Currently, two in three women of reproductive age are overweight or obese (body mass index [BMI] 25 kg/m2 or greater)in the United States.1,2 Maternal prepregnancy obesity is associated with an increased risk of pregnancy complications and adverse pregnancy outcomes.3–10 In addition, maternal obesity may be associated with metabolic changes that “program” a set of physiologic responses in the fetus that predisposes offspring to metabolic and cardiovascular disease later in life.11,12 One important factor that may mediate these effects is lipid metabolism.
Pregnancy is a unique metabolic state that is characterized by progressive increases of circulating lipids to optimize the availability of substrates necessary for fetal growth and development.13–16 Pregnancy-related metabolic changes are generally associated with increased maternal fat deposition and adiposity.15,16 However, there is growing evidence that the pathogenic effects of obesity may be associated with metabolic dysregulation and disruption of the normal feedback systems that maintain metabolic homeostasis.17–19 It is reasonable to suspect that such metabolic dysregulation may have an effect on pregnancy-related physiologic changes and their sequelae in obese women.
Although several studies have documented lipid profiles over the course of pregnancy, few of these studies have investigated how maternal obesity may influence these levels. Moreover, many of these studies are cross-sectional and do not permit analysis of changes in levels across time.20–23 Studies that have used longitudinal methods are limited to relatively few data points, usually in mid to late gestation, small samples sizes, or both.24–26 Several large studies have documented temporal changes in lipid levels in women with gestational diabetes.24–26 While gestational diabetes is associated with altered lipid metabolism, the pathophysiological mechanisms are likely to be very different from women who are only obese.18 As a result, such findings may have limited generalizability in understanding the effects of maternal obesity in pregnancy.
This analysis sought to estimate longitudinal trends in maternal serum lipid levels during pregnancy in overweight and obese women, compared with their non-overweight counterparts. In doing so, this analysis is a first step toward defining how metabolic dysregulation associated with maternal overweight and obesity may influence human pregnancy.
MATERIALS AND METHODS
Data from the Gestational Regulators of Weight (GROW) study (N=142) were used for this analysis. The GROW Study is an ongoing prospective cohort study of factors related to maternal adiposity, placental vascular development, and fetal growth. Women recruited between March 2006 and January 2008 were enrolled early in pregnancy (6 weeks, 0 days to 9 weeks, 6 days gestation) and attended four follow-up antepartum visits at 10–14, 16–20, 22–26, and 32–36 weeks of gestation. We analyzed data obtained at each visit from a short interview, a blood draw, and a maternal anthropometric assessment. The Institutional Review Board of the University of Michigan Medical School approved this study protocol.
Our outcome of interest was serologic measures of maternal total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol at five time points during pregnancy. Serum total cholesterol was enzymatically determined using reagent for cholesterol (No. 3313018) from Roche Diagnostics Corporation (Indianapolis, IN).27 Serum triglycerides were measured using a colorimetric enzymatic assay from Roche Diagnostics (No. 3034658). Serum LDL cholesterol was measured using the LDL Direct Liquid Select system from Equal Diagnostics (No.7120; Equal Diagnostics, Exton, PA). High-density lipoprotein cholesterol was measured directly using the HDL Direct reagent (No. 3034569) from Roche Diagnostics Corporation.28 These assays were performed in the Chemistry Laboratory of the Michigan Diabetes Research and Training Center.
The primary exposure of interest, maternal prepregnancy overweight and obesity, was reported as an index of weight-for-height (body mass index; BMI) and defined as the weight in kilograms divided by the square of height in meters (kg/m2). Prepregnancy weight was ascertained by maternal self-report, and height was measured via a stadiometer at the baseline study visit (6–10 weeks gestation). The Institute of Medicine's classification for weight-for-height29 was used in classifying an exposure variable with two levels: normal weight (BMI 18.5–26.0 kg/m2), and overweight or obese (BMI greater than 26.0 kg/m2) for all analyses.
All statistical analyses were performed using the SAS for Windows Version 9.1.3 (Cary, NC). Descriptive analyses were conducted to ascertain demographic characteristics of the study population and to document variations in lipid levels across pregnancy by BMI. The χ2 test was used to assess statistical significance of categorical variables, while the Student t test was used for continuous variables. A P value of less than .05 was considered statistically significant.
