ABSTRACT
Objective
Maternal lipid levels increase in normal pregnancies. Here, we examine whether pregnancies with the highest total cholesterol, low‐density lipoprotein (LDL) or triglyceride levels or the lowest high‐density lipoprotein (HDL) levels predict future dyslipidemia post‐pregnancy.
Design
Longitudinal cohort study.
Setting
Five communities in Michigan, USA.
Sample
Pregnant women (n = 649) with blood lipid levels measured at mid‐pregnancy in the Pregnancy Outcomes and Community Health (POUCH) Study and at the POUCHmoms Study follow‐up, 7–15 years later.
Methods
Maternal mid‐pregnancy lipid levels were defined as ‘high’ (upper quartile of triglycerides ≥ 216 mg/dL, LDL ≥ 145 mg/dL and total cholesterol ≥ 256 mg/dL) or ‘low’ (lower quartile, HDL < 58 mg/dL) using whole sample lipid distributions. At follow‐up, dyslipidemia was classified by the clinical cutoffs of triglycerides and total cholesterol ≥ 200 mg/dL, LDL ≥ 130 mg/dL and HDL < 50 mg/dL. Weighted regression models estimated the risk of dyslipidemia at follow‐up in relation to pregnancy lipid levels, adjusted for baseline confounders.
Main Outcome Measure
Dyslipidemia later in life.
Results
Mid‐pregnancy triglycerides, LDL, and total cholesterol levels at the upper quartile were associated with at least threefold increase in the risk of abnormal triglycerides, LDL and total cholesterol levels later in life. Women with low mid‐pregnancy HDL levels had just over a twofold increased risk of abnormally low HDL levels at follow‐up. These associations persisted following adjustment for covariates, i.e. demographics, lifestyle, and years of follow‐up.
Conclusions
Higher mid‐pregnancy LDL, total cholesterol and triglycerides and lower levels of HDL may signal future dyslipidemia risk and the need for closer lipid monitoring to ensure timely interventions that can attenuate cardiovascular disease risk.
Keywords: high‐density lipoprotein cholesterol, lipids, low‐density lipoprotein cholesterol, pregnancy, total cholesterol, triglycerides
1. Introduction
Dyslipidemia is defined as elevated levels of total cholesterol, low‐density lipoprotein (LDL) cholesterol and triglycerides, or low levels of high‐density lipoprotein (HDL) cholesterol, and is prevalent among a fifth of women worldwide [1]. As a leading cause of atherosclerotic cardiovascular disease (ASCVD), dyslipidemia contributes to morbidity and mortality among women and men [2, 3, 4].
In normal pregnancies, lipid concentrations increase with gestational age [5]. Relative to pre‐pregnancy, total cholesterol and triglyceride concentrations could increase up to fourfold by the third trimester but typically decrease to pre‐pregnancy levels in the first month after delivery [5, 6]. Similarly, levels of both HDL and LDL cholesterol also rise along the pregnancy, though HDL peaks in mid‐pregnancy and then decreases during the third trimester [7, 8]. High lipid levels in pregnancy have been linked to maternal hypertension, preeclampsia and gestational diabetes [7, 9, 10]. Dyslipidemia also has been recognised as a strong determinant of cardiovascular disease (CVD) in non‐pregnant populations. However, an association between maternal lipid concentrations in pregnancy and later dyslipidemia—although plausible—has received minimal attention.
If detected early, dyslipidemia can be managed through lifestyle changes and medication when indicated, thereby lowering the risk of later ASCVD [11]. Moreover, maternal health pre‐conception or in early gestation may influence the development of metabolic disorders later in pregnancy, including gestational diabetes mellitus (GDM) [10, 12]. Therefore, pregnancy has become an important window for early detection of later‐life hypertension and CVD risk [13, 14] and also may serve as an opportunity to uncover future dyslipidemia risk. Few studies have examined lipid trajectories from pregnancy onward. One study noted that women with gestational triglycerides and cholesterol levels at the highest quartile and HDL cholesterol levels at the lowest quartile had an increased risk for metabolic syndrome 6 years after their pregnancy [15].
