The use of angiogenic factors in discriminating preeclampsia: are they ready for prime time?

Objectives.?We sought to evaluate the association between soluble fms-like tyrosine kinase 1 (sFlt1) and endoglin (ENG) and preeclampsia in an urban population, to develop a discriminatory model, and evaluate the association of these biomarkers with small for gestational age (SGA).

Methods.?Cases are prospectively identified with preeclampsia. Controls are term patients without preeclampsia. Commercially available ELISAs were used to measure levels of sFlt1, ENG, and placental growth factor (PlGF). Log-transformed levels were compared and multivariable logistic regression analyses were performed to control for confounders. Receiver operating characteristic curves were developed.

Results.?In cases (n?=?86) compared to controls (n?=?288), sFlt1 (p?=?0.24) levels were no different. However, ENG levels were higher (p?<?0.001), and PlGF levels were lower (p?<?0.001). Further, levels of sFlt1 had poor discriminatory ability between cases and controls [AUC?=?0.56, (0.48–0.63)]. The best model to discriminate between groups included clinical risk factors, ENG, and PlGF [AUC?=?0.89, (0.85–0.92)].

Conclusions.?Unlike recent reports, this study suggests that sFlt1 may have limited diagnostic utility in predicting preeclampsia, especially term disease.     

Is preeclampsia an infectious disease?

BACKGROUND: Studies have suggested a strong paternal factor in the etiology of preeclampsia. If preeclampsia is caused by an infectious agent transmitted by the woman's partner, seronegative women who may experience primary infection in pregnancy should be at increased risk of preeclampsia as compared to previously infected women. The aim of this study was to assess the impact of being seronegative for some viruses transmitted by close contact on the risk of developing preeclampsia. METHODS: Nine hundred and seventy-eight women were randomly drawn from a basic study population of 35,940 pregnant women in Norway. A serum sample drawn at the first antenatal visit was analyzed for specific IgG antibodies against herpes simplex virus type-2, cytomegalovirus and Epstein-Barr virus. For comparison, antibody status against Toxoplasma gondii was also assessed. Information on preeclampsia in pregnancy was obtained through linkage to the Medical Birth Registry of Norway. RESULTS: Thirty-three (3%) women developed preeclampsia. The risk of developing preeclampsia seemed to be increased for women who were seronegative for the viruses studied. Seronegativity for Toxoplasma gondii did not show such a pattern. INTERPRETATION: Women who are seronegative for antibodies against viral agents transmitted through close contact seem more likely to develop preeclampsia. This finding indicates that women who are seronegative to such agents may acquire primary infection in pregnancy, and subsequently be at increased risk of preeclampsia. This hypothesis could represent a new approach to the causes of preeclampsia, and encourage search for yet unidentified microbes as a possible causal factor.     

Genetics of Preeclampsia: What are the Challenges?

Despite recent efforts to identify susceptibility gènes of preeclampsia, the genetic determinants of the condition remain ill-defined, as is the situation for most disorders of complex inheritance patterns. The angiotensinogen, factor V, and methylenetetrahydrofolate reductase genes have been investigated in different populations, as have other genes involved in blood pressure, vascular volume control, thrombophilia, lipid metabolism, oxidative stress, and endothelial dysfunction. The study of the genetics of complex traits is faced with both methodological and genetic issues; these include adequate sample size to allow for the identification of modest genetic effects, of gene-gene and gene-environment interactions, the study of adequate quantitative traits and extreme phenotypes, haplotype analyses, statistical genetics, genome-wide (hypothesis- free) versus candidate-gene (hypothesis-driven) approaches, and the validation of positive associations. The use of genetically well-characterized populations showing a founder effect, such as the French-Canadian population of Quebec, in genetic association studies, may help to unravel the susceptibility genes of disorders showing complex inheritance, such as preeclampsia. It is necessary to better evaluate the role of the fetal genome in the resulting predisposition to preeclampsia and its complications. Eventually, we may be able to integrate genetic information to better identify the women at risk of developing preeclampsia, and to improve the management of those suffering from this condition.     

Is there any role of prolidase enzyme activity in the etiology of preeclampsia?

Objective: To evaluate a relationship between preeclampsia and prolidase enzyme activity.

Methods: A prospective cohort study of 41 pregnant women diagnosed with preeclampsia and 31 healthy pregnant women as control group was selected at Harran University Hospital Department of Obstetrics and Gynecology. The prolidase enzyme activity was analyzed in maternal and umbilical cord plasma, amniotic fluid and placental and umbilical cord tissues by Chinard method in addition to maternal serum levels of lactate dehydrogenase (LDH), serum glutamate pyruvate transaminase (SGPT) and serum glutamate oxaloacetate transaminase (SGOT).

Results: A significant relationship was found between plasma prolidase activity (635?±?83?U/L) (p =?0.007), umbilical cord plasma prolidase activity (610?±?90?U/L) (p?=?0.013), amniotic fluid prolidase activity (558?±?100?U/L) (p =?0.001), umbilical cord tissue prolidase activity (4248?±?1675?U/gr protein) (p =?0.013) and placental tissue prolidase activity (2116?±?601?U/gr protein) (p =?0.001) in preeclamptic group when compared to healthy pregnant women.

Conclusion: There is a strong correlation between prolidase enzyme activity and preeclampsia. Prolidase enzyme activity may play a role in preeclampsia.     

Correlation between oral sex and a low incidence of preeclampsia: a role for soluble HLA in seminal fluid?

The involvement of immune mechanisms in the aetiology of preeclampsia is often suggested. Normal pregnancy is thought to be associated with a state of tolerance to the foreign antigens of the fetus, whereas in preeclamptic women this immunological tolerance might be hampered. The present study shows that oral sex and swallowing sperm is correlated with a diminished occurrence of preeclampsia which fits in the existing idea that a paternal factor is involved in the occurrence of preeclampsia. Because pregnancy has many similarities with transplantation, we hypothesize that induction of allogeneic tolerance to the paternal HLA molecules of the fetus may be crucial. Recent data suggest that exposure, and especially oral exposure to soluble HLA (sHLA) or HLA derived peptides can lead to transplantation tolerance. Similarly, sHLA antigens, that are present in the seminal plasma, might cause tolerance in the mother to paternal antigens. In order to test whether this indeed may be the case, we investigated whether sHLA antigens are present in seminal plasma. Using a specific ELISA we detected sHLA class I molecules in seminal plasma. The level varied between individuals and was related to the level in plasma. Further studies showed that these sHLA class I molecules included classical HLA class I alleles, such as sHLA-A2, -B7, -B51, -B35 and sHLA-A9. Preliminary data show lower levels of sHLA in seminal plasma in the preeclampsia group, although not significantly different from the control group. An extension of the present study is necessary to verify this hypothesis.     

Prediction of preeclampsia: can it be achieved?

In this review, the various biochemical tests that have been proposed for the prediction of preeclampsia are described and evaluated. Placenta hormone markers do not predict future disease. They denounce the early placental changes that are part of the evolving disease and only predict the imminent of preeclamptic syndrome. This explains why tests are better predictors when preeclampsia supervenes shortly, and why screening in the first trimester is unlikely to work as well as in the second trimester. The use of multiple markers in the screening should reflect different aspects of the disease process and could increase the specificity and sensitivity of the screening and work on different etiologic factors. The possible use of second-trimester biochemical screening to predict the risk of preeclampsia remains to be investigated in the high-risk population. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians LEARNING OBJECTIVES: After completion of this article, the reader should be able to list the various theories on the etiology of preeclampsia, to relate the various risk factors for the development of preeclampsia, and to describe the various screening tests for preeclampsia.