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Lipid and Lipoprotein Concentrations in Pregnancies Complicated by Intrauterine Growth Restriction¹

Departments of Pathological Biochemistry (N.S., P.J.G., C.J.P., J.S.), and Obstetrics and Gynaecology (I.A.G., T.K., A.M.), Royal Infirmary University NHS Trust, Glasgow G4 OSF, United Kingdom

Address all correspondence and requests for reprints to: Dr. Naveed Sattar, Department of Pathological Biochemistry, Macewen Building, Royal Infirmary NHS Trust, Glasgow G4 0SF, United Kingdom. E-mail: nsattar{at}clinmed.gla.ac.uk

	Abstract

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Previous studies have shown that in preeclampsia, plasma lipids climb substantially above levels seen in normal pregnancies. Such lipid changes may play a role in the endothelial damage characteristic of preeclampsia. Pregnancies complicated by intrauterine growth restriction (IUGR), without preeclampsia, have similar placental pathology to preeclampsia despite the absence of the maternal systemic manifestations of hypertension and proteinuria. The aim of this study was to perform a cross-sectional study of lipid and lipoprotein concentrations in the third trimester, from normal pregnancies, and those complicated by IUGR without preeclampsia. Our hypothesis was that, in contrast to the exaggerated lipid changes seen in preeclampsia, lipid and lipoprotein concentrations in IUGR would be similar to those of matched healthy pregnant controls. Fasting blood samples for lipids and lipoprotein fractions were taken in the third trimester, from eight women with IUGR; and eight women with uncomplicated pregnancies, matched as a group for age, booking weight, parity, and gestational age at sampling. There were no significant differences (P > 0.05) in the median concentrations of triglyceride, high-density lipoprotein, and very-low-density lipoprotein 1 (VLDL₁), between cases and controls. However, women with IUGR pregnancies had significantly lower cholesterol [4.95 mmol/L (3.35–7.10) vs. 7.47 (5.75–8.45); median (range) for IUGR patients and controls, respectively; P < 0.01], low-density lipoprotein (LDL)-cholesterol [2.45 mmol/L (0.95–3.60) vs. 4.25 (3.35–5.60); P < 0.01], VLDL₂ mass [59.0 mg/dL (37–87) vs. 103.0 (64–168); P < 0.01], intermediate-density lipoprotein mass [56.0 mg/dL (31–110) vs. 125.6 (91–157); P < 0.01], and total LDL mass [221.0 mg/dL (104–237) vs. 380.3 (267–534); P < 0.01]. In addition, it was noteworthy that, with respect to LDL-cholesterol and total LDL mass, there was little or no overlap in the ranges of concentrations measured between cases and controls. Because VLDL₂ and intermediate-density lipoprotein are the synthetic precursors to LDL in the circulation, their significantly lower median concentrations imply a failure of appropriate LDL synthesis in IUGR pregnancies. Whatever the mechanism, if our results are confirmed in larger studies and longitudinal investigations, then LDL-cholesterol measurements (when LDL-cholesterol fails to rise appropriately or is low in the third trimester) may be of use in identifying mothers with, or at risk of, a pregnancy complicated by IUGR.

	Introduction

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PREVIOUS studies have shown that in preeclampsia, plasma lipids climb substantially above levels seen in normal pregnancies (1, 2, 3, 4, 5). It has been proposed that such lipid changes may play a role in the endothelial damage characteristic of preeclampsia (1, 2, 3, 4, 5, 6). Pregnancies complicated by intrauterine growth restriction (IUGR) without preeclampsia have placental pathology similar to that of preeclampsia despite the absence of the maternal systemic manifestations of hypertension and proteinuria (7). In both conditions, there is failure of trophoblast invasion of the maternal spiral arteries, vascular damage, and placental infarction.

Given the physiological role of gestational hyperlipidemia in supplying both cholesterol and triglyceride to the rapidly developing fetus (8), it is conceivable that pregnancies complicated by IUGR exhibit abnormal lipoprotein metabolism in an attempt to compensate for the placental insufficiency. Such a mechanism has been proposed to explain the higher triglyceride concentrations observed in women with preeclampsia (6). In IUGR, however, abnormal lipoprotein metabolism may be a factor underlying poor fetal growth. The aim of this study was to perform a cross-sectional study of lipid and lipoprotein concentrations in the third trimester, from normal pregnancies and those complicated by IUGR without preeclampsia. Our hypothesis was that, in contrast to the exaggerated lipid changes seen in preeclampsia, lipid and lipoprotein concentrations in IUGR would be similar to those of healthy pregnant controls.

	Subjects and Methods

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Eight women with IUGR and eight women matched as a group for age, booking weight, parity, and gestational age at sampling with uncomplicated pregnancies were studied. The patient characteristics are shown in Table 1. The study was approved by the Ethics Committee of Glasgow Royal Infirmary, and all women gave written informed consent.

All subjects were sampled after an overnight fast of at least 10 h. Twenty milliliters of blood was collected by venepuncture into K2EDTA (final concentration 1 mg/mL) tubes. Plasma was harvested at 4 C by low-speed centrifugation, and aliquots of plasma for lipid and lipoprotein measurements were used immediately.

Plasma total cholesterol, triglyceride, and high-density lipoprotein (HDL)-cholesterol measurements were performed by a modification of the standard Lipid Research Clinics Protocol (9) using enzymatic reagents for lipid determinations. Very-low-density lipoprotein 1 (VLDL₁ [Sf 60–400]), VLDL₂ (Sf 20–60), intermediate-density lipoprotein (IDL) (Sf 12–20), and low-density lipoprotein (LDL) (Sf 0–12) were prepared and quantified as a modification of the cumulative flotation gradient ultracentrifugation technique first described by Lindgren (10). The cholesterol, triglyceride, free cholesterol, phospholipid, and proteins of the lipoprotein fractions were assayed as described previously (11), and concentrations were calculated as the sum of the components (expressed as mg/dL plasma).

Statistical analysis

The data are presented as median and range, and (where appropriate) differences were tested for statistical significance using the Mann-Whitney U test (Minitab, State College, PA).

	Results

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Baseline characteristics

The two groups of patients were matched for age, parity, booking weights, and gestational age at sampling. Women with IUGR pregnancies gave birth to babies with significantly lower birth weights (P < 0.001) than those of controls and also had earlier delivery, by a median of around 4 weeks (P < 0.01).

Lipid and lipoprotein concentrations

Women with pregnancies that were complicated by IUGR had significantly lower median cholesterol (34% lower), LDL-cholesterol (42%), total VLDL₂ (43%), IDL (55%), and LDL (42%) concentrations, relative to control patients (P < 0.01) (Table 2). In contrast, there were no significant differences in the median concentrations of triglyceride, HDL, and VLDL₁ between cases and controls (Table 2).

When the composition of these particles was determined (data not shown), the following was found: the cholesteryl-ester to triglyceride ratio (the lipid composition of the hydrophobic core of the particle) was reduced in VLDL₂ [0.45 (0.34–0.64) vs. 0.58 (0.45–0.88), median (range), for IUGR patients and controls respectively, P = 0.04] but not in VLDL₁, IDL, or LDL (P > 0.05). In addition, LDL particles were significantly enriched (P < 0.05) in cholesteryl-ester and depleted in free cholesterol.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In this study, we set out to establish the pattern of lipid and lipoprotein concentrations in the third trimester in women with pregnancies complicated by IUGR. We hypothesized that (in contrast to the pattern of lipid changes seen in preeclampsia, and because the systemic manifestations of hypertension and proteinuria are absent in