Here, we use data from 649 women of the Pregnancy Outcomes and Community Health (POUCH) Study who had blood lipids measured in mid‐pregnancy and again 7–15 years later during the POUCHmoms Study. The aim was to investigate whether those with the highest LDL, total cholesterol and triglyceride levels or lowest HDL levels at mid‐pregnancy would be more likely to meet clinical cutoffs for dyslipidemia years later.
2. Methods
2.1. Study Design and Analytic Sample
These longitudinal data are obtained from the Pregnancy Outcomes and Community Health (POUCH) cohort study, which enrolled and followed to delivery 3019 prenatal patients from 52 clinics in Michigan (1998–2004) [16] A subset of women from the POUCH study was enrolled 7–15 years later in the POUCHmoms study [13]. The POUCH studytudy focused on adverse pregnancy outcomes, while the follow‐up POUCHmoms study sought to identify potential links between adverse pregnancy outcomes and later‐life maternal health, particularly cardiovascular health. Institutional review boards at University of Pittsburgh, Michigan State University, the Michigan Department of Community Health, and nine community hospitals, which collectively covered all study clinics, approved the studies.
Inclusion criteria for the original POUCH studytudy were singleton pregnancy in the 16th to 27th week of gestation, no pre‐pregnancy diabetes, maternal serum alpha‐fetoprotein (MSAFP) screening at 15–22 weeks of gestation, age greater than 15 years and English‐speaking. A subcohort of POUCH studytudy (N = 1371 women) was evaluated in greater detail and included all those who delivered preterm, or had elevated MSAFP, and a random sample (with oversampling of Blacks) of those who delivered at term. Women included in the subcohort had biomarkers measured in blood collected at 16–27 weeks' gestation (N = 1301) [16]. The POUCHmoms study enrolled 678 of the women included in the subcohort 7–15 years after the POUCH study pregnancy and again collected blood for biomarker assesment. The present analysis included 649 women with blood lipid measurements, both at mid‐pregnancy and at POUCHmoms follow‐up (Figure 1). Inverse probability weighting is used in all analyses to reflect the POUCH study and subcohort sampling scheme.
FIGURE 1.
Flowchart of the POUCHmoms study.
At the POUCH study enrollment, the protocol included signing of consent forms, self‐administered surveys, in‐person interviews and a non‐fasting venous blood draw. Following delivery, prenatal and labor and delivery records were abstracted. At the follow‐up POUCHmoms study, again consent forms were signed, fasting blood samples were collected and surveys and interviews were completed. Specially trained study staff measured blood pressure and conducted carotid artery ultrasound among all women.
2.2. Lipid Measures
Non‐fasting blood samples drawn at mid‐pregnancy were aliquoted, stored at −80°C and later sent on dry ice to the Nutrition Lab in the Department of Epidemiology at the University of Pittsburgh for lipid analyses. This laboratory was Clinical Laboratory Improvement Act (CLIA)‐certified and participated in College of American Pathologists proficiency programs. Total cholesterol (total cholesterol mg/dL) was determined using the enzymatic method of Allain et al. [17]. High‐density lipoprotein (HDL mg/dL) levels were measured directly with a homogeneous two‐reagent method using materials obtained from Equal Diagnostics. Low‐density lipoprotein levels (LDLc mg/dL) were calculated indirectly using the Friedewald equation: LDLc = total cholesterol—HDLc 0.2 × (triglycerides), except when total triglycerides exceeded 400 mg/dL, in which case LDLc was measured directly using an automated spectrophotometric assay (LDL Direct Liquid Select) from Equal Diagnostics [17]. Triglyceride levels (mmol/L) were determined enzymatically by the Bucolo et al. procedure [17]. Duplicate samples with standards, control sera and serum calibrators were used in each run. The coefficients of variation ranged from 1.3% to 6.7%. At follow‐up in the POUCHmoms study, a fasting blood sample was obtained, aliquoted, stored at −80°C and sent to the same University of Pittsburgh laboratory for analysis using the methods described above.
