotein (HRG), a protein with angiogenic properties, was furthermore evaluated. HRG levels decreased in all women, with significantly lower levels at gestational week 10, 25 and 28 in women who later developed pre-eclampsia. Thus both Ang-1/Ang-2 ratio and HRG may predict pre-eclampsia.

To evaluate the predictive value of HRG in combination with uterine artery Doppler early in pregnancy a study was performed in a high-risk population. The results revealed that the combination was better able to predict preterm pre-eclampsia than each marker individually, with a sensitivity of 91% at a specificity of 62%. 

A possible association between hyperemesis gravidarum and pre-eclampsia, as well as other placental dysfunctional disorders, was investigated. Hyperemesis gravidarum may be caused by high levels of human chorionic gonadotrophin (hCG) and increased levels of hCG in the second trimester is associated with later development of pre-eclampsia. A cohort of all pregnancies in the Swedish medical birth register between 1997 and 2009 was studied. After adjustment for confounding factors an association between hyperemesis gravidarum in the second trimester and preterm pre-eclampsia, placental abruption and infants born small for gestational age was demonstrated.

In conclusion, the ratio of Ang-1/Ang-2 as well as HRG in plasma may be potential predictors of pre-eclampsia. Combination with uterine artery Doppler further increases the predictive value of HRG for preterm pre-eclampsia. Hyperemesis gravidarum in the second trimester may be considered as a clinical risk predictor of pre-eclampsia and other placental dysfunctional disorders.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. , 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 835
Keyword [en]
pre-eclampsia, angiopoietin, histidine-rich glycoprotein, hyperemesis gravidarum
National Category
Medical and Health Sciences
Research subject
Obstetrics and Gynaecology
Identifiers
URN: urn:nbn:se:uu:diva-183394ISBN: 978-91-554-8523-8 (print)OAI: oai:DiVA.org:uu-183394DiVA: diva2:563136
Public defence
2012-12-14, Rosénsalen, Akademiska sjukhuset ingång 95, Uppsala, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2012-11-23 Created: 2012-10-25 Last updated: 2013-02-11Bibliographically approved
List of papers
1. Angiopoietin-1/angiopoietin-2 ratio for prediction of preeclampsia
Open this publication in new window or tab >>Angiopoietin-1/angiopoietin-2 ratio for prediction of preeclampsia
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2009 (English)In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 22, no 8, 891-895 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: A number of different biophysical and biochemical markers have been proposed as predictors of preeclampsia. Factors involved in the angiogenic balance are suggested as candidate markers. The purpose of this prospective, longitudinal cohort study was to determine whether a ratio between Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2) can be used to predict preeclampsia in a low-risk population. METHODS: A cohort of healthy pregnant women (n = 469) were enrolled at gestational weeks 8-12. Plasma samples were collected at gestational weeks 10, 25, 28, 33, and 37. By using commercially available enzyme-linked immunosorbent assay kits Ang-1 and Ang-2 were analyzed. RESULTS: The median Ang-1/Ang-2 ratio increased during pregnancy in all women, but the ratios were significantly lower at gestational weeks 25 and 28 in women who later developed preeclampsia than in normal pregnant women (1.49 compared to 2.19 and 2.12 compared to 3.54, P < 0.05 and P < 0.05). CONCLUSION: Our data indicate that in a low-risk population of women the Ang-1/Ang-2 ratio in plasma constitutes a possible biomarker for prediction of later onset of preeclampsia.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-120865 (URN)10.1038/ajh.2009.97 (DOI)000268914800019 ()19478794 (PubMedID)
Available from: 2010-03-18 Created: 2010-03-16 Last updated: 2017-12-12Bibliographically approved
2. Histidine-Rich Glycoprotein as an Early Biomarker of Preeclampsia
Open this publication in new window or tab >>Histidine-Rich Glycoprotein as an Early Biomarker of Preeclampsia
2011 (English)In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 24, no 4, 496-501 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Prediction of preeclampsia is of great interest and the coagulation system as well as the angiogenic pathway is known to be dysfunctional in preeclampsia. Histidine-rich glycoprotein (HRG) is a protein interacting with both these biological systems and the purpose of this prospective, longitudinal cohort study was to analyze whether there is a difference in circulating levels of HRG during pregnancy in women developing preeclampsia compared to normal healthy pregnancies. We furthermore wanted to evaluate whether HRG has the potential of being an early biomarker of preeclampsia. METHODS: A cohort of healthy pregnant women (n = 469) was enrolled at gestational weeks 8-12. Plasma samples were collected at gestational weeks 10, 25, 28, 33, and 37 and analyzed with an enzyme-linked immunosorbent assay. RESULTS: The levels of HRG decreased during pregnancy in all women, but the levels were significantly lower at gestational weeks 10, 25, and 28 in women who later developed preeclampsia than in normal pregnant women (P < 0.05, P < 0.05, and P < 0.05). CONCLUSION: Our data indicates that HRG levels in plasma might be a possible biomarker already in gestational week 10 for prediction of later onset of preeclampsia in a low risk population.

