Discussion
Our meta-analysis shows that maternal serum total cholesterol, non-HDL-C, and triglyceride levels during pregnancy are elevated during the first/second and third trimesters in women who subsequently develop preeclampsia compared with women who remain normotensive during pregnancy. Additionally, our results suggest that women who subsequently develop preeclampsia likely have increased levels of LDL-C in the first/second and third trimesters compared with normotensive women, though these results were of marginal significance. Finally, maternal HDL-C levels during the third trimester of pregnancy are lower in preeclamptic women compared with normotensive pregnant women.
A recent meta-analysis of hypertriglyceridemia and preeclampsia reported that maternal triglyceride levels during pregnancy were elevated in women who subsequently developed preeclampsia; however, our methodological approach was substantially more inclusive and comprehensive. The authors of that study located 24 case-control and 5 cohort studies for inclusion in their meta-analysis, whereas our search strategy led us to 86 articles (13 of which we excluded because of low quality scores), 3 times the number of articles found in the previous analysis. However, despite the additional articles, we found very similar WMDs in our analysis when we stratified by trimester of measurement. The authors also detected significant heterogeneity after stratification by trimester, which they attributed to difference in BMI; this hypothesis, however, was not tested. We performed meta-regression analyses to assess BMI as a possible source of heterogeneity and found that BMI differences across studies were possible sources of heterogeneity for triglycerides and LDL-C.
During the course of a normal pregnancy, total cholesterol, HDL-C, triglycerides, and LDL-C levels rise markedly. Cholesterol is necessary for placental steroid synthesis, and increases in cholesterol levels during pregnancy promote the accumulation of maternal fat stores in the first two-thirds of pregnancy to serve as a source of calories for the mother and fetus during the later stages of pregnancy and lactation. Results from this meta-analysis suggest that women with preeclampsia experience greater changes in lipid metabolism than normotensive women. For example, the difference in triglycerides between preeclamptic and normotensive pregnancies is substantially greater during the third trimester (WMD = 80.29) compared with the first/second trimesters (WMD = 25.08). This same trend of greater differences in the third trimester compared with the first/second trimesters was also observed for total cholesterol, HDL-C, LDL-C, and non-HDL-C, suggesting that preeclamptic women experience larger changes in lipid levels during pregnancy than normotensive women.
Dyslipidemia in preeclamptic women is characteristic of what occurs in insulin-resistant, hyperglycemic women who are not pregnant, many of whom also have the clustering of metabolic syndrome characteristics that include hypertension. This suggests that a similar pathophysiological process may be occurring in women with preeclampsia and could be contributing to the dyslipidemic changes. Insulin resistance and type 2 diabetes are characterized by the increased overproduction of the triglyceride-rich very-low-density lipoprotein cholesterol and subsequent increased levels of other triglyceride-rich lipoproteins, which are included in non-HDL-C and reflected in elevated triglyceride levels.
Preeclampsia has been proposed to have a 3-stage disease process that stems from an imbalance between placental factors and maternal adaptation to them. The disease begins with incomplete maternal tolerance to the allogeneic trophoblasts (stage 1), followed by poor placentation that leads to reduced placental perfusion and poor spiral artery remodeling (stage 2). As a result, the oxidatively stressed placenta releases a number of trophoblast-derived antiangiogenic (e.g., soluble fms-like tyrosine kinase-1, soluble vascular endothelial growth factor, and soluble endoglin) and proangiogenic (e.g., placenta growth factor) factors that contribute to an exaggerated maternal inflammatory response (stage 3). The imbalance of angiogenic factors is thought to increase maternal vascular inflammation with generalized endothelial dysfunction. Women with elevated lipid levels likely have preexisting endothelial dysfunction that is worsened as a result of the physiological burden of pregnancy; this condition may be further exacerbated by increased maternal vascular inflammation. It is possible that preeclamptic women have higher baseline levels of total cholesterol, triglycerides, and LDL-C and lower levels of HDL-C prepregnancy, but only a handful of studies have taken prepregnancy measurements in preeclamptic women, and we were not able to assess the impact of prepregnancy lipid levels on the risk of preeclampsia.
Recent research has demonstrated that LDL-C is not the only form of cholesterol associated with adverse outcomes. In fact, it has been shown that the inclusion of other atherogenic lipoproteins, referred to as non-HDL, which include very-low-density lipoproteins and other apolipoprotein B–containing lipoproteins, is more predictive of cardiovascular disease than LDL-C levels alone. Previous research suggests that LDL-C levels are higher among women who develop preeclampsia than among those who remain normotensive throughout pregnancy; however, our results suggest only a moderate difference in LDL-C levels between the 2 groups. Alternatively, we did find that levels of very-low-density lipoproteins (results not shown) and non-HDL-C are significantly higher among preeclamptic women than among normotensive women, suggesting that, although LDL-C levels may not be the most useful measure for preeclampsia prediction, a combined measure of all types of non-HDL-C may be useful.