In the absence of clinical thresholds for gestational dyslipidemia, we used the top quartile to define ‘high’ total cholesterol (≥ 256 mg/dL), LDL (≥ 145 mg/dL) or triglycerides (≥ 216 mg/dL). The bottom quartile was considered as having ‘low’ HDL (< 58 mg/dL). At follow‐up, clinical cutoffs were used to classify all women as having dyslipidemia, i.e., total cholesterol > 200 mg/dL, LDL > 130 mg/dL, HDL < 50 mg/dL or triglycerides > 200 mg/dL [18].
2.3. Covariates
Covariates were selected a priori based on their relationships to lipid levels in the literature for pregnant and non‐pregnant populations and collected as part of pregnancy and follow‐up surveys/interviews and pregnancy medical record abstraction. Self‐reported race/ethnicity was dichotomized for this study as Non‐Hispanic Whites (58%) or other (37% Blacks, 1% Asians, 3% Hispanics and 1% Native Americans). While race and ethnicity are not considered biological constructs, they were included to account for variation in distinct lipid profiles and risk of cardiovascular morbidity. Race and ethnicity are important social constructs to demonstrate health disparities associated with social, environmental and behavioural determinants [19, 20]. We incorporated Medicaid Insurance enrollment in pregnancy as a proxy for socio‐economic status. Body mass index (BMI) (kg/m2) was calculated from self‐reported height and pre‐pregnancy weight and used as a continuous variable in analyses. Parity was recorded as a continuous variable and modelled here as nulliparity (yes, no). Gestational age was calculated using the last menstrual period, except when it disagreed by more than 2 weeks with estimates generated by an ultrasound before 25 weeks' gestation, in which case the latter estimate was used. In 6% of the cohort, only last menstrual period estimates were available. Covariates were modelled as follows: age at POUCH study (continuous), interval to follow‐up (continuous years), race/ethnicity (non‐Hispanic White vs. other), education attainment (≤ 12 years or > 12 years), ever insured by Medicaid (yes/no), ever smoked for more than 3 months (yes/no), pre‐pregnancy BMI (continuous and obese vs. non‐obese), nulliparity (yes, no) and maternal alcohol consumption during pregnancy (yes/no). Women who had missing demographic or lipids data or those who reported taking lipid‐lowering medications at follow‐up were excluded from analyses (n = 89); see Figure 1.
2.4. Statistical Analysis
We used univariate and bivariate descriptive statistics for survey data to examine variable distributions overall and within the categories of lipid levels in pregnancy and dyslipidemia at follow‐up. With Poisson regression models for survey data, we estimated crude and adjusted risk ratios (RRs) and 95% confidence intervals (CIs) for dyslipidemia at follow‐up. For each category of ‘high’ or ‘low’ lipid levels, the referent category at follow‐up included values below or above clinical cutoffs, while the referent category for gestational lipid levels included values not in ‘high’ or ‘low’ quartile (depending on the lipid risk quartile). Regression models were initially unadjusted and then adjusted for age, race/ethnicity, Medicaid status, smoking status and years of follow‐up. The consideration of both maternal age at baseline and years of follow‐up as confounders accounts for maternal age at follow‐up and the longitudinal study design.
An additional model was used to examine the influence of nulliparity and pre‐pregnancy BMI as potential confounders. Alcohol consumption in pregnancy was found to be a potential confounder in the model with LDL levels only. In addition, we classified women with obesity (BMI ≥ 30) versus those without obesity (BMI < 30) to examine whether lipid patterns from pregnancy to follow‐up would be observed in both groups.
All analyses were run with the survey procedures in SAS v9.4 (SAS Institute Inc., Cary, NC) to incorporate the original POUCH study sampling design and weighting. These weights accounted for the oversampling of women delivering preterm with elevated MSAFP and of Blacks. Each study participant was assigned a sampling weight that reflects group‐specific sampling fractions and their effects on calculated variances [21].
3. Results
At follow‐up, nearly 41% of the 649 women had low HDL levels; 30% and 23% had cholesterol and LDL levels above clinical cutoffs, respectively. Mean age was 26.6 years (range 15.4–47.3 years) at pregnancy and 37.9 years (range 25.7–58. years) at follow‐up (Table 1). The average pre‐pregnancy BMI was 27.2 kg/m2. Most women in the sample were non‐Hispanic White, had obtained high school or vocational education and were non‐smokers.
