Maternal Hyperlipidemia and the Risk of Preeclampsia
Maternal Hyperlipidemia and the Risk of Preeclampsia
This study consisted of a systematic literature review followed by a meta-analysis, both conducted taking into account the Meta-analysis of Observational Studies in Epidemiology: a Proposal for Reporting Criteria and Preferred Reporting Items for Systematic Reviews and Meta-analyses group guidelines. A systematic literature search of eligible studies was conducted in the PubMed/MEDLINE and Scopus databases from the index date through July 2013 for studies evaluating the association between lipid levels during pregnancy and preeclampsia using the following search strategy: ("preeclampsia" OR "eclampsia" OR "toxemia" OR "pregnancy-induced hypertension" OR "gestational hypertension") AND ("cholesterol" OR "lipid" OR "HDL" OR "LDL" OR "triglycerides" OR "dyslipidemia" OR "hyperlipidemia" OR "hypertriglyceridemia"). The search was not restricted by language, and no limits or filters were placed on the search to ensure maximal sensitivity. References from these publications were also manually searched for potentially relevant citations not detected by the electronic search. A research librarian assisted in creating the most efficient and effective search strategy possible.
Records identified from the literature search were screened for duplicates. Titles and abstracts were screened, and potentially relevant articles were selected for full-text review. Studies were considered for inclusion in our meta-analysis if they met the following criteria: 1) an original study that examined the association between lipid levels during pregnancy and preeclampsia; 2) raw lipid levels presented as a group mean with either a standard error or standard deviation or as a median with the 95% confidence interval; and 3) a proper control group of normotensive pregnant women.
Full manuscripts were obtained for studies that appeared to examine lipid levels in women with preeclampsia. Full-text review was performed by 2 independent investigators (C.N.S. and C.J.S.) using a piloted data abstraction form and resulting in 91% concordance. Information collected included study characteristics (author, year of publication, study location, dates, and design); participant characteristics (definitions of the preeclampsia and control groups, diagnostic criteria, mean age, mean prepregnancy body mass index (BMI) (weight (kg)/height (m)), and mean gestational age at blood sampling); lipid measurements (mean or median, along with standard error (SE), standard deviation (SD), or 95% confidence interval (CI)); number of subjects in each group; and statistical significance for tests between the groups). Inconsistencies between the 2 reviewers were adjudicated by a third, independent reviewer (K.K.R.).
The quality assessment was performed by applying the Newcastle-Ottawa Scale. In tailoring the scale to fit this study, we took into account the sampling methods of the studies and the similarities between the study groups on age and BMI, exposure and outcome ascertainment, and study design. Our abstracting instrument included a total of 8 questions with 11 points possible. While abstracting the data for the meta-analysis, C.N.S. and C.J.S. independently performed the quality assessment. Overall, the publications were classified as high quality (scoring ≥5 points) or low quality (scoring <5 points). Only studies scoring 5 or more points were included, ensuring only high-quality research articles were included in this meta-analysis.
Lipid measurements originally reported in millimolars were converted to milligrams per deciliter. When standard errors for the means were provided, they were converted to standard deviations. Because our meta-regression results suggest that variation in trimester of lipid measurement is a potential source of heterogeneity, studies were categorized by trimester on the basis of the mean gestational age reported at blood sampling. First, second, and third trimesters were defined as 1–13, 14–26, and 27 or more weeks, respectively. Blood collection times that overlapped 2 trimesters were classified as the latter of the 2 trimesters. Because of the low number of studies with lipid measurements in the first trimester, the first and second trimesters were combined for all analyses. If measured non-HDL-C was not available, non-HDL-C was calculated as total cholesterol minus HDL-C.
Lipid levels among women with preeclampsia and healthy pregnant controls were compared by calculating weighted mean differences (WMDs) and 95% confidence intervals, stratified by trimester of lipid measurement. Because significant heterogeneity was observed in all comparisons (P < 0.05), random-effects models were used to allow for the inherent heterogeneity found between studies. We also performed similar meta-analyses stratified by preeclampsia severity. Statistical heterogeneity was assessed using the Mantel-Haenszel Q statistic and the I statistic. An I value of more than 50% is considered moderate heterogeneity, and an I value greater than 75% is considered high heterogeneity. Random-effects meta-regression analyses were conducted to assess whether BMI, trimester of blood sampling, and fasting blood sampling status were acting as potential modifiers of the association between maternal lipid levels and preeclampsia, causing the observed high level of heterogeneity. Possible publication bias was evaluated using funnel plots and the Egger test. All statistical analyses were 2-sided and were performed using Stata, version 9.0, software (StataCorp LP, College Station, Texas).
Methods
Search Strategy
This study consisted of a systematic literature review followed by a meta-analysis, both conducted taking into account the Meta-analysis of Observational Studies in Epidemiology: a Proposal for Reporting Criteria and Preferred Reporting Items for Systematic Reviews and Meta-analyses group guidelines. A systematic literature search of eligible studies was conducted in the PubMed/MEDLINE and Scopus databases from the index date through July 2013 for studies evaluating the association between lipid levels during pregnancy and preeclampsia using the following search strategy: ("preeclampsia" OR "eclampsia" OR "toxemia" OR "pregnancy-induced hypertension" OR "gestational hypertension") AND ("cholesterol" OR "lipid" OR "HDL" OR "LDL" OR "triglycerides" OR "dyslipidemia" OR "hyperlipidemia" OR "hypertriglyceridemia"). The search was not restricted by language, and no limits or filters were placed on the search to ensure maximal sensitivity. References from these publications were also manually searched for potentially relevant citations not detected by the electronic search. A research librarian assisted in creating the most efficient and effective search strategy possible.
Study Selection
Records identified from the literature search were screened for duplicates. Titles and abstracts were screened, and potentially relevant articles were selected for full-text review. Studies were considered for inclusion in our meta-analysis if they met the following criteria: 1) an original study that examined the association between lipid levels during pregnancy and preeclampsia; 2) raw lipid levels presented as a group mean with either a standard error or standard deviation or as a median with the 95% confidence interval; and 3) a proper control group of normotensive pregnant women.
Data Abstraction
Full manuscripts were obtained for studies that appeared to examine lipid levels in women with preeclampsia. Full-text review was performed by 2 independent investigators (C.N.S. and C.J.S.) using a piloted data abstraction form and resulting in 91% concordance. Information collected included study characteristics (author, year of publication, study location, dates, and design); participant characteristics (definitions of the preeclampsia and control groups, diagnostic criteria, mean age, mean prepregnancy body mass index (BMI) (weight (kg)/height (m)), and mean gestational age at blood sampling); lipid measurements (mean or median, along with standard error (SE), standard deviation (SD), or 95% confidence interval (CI)); number of subjects in each group; and statistical significance for tests between the groups). Inconsistencies between the 2 reviewers were adjudicated by a third, independent reviewer (K.K.R.).
Quality Assessment
The quality assessment was performed by applying the Newcastle-Ottawa Scale. In tailoring the scale to fit this study, we took into account the sampling methods of the studies and the similarities between the study groups on age and BMI, exposure and outcome ascertainment, and study design. Our abstracting instrument included a total of 8 questions with 11 points possible. While abstracting the data for the meta-analysis, C.N.S. and C.J.S. independently performed the quality assessment. Overall, the publications were classified as high quality (scoring ≥5 points) or low quality (scoring <5 points). Only studies scoring 5 or more points were included, ensuring only high-quality research articles were included in this meta-analysis.
Data Synthesis and Analysis
Lipid measurements originally reported in millimolars were converted to milligrams per deciliter. When standard errors for the means were provided, they were converted to standard deviations. Because our meta-regression results suggest that variation in trimester of lipid measurement is a potential source of heterogeneity, studies were categorized by trimester on the basis of the mean gestational age reported at blood sampling. First, second, and third trimesters were defined as 1–13, 14–26, and 27 or more weeks, respectively. Blood collection times that overlapped 2 trimesters were classified as the latter of the 2 trimesters. Because of the low number of studies with lipid measurements in the first trimester, the first and second trimesters were combined for all analyses. If measured non-HDL-C was not available, non-HDL-C was calculated as total cholesterol minus HDL-C.
Lipid levels among women with preeclampsia and healthy pregnant controls were compared by calculating weighted mean differences (WMDs) and 95% confidence intervals, stratified by trimester of lipid measurement. Because significant heterogeneity was observed in all comparisons (P < 0.05), random-effects models were used to allow for the inherent heterogeneity found between studies. We also performed similar meta-analyses stratified by preeclampsia severity. Statistical heterogeneity was assessed using the Mantel-Haenszel Q statistic and the I statistic. An I value of more than 50% is considered moderate heterogeneity, and an I value greater than 75% is considered high heterogeneity. Random-effects meta-regression analyses were conducted to assess whether BMI, trimester of blood sampling, and fasting blood sampling status were acting as potential modifiers of the association between maternal lipid levels and preeclampsia, causing the observed high level of heterogeneity. Possible publication bias was evaluated using funnel plots and the Egger test. All statistical analyses were 2-sided and were performed using Stata, version 9.0, software (StataCorp LP, College Station, Texas).
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