Keyword
angiogenesis, blood pressure, histidine-rich glycoprotein, hypertension, prediction, preeclampsia
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-144193 (URN)10.1038/ajh.2010.264 (DOI)000288823200023 ()21252863 (PubMedID)
Available from: 2011-01-28 Created: 2011-01-28 Last updated: 2017-12-11Bibliographically approved
3. Prediction of Preeclampsia by Combining Serum Histidine-Rich Glycoprotein and Uterine Artery Doppler
Open this publication in new window or tab >>Prediction of Preeclampsia by Combining Serum Histidine-Rich Glycoprotein and Uterine Artery Doppler
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2012 (English)In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 25, no 12, 1305-1310 p.Article in journal (Refereed) Published
Abstract [en]

Background

Preeclampsia is associated with both maternal and perinatal morbidity and mortality. Histidine-rich glycoprotein (HRG) is a protein interacting with angiogenesis, coagulation, and inflammatory responses, processes known to be altered in preeclamptic pregnancies. Significantly lower levels of HRG have been demonstrated as early as in the first trimester in women later developing preeclampsia compared with normal pregnancies. The aim of this study was to investigate whether the combination of HRG and uterine artery Doppler ultrasonography can be used as a predictor of preeclampsia.

Methods

A total of 175 women were randomly selected from a case-control study; 86 women had an uncomplicated pregnancy and 89 women later developed preeclampsia. Blood samples and pulsatility index (PI) were obtained from both cases and controls in gestational week 14.

Results

HRG levels were significantly lower in women who developed preterm preeclampsia compared with controls, but not for women developing preeclampsia in general. PI was significantly higher in the preeclampsia group compared with controls, especially in preterm preeclampsia. The combination of HRG and PI revealed a sensitivity of 91% and a specificity of 62% for preterm preeclampsia.

Conclusions

The combination of HRG and uterine artery Doppler may predict preterm preeclampsia in early pregnancy.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-180199 (URN)10.1038/ajh.2012.112 (DOI)000311175300012 ()22895448 (PubMedID)
Available from: 2012-08-31 Created: 2012-08-31 Last updated: 2017-12-07Bibliographically approved
4. Hyperemesis gravidarum and risks of placental dysfunction disorders: a population-based cohort study
Open this publication in new window or tab >>Hyperemesis gravidarum and risks of placental dysfunction disorders: a population-based cohort study
Show others...
2013 (English)In: British Journal of Obstetrics and Gynecology, ISSN 1470-0328, E-ISSN 1471-0528, Vol. 120, no 5, 541-547 p.Article in journal, Editorial material (Refereed) Published
Abstract [en]

Objective To study whether pregnancies complicated by hyperemesis gravidarum in the first (<12weeks) or second (1221weeks) trimester are associated with placental dysfunction disorders. Design Population-based cohort study. Setting Sweden. Population All pregnancies in the Swedish Medical Birth Register estimated to have started on 1 January 1997 or later and ended in a single birth on 31 December 2009 or earlier (n=1156050). Methods Odds ratios with 95% confidence intervals were estimated for placental dysfunction disorders in women with an inpatient diagnosis of hyperemesis gravidarum, using women without inpatient diagnosis of hyperemesis gravidarum as reference. Risks were adjusted for maternal age, parity, body mass index, height, smoking, cohabitation with the infant's father, infant's sex, mother's country of birth, education, presence of hyperthyreosis, pregestational diabetes mellitus, chronic hypertension and year of infant birth. Main outcome measures Placental dysfunction disorders, i.e. pre-eclampsia, placental abruption, stillbirth and small for gestational age (SGA). Results Women with hyperemesis gravidarum in the first trimester had only a slightly increased risk of pre-eclampsia. Women with hyperemesis gravidarum with first admission in the second trimester had a more than doubled risk of preterm (<37weeks) pre-eclampsia, a threefold increased risk of placental abruption and a 39% increased risk of an SGA birth (adjusted odds ratios [95% confidence intervals] were: 2.09 [1.383.16], 3.07 [1.885.00] and 1.39 [1.061.83], respectively). Conclusions There is an association between hyperemesis gravidarum and placental dysfunction disorders, which is especially strong for women with hyperemesis gravidarum in the second trimester.

Keyword
hyperemesis gravidarum, placental abruption, pre-eclampsia, small for gestational age, stillbirth
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-183390 (URN)10.1111/1471-0528.12132 (DOI)000316284300005 ()
Available from: 2012-10-25 Created: 2012-10-25 Last updated: 2017-12-07Bibliographically approved

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