TABLE 1.
Sociodemographic, health and lifestyle characteristics from 649 women participants of the POUCH study by lipid levels at the follow‐up POUCHmoms study: Unweighted frequencies and weighted proportions.
| Sociodemographic and lifestyle characteristics | N (%) | Triglycerides ≥ 200 mg/dL n = 54 (8%) | HDL < 50 mg/dL n = 266 (41%) | LDL ≥ 130 mg/dL n = 147 (23%) | Total cholesterol ≥ 200 mg/dL n = 194 (30%) |
|---|---|---|---|---|---|
| Age, mean (SD) | 38 (12.4) | 39 (12.6) | 37 (11.6) | 39 (12.7) | 39 (12.1) |
| Race/ethnicity | |||||
| Non‐Hispanic White | 377 (68) | 46 (88) | 152 (66) | 73 (60) | 113 (68) |
| Other a | 272 (32) | 8 (12) | 114 (34) | 74 (40) | 81 (32) |
| Education | |||||
| ≤ 12 years | 489 (43) | 47 (85) | 226 (83) | 110 (72) | 142 (71) |
| > 12 years | 160 (57) | 7 (15) | 40 (17) | 37 (28) | 52 (29) |
| Body mass index b , mean (SD) | 27.2 (16.5) | 31.3 (20.6) | 30.3 (18.5) | 28.8 (16.4) | 27.8 (14.9) |
| Medicaid Insurance | |||||
| Enrolled now or previously | 330 (46) | 29 (52) | 162 (60) | 76 (55) | 94 (50) |
| Never on Medicaid | 314 (54) | 25 (48) | 104 (40) | 70 (45) | 99 (50) |
| Ever smoker c | |||||
| Yes | 298 (45) | 34 (63) | 142 (52) | 64 (41) | 84 (43) |
| No | 351 (55) | 20 (37) | 124 (48) | 83 (59) | 110 (57) |
| Alcohol consumption | |||||
| Yes | 121 (20) | 9 (21) | 41 (16) | 31 (24) | 40 (23) |
| No | 520 (80) | 44 (79) | 220 (84) | 113 (76) | 152 (77) |
| Nulliparity | |||||
| Yes | 284 (44) | 16 (25) | 114 (40) | 62 (47) | 85 (45) |
| No | 365 (56) | 38 (75) | 152 (60) | 85 (53) | 109 (55) |
| Preterm delivery | |||||
| Yes | 159 (11) | 17 (11) | 66 (11) | 38 (14) | 54 (14) |
| No | 490 (89) | 37 (89) | 200 (89) | 109 (86) | 140 (86) |
African American, Hispanic, Asian, Native American or other.
Pre‐pregnancy body mass index.
Past or current regular smoker (3+ months).
Nearly 60% of women with ‘high’ total cholesterol at mid‐gestation (in the upper quartile of total cholesterol) had high levels at follow‐up. In contrast, only 20% of women who did not have ‘high’ mid‐pregnancy total cholesterol had high levels at follow‐up. Among the women with ‘low’ HDL levels in mid‐pregnancy, 80% had low HDL levels at follow‐up. By comparison, just under 30% of women without ‘low’ mid‐pregnancy HDL had low HDL levels at follow‐up (Figure 2).
FIGURE 2.
Proportion of women with abnormal lipid levels 7–15 years after pregnancy by gestational lipid levels; (A) Total cholesterol, (B) triglycerides, (C) LDL, and (D) HDL. The green‐framed rectangle represents women with normal levels of mid‐pregnancy lipids, while the red‐framed rectangle represents women with mid‐pregnancy lipid levels at the upper quartile. For example, among women who had normal cholesterol levels in mid‐pregnancy, 82% had normal levels of total cholesterol at follow‐up and only 18% had abnormal levels at follow‐up. (Panel A) However, among women at the upper quartile of total cholesterol in mid‐pregnancy, 44% had normal cholesterol levels at follow‐up and 56% had abnormal levels of total cholesterol at follow‐up.
Associations between gestational lipids levels and later‐life dyslipidemia are presented in Table 2.
TABLE 2.