As this analysis included repeated measures of our outcomes of interest, mixed linear models with special parametric structures on the covariance matricies were utilized. A detailed overview of mixed model methods can be found elsewhere.30,31 Briefly, repeated measures of total cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol levels for each individual woman will necessarily be interrelated. Such measurements tend to be more highly correlated if taken close in time rather than further apart. Unlike conventional linear regression, a mixed linear regression model allows the data to exhibit correlation and nonconstant variability by including both fixed effect and covariance parameters. In turn, it is possible to model the covariance structure of the repeated measurements so that the estimates and standard errors can be generated. Mixed linear modeling also accommodates missing data. Unlike other statistical techniques, the MIXED procedure in SAS uses all available data in the analysis instead of excluding subjects with missing data because it uses a likelihood-based estimation method.
For these analyses, each lipid level was analyzed using a model in which BMI group was a between-patients factor (BMI group varied between patients); time (gestational age at the visit when lipids were measured) was a within-patients factor (lipid measurements on the same subject were taken at different times); and an interaction term between BMI and time was included to estimate differences in the rate of change of the measurements over the course of gestation for both BMI groups. Thus for each model, it was possible to assess how 1) mean values of each lipid measure varied by BMI group, 2) how mean values of each lipid measure changed over time, and 3) how differences between mean values of each lipid measure by BMI group changed over time. The spatial power law time-series covariance structure was used in these models, as it allows for unequal spacing between repeated measures.30 The GPLOT procedure in SAS was used to generate Figures 1A through D from the mixed linear models.
Sociodemographic and reproductive health characteristics of the 142 GROW Study participants overall and stratified by BMI (58 normal weight, 84 overweight or obese) are presented in Table 1. Although our sample is very homogeneous with regard to measures of socioeconomic status and race, there is considerable variation in prepregnancy BMI. There were statistically significant differences in race, ethnicity, educational attainment, and household income when stratified by BMI.
Maternal serum lipid concentrations and their mean trajectories during pregnancy are presented in Figure 1 for normal weight and overweight or obese women. Maternal serum lipid levels of total cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol significantly increased with advancing gestation for both strata (P<.001). We were able to assess the trajectory of the lipid levels over the course of gestation for both BMI strata between 6 and 36 weeks of gestation. The total cholesterol levels increased by 46% and 60% in overweight or obese women and normal-weight women, respectively (Fig. 1Aa), while levels of LDL cholesterol increased by 50% in overweight or obese women and 77% in normal-weight women (Fig. 1B). High-density lipoprotein cholesterol levels increased by 18% and 19% in overweight or obese and normal-weight women, respectively (Fig. 1C), while triglycerides increased by 134% in overweight or obese women and 149% in normal-weight women over this time period (Fig. 1D).
Inspecting the trajectories of total cholesterol and LDL cholesterol in Figures 1A and 1B, respectively, reveals that the concentrations for overweight or obese and normal-weight women diverge in second trimester. The rate of change in the dependent variables (total cholesterol and LDL cholesterol) is lower for overweight or obese women as compared with normal-weight women in the latter part of pregnancy. Accordingly, the BMI by gestational age interaction was statistically significant for total cholesterol (P=.01) and LDL cholesterol (P<.001) in our model. These differences result in significantly lower total cholesterol and LDL cholesterol levels for overweight or obese women than those of their normal-weight counterparts in the third trimester. For example, average total cholesterol levels were 13.3 mg/dL lower for overweight or obese women compared with normal-weight women at 32–36 weeks of gestation, while average LDL cholesterol levels were 17.7 mg/dL lower for overweight or obese women compared with normal-weight women at 32–36 weeks of gestation. The trajectories of HDL cholesterol and triglycerides (Figs. 1C and 1D) did not differ for the BMI groups, that is, the BMI by time interaction was not statistically significant (P>.1) for either HDL cholesterol or triglycerides. The results presented here did not change after accounting for maternal weight and gestational weight gain across pregnancy (data not shown).
We have documented differences in the trajectory of maternal serum lipid levels in overweight or obese compared with normal-weight gravid women. Consistent with smaller studies using limited analytic methods, we found levels of all lipids measured (total cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol) increased across gestation. However, in our cohort, the rate of change in total cholesterol and LDL cholesterol levels was significantly lower for overweight or obese women compared with their normal-weight counterparts in the latter half of pregnancy. As a result, third-trimester total cholesterol and LDL cholesterol levels were significantly lower in the overweight or obese stratum. We speculate that these differences may be related to metabolic dysregulation associated with maternal overweight and obesity that can influence the course of pregnancy and its effects on the fetus.