Previous studies evaluating the association between lipid levels during pregnancy and preeclampsia have suggested measuring lipid levels in all pregnant women as a means of early-pregnancy "screening" of women who may be at higher risk for development of the disease. However, results from our meta-analysis indicate that LDL-C and HDL-C levels measured during pregnancy would not be as useful in predicting preeclampsia as other lipid types. HDL-C levels were significantly different between preeclamptic and normotensive women during only the third trimester of pregnancy, which may be too late for an effective prediction tool. Preeclamptic and normotensive women showed marginally significant differences in LDL-C levels during both the second and third trimesters of pregnancy; however, with a WMD of only 3.89 mg/dL in the second trimester, this marker may not be clinically useful as a prediction tool.
Women who developed preeclampsia did have significantly elevated total cholesterol, triglyceride, and non-HDL-C measurements as early as the second trimester; thus, these lipid measurements obtained early in pregnancy may be helpful in identifying women at higher risk of developing preeclampsia. Although a WMD of 12.49 (for total cholesterol), 25.08 (for triglycerides), or 11.57 (for non-HDL-C) may not be clinically significant as an individual marker, when combined with other biomarkers known to differ in preeclamptic women, such as increased mean arterial pressure, soluble fms-like tyrosine kinase-1, and placental growth factor, total cholesterol, triglyceride, and/or non-HDL-C measurements could be clinically useful in identifying women at higher risk for developing preeclampsia. The American College of Obstetricians and Gynecologists Task Force on Hypertension in Pregnancy recently revised the guidelines for the diagnosis of preeclampsia in an effort to increase the diagnostic sensitivity and specificity for preeclampsia by allowing for its diagnosis in the absence of proteinuria when any 1 of 6 severe features of preeclampsia is found. Because these severe features are relatively infrequent during pregnancy, implementation of the revised definition is unlikely to alter the conclusions of the meta-analysis or lessen the potential clinical utility of including lipid measurements in preeclampsia prediction algorithms.
Strengths and Limitations
A key strength of our meta-analysis is the sensitive search strategy that we developed in consultation with a research librarian. Specifically, we searched 2 databases and did not apply any language, country, or date restrictions to the search to increase our chances of identifying all possible publications related to the topic. Additionally, the high yield of articles eligible for inclusion allowed us to limit our analysis to the studies of higher quality. Finally, we were able to perform meta-regression to illustrate that fasting status at the time of lipid measurement did not affect our results. This is an important finding for studies of lipid measurements and pregnancy outcomes, because it is particularly difficult to obtain fasting measurements longitudinally throughout pregnancy. If incorporated with routinely measured markers in pregnancy, such as pregnancy-associated plasma protein A and glucose, most, if not all, samples could be collected during a nonfasting state. Therefore, we demonstrate that lipid measurements may be incorporated with routine clinical analysis of other biomarkers, which is particularly important when evaluating the feasibility of universal screening for lipid levels during pregnancy.
This meta-analysis also included a separate analysis of severe and mild preeclampsia. It should be noted, however, that we did not use our own specific criteria for the definitions of severity. Preeclampsia definitions have varied slightly over time, and many countries have their own definitions of severity. Thus, some of the heterogeneity between the severity studies could be explained by varying definitions. Of the studies included in this subanalysis, 2 did not report their classification criteria for severe preeclampsia. Among those that did, the most common criteria for diagnosis of severe preeclampsia were systolic blood pressure of 160 mm Hg or higher, diastolic blood pressure of 110 mm Hg or higher, proteinuria of either 2 g/24 hours or more or 5 g/24 hours or more, or the presence of another severe symptom. Further, it is increasingly believed that early- and late-onset preeclampsia may be different diseases with different pathophysiologies; however, we did not locate an adequate number of studies that distinguished between early- and late-onset preeclampsia.
Although we were able to perform meta-regression to identify BMI as a potential confounder and source of heterogeneity, we were unable to incorporate this factor into our mean difference meta-analysis. This was not possible because the included studies would have to have presented their mean lipid levels stratified by BMI, and those levels of stratification would have to have been equivalent across all studies.
This meta-analysis could not be performed with all of the studies located in the systematic literature review because of the lack of information about the mean and standard deviation in each group (or lack of information necessary to convert the information into means and standard deviations) (n = 17). These studies, if added to the meta-analysis, might have altered our findings. However, a comparison of our triglyceride results to those of the previous meta-analysis on the topic that included one-third of the studies included here shows very similar results, indicating that the addition of further studies to this meta-analysis is unlikely to alter our findings.
Conclusion
Total cholesterol, triglyceride, non-HDL-C, and HDL-C levels measured during pregnancy are significantly related to the risk of preeclampsia. This finding is clinically useful because maternal lipid levels can be easily measured in all clinical laboratories with routine, well-established lipid panels; thus, inexpensive lipid panels could serve as a cost-effective method for identifying pregnant women at risk for developing preeclampsia. Future research is needed to understand the role of dyslipidemia and other components of metabolic syndrome, such as insulin resistance and obesity, in the pathogenesis of preeclampsia and the mechanisms by which this relationship could be moderated.