Associations between lipid levels in mid‐pregnancy and dyslipidemia 7–15 years following pregnancy among 649 women from the POUCHmoms study; Mid‐pregnancy cutoffs were based on upper/lower quartile, and cutoffs of lipid levels at follow‐up were clinic‐based.
| Risk ratio (95% confidence interval) a | ||||
|---|---|---|---|---|
| Triglycerides ≥ 200 mg/dL n = 54 (8) | HDL < 50 mg/dL n = 266 (41) | LDL ≥ 130 mg/dL n = 147 (23) | Total cholesterol ≥ 200 mg/dL n = 194 (30) | |
|
Unadjusted |
5.40 (4.24, 6.87) | 2.68 (2.40, 3.00) | 3.13 (2.66, 3.67) | 3.05 (2.66, 3.49) |
|
Adjusted b |
4.36 (3.39, 5.60) | 2.54 (2.26, 2.87) | 3.00 (2.54, 3.54) | 2.91 (2.53, 3.35) |
| Adjusted c | 3.52 (2.74, 4.53) | 2.20 (1.95, 2.49) | 3.35 (2.83, 3.96) | 2.98 (2.59, 3.43) |
Note: Risk ratios were estimated using generalised linear models with a Poisson distribution and log link function.
Sample weights were included in all regression models.
Adjusted for age, race/ethnicity, Medicaid status, smoking status and number of years of follow‐up.
Additional adjustments for pre‐pregnancy body mass index and nulliparity; LDL was further adjusted for maternal alcohol consumption in pregnancy.
Adjusted models for LDL, HDL and total cholesterol included age, race/ethnicity, Medicaid status, smoking status (ever smoking), pre‐pregnancy BMI, nulliparity and years of follow‐up. In models with LDL, we further adjusted for alcohol consumption. Overall, women whose total cholesterol, LDL and triglycerides were at the highest quartile in mid‐pregnancy had substantially increased risk of dyslipidemia after 7–15 years of follow‐up. Mid‐pregnancy levels of triglycerides or total cholesterol at the upper quartile were associated with 3.5‐ and 3‐fold increased risk of triglyceride levels and total cholesterol levels above 200 mg/dL later in life, respectively. Similarly, risk of LDL levels above 130 mg/dL later in life was nearly 3.4‐fold greater among women with mid‐pregnancy LDL levels at the highest quartile. Women with mid‐pregnancy HDL levels below the lower quartile had 2.2‐fold greater risk of HDL levels below 50 mg/dL at follow‐up (Table 2). In stratified analysis by obese vs. non‐obese, the associations between mid‐pregnancy lipids and lipids at follow‐up persisted in both BMI groups.
4. Discussion
4.1. Main Findings
In a longitudinal cohort study of pregnant women who were followed at 7–15 years post index pregnancy, we demonstrated strong and robust associations between mid‐pregnancy levels of lipids and later‐life dyslipidemia. These findings highlight the potential for gestational lipid levels to identify a subgroup of individuals who could benefit from closer monitoring of lipid levels and treatment strategies during postpartum visits and later in life. The significant burden of dyslipidemia among young and midlife women warrants early treatment to attenuate the risk of cardiovascular disease [22].
4.2. Strengths and Limitations
The strengths of this study include the long time to follow‐up and the original multicommunity pregnancy cohort recruited from a large number of prenatal clinics, thereby enhancing its generalizability. All lipids, at pregnancy and follow‐up, were measured in the same research laboratory with expertise in blood lipid assessment. In addition, there is some suggestion that the timing of our lipid measures in pregnancy, i.e., mostly second trimester, is preferable over the first trimester for predicting lipid trajectories [23]. The study had some limitations as well. We were unable to follow‐up all eligible subcohort women from the original POUCH study. However, it seems unlikely that any selection bias of follow‐up would affect the estimates of lipid trajectories. Consistent with other large population‐based pregnancy cohorts, blood samples were collected in the non‐fasting state [24, 25, 26, 27, 28, 29]. These studies reported small differences between fasting and non‐fasting plasma lipids. Moreover, POUCH study clinicians advised against requiring pregnant women to fast given that many travelled significant distances to participate in the study. Finally, 39 (6%) women in our analytic sample had GDM in the POUCH pregnancy, and GDM was more common among women with pre‐pregnancy obesity (BMI ≥ 30 kg/m2). The strong relationship between pre‐pregnancy BMI and GDM precluded adding GDM as a covariate to avoid overadjustment in regression models.