Growing evidence suggests that the regulation of metabolic pathways may be substantially different in overweight and obese individuals compared with their normal-weight counterparts.17–19 However, there are very few descriptions of how metabolic dysregulation associated with obesity may influence the physiologic changes of pregnancy. As one example, it has recently been shown that early pregnancy BMI modified the association between insulin homeostasis and gestational weight gain.32 Our findings are among the first to describe the dynamic course of lipid levels from the earliest stages of pregnancy and emphasize the substantial differences in the trajectories between these groups.
The prospective cohort design is a significant strength of the current study. Few studies have systematically explored the time-dependent changes in lipid levels during pregnancy using repeated serum lipid measurements from the same participant.24,25 In contrast, we were able to obtain multiple measures of maternal serum lipid concentrations on each participant starting in early first trimester and at multiple time points across pregnancy. Our analytic approach used linear mixed models that accounted for the longitudinal data structure. As a result, we were able to map a detailed trajectory of maternal serum lipid concentrations in a population-based cohort of pregnant women. Our study design and analytic plan specifically enabled us to discern effects of factors, such as maternal overweight or obesity, that could influence these trajectories.
Our study design inherently limits study participation to a group of women who present for early prenatal care and are able to attend multiple study visits. Women without prenatal care or with late, interrupted, or sporadic care are less likely to have been included. As a result, maternal sociodemographic covariates show limited variation. While our sample is homogeneous with regard to measures of socioeconomic status and race, there is considerable variation in prepregnancy BMI. By focusing on this population, many potential confounding factors are accounted for by our sampling, allowing us to focus primarily on the effects of maternal overweight or obesity.
Although we collected multiple measures of our covariates, our analysis was limited by our relatively modest sample size. Our sample size lacks the power for statistically meaningful multivariable models to investigate the interrelationships among covariates. The effects of psychosocial, nutritional, and other variables on the relationship between maternal prepregnancy BMI and lipid trajectory remain to be determined.
Our results suggest that the factors associated with LDL cholesterol metabolism during pregnancy may differ between overweight or obese and normal-weight women in the latter half of pregnancy. Low-density lipoprotein particles are heterogeneous with regard to their lipid composition and physical properties.33 Prior work suggests that the composition of LDL particles changes across gestation so that these particles become increasingly enriched in triglycerides as pregnancy progresses.34 This shift is thought to be a consequence of reduced hepatic triglyceride lipase activity with advancing gestation.34,35 Thus, in late pregnancy, there is a shift from larger, more buoyant subclasses of LDL containing cholesterol esters to smaller, denser LDL particles containing larger quantities of triglycerides. Accordingly, high LDL triglycerides are indicative of cholesterol esters–depleted LDL. In our work, the smaller late-pregnancy rise in LDL cholesterol levels in overweight or obese women may suggest a more pronounced shift to small, dense triglycerides containing particles. One possibility is that this difference may reflect reduced hepatic triglyceride lipase activity compared with normal-weight gravid women. Such differences may influence the provision of lipid substrates to the growing fetus36 and affect the offspring's risk of chronic disease later in life.
In nonpregnant adults, the elevation of plasma triglyceride concentrations and the accumulation of small, dense LDL is associated with the atherogenic lipoprotein phenotype.37 Thus, in the metabolic syndrome and diabetes, LDL-triglycerides increase while LDL cholesterol decreases.38 Increases in LDL-triglycerides are also associated with systemic markers of low-grade inflammation and vascular adhesion molecules.38 During pregnancy, it has been suggested that elevated triglycerides and the accumulation of small, dense LDL during pregnancy may increase the risk of endothelial damage in obese or overweight women39,40 despite concomitant increases in HDL concentration.34,35 If the smaller increase in LDL cholesterol during late pregnancy in overweight or obese women reflects a shift to small, dense triglycerides containing particles, we speculate that such changes may mediate the increased risk of preeclampsia found in obese or overweight women.34
Our analysis is a first step toward defining how metabolic dysregulation associated with maternal overweight and obesity may influence pregnancy. Such an understanding may have important implications for the design of interventions. If the consequences of maternal obesity result in lasting dysregulation of metabolic homeostasis, then efforts to change health behaviors and nutrition without correcting underlying metabolic defects may be less effective without other types of interventions. Future studies should focus on how the pathogenic effects of obesity may be associated with metabolic dysregulation and disruption of the normal feedback systems that maintain metabolic homeostasis during pregnancy.
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