4.3. Interpretation
Studies of associations between gestational lipid levels and later life dyslipidemia surprisingly are scant and mainly limited to pregnancy and the first year after delivery [15]. A prospective, large study with 3510 women examined relationships between lipid levels in pregnancy and those 6 years later [15]. The sample was mostly of European ancestry, nulliparous and had a normal BMI (mean BMI = 22.7 kg/m2). As expected, all lipids—triglycerides, total cholesterol, HDL and LDL cholesterol—were positively associated at the two time points. For example, both total cholesterol and LDL levels in pregnancy were associated with an increase of nearly 0.6 standard deviation score 6 years later. A similar trend was observed for triglycerides, with an increase of 0.5 standard deviation score at the 6‐year follow‐up. Further evidence from an Australian study of 141 women suggested associations between cardiometabolic risk factors, including lipids, assessed in early first pregnancy and increased prevalence of metabolic syndrome a decade later [30]. This study found that relative to women without cardiometabolic risk factors, those with at least one risk factor during pregnancy had over fivefold risk of metabolic syndrome and high levels of total cholesterol a decade later [30]. Additional evidence for strong associations between pregnancy lipids and later‐in‐life dyslipidemia was provided by a study with nearly 4700 women who were assessed for pregnancy lipids and glycemia levels and then followed up for 10–14 years post‐pregnancy [31]. This study found that total cholesterol, triglycerides, LDL and HDL assessed in pregnancy were associated with later‐in‐life dyslipidemia after adjustment for gestational diabetes. Consistent with prior reports, the findings of the present study indicate strong relationships between lipid levels in mid‐pregnancy and those 7–15 years later after accounting for demographics, BMI and smoking status. The magnitude of dyslipidemia risk later in life was 3.5‐fold greater for women with ‘high’ mid‐pregnancy levels of triglycerides, nearly threefold greater for those with ‘high’ mid‐pregnancy LDL and total cholesterol and over twofold greater for those with ‘low’ mid‐pregnancy HDL levels.
5. Conclusions
This study found that high maternal lipids (LDL, total cholesterol and triglycerides) and low levels of HDL in mid‐pregnancy are associated with increased risk of dyslipidemia 7–15 years after pregnancy, independent of demographics and other health characteristics. Our findings highlight the potential of gestational lipid levels to identify individuals who may have an increased risk of developing dyslipidemia after delivery and could benefit from closer lipid monitoring and intervention to attenuate cardiovascular disease risk.
Author Contributions
G.L.D. originated the idea for this specific project, and G.L.D. and C.H. designed this project with inputs from R.T. and J.M.C. C.H. and J.M.C. contributed to the design of the POUCH and POUCHmoms studies and the acquisition of data. All authors contributed to the development of the analytic plan and interpretation of results. G.L.D. analysed the data with assistance from X.L. All authors participated in co‐drafting of the article. All authors reviewed and revised the drafts and approved the final version of the manuscript.
Ethics Statement
The original POUCH study was approved by the institutional review boards at Michigan State University, the Michigan Department of Community Health and nine community hospitals, while the POUCHmoms study was approved by the institutional review boards at Michigan State University and the University of Pittsburgh.
Conflicts of Interest
The authors declare no conflicts of interest.
Acknowledgements
The authors thank all women who participated in this study.
Funding: The POUCH study was supported by the Perinatal Epidemiological Research Initiative Program Grant from the March of Dimes Foundation (20FY01‐38 and 20FY04‐37), the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Nursing Research (R01‐HD34543), the Thrasher Research Fund (02816–7) and the Centers for Disease Control and Prevention (U01‐DP000143‐01). The POUCHmoms study was supported by the National Heart, Lung, and Blood Institute (R01‐HL103825). Dr. Dunietz is supported by a Mentored Research Scientist Development Award from the National Heart, Lung, and Blood Institute (K01 HL144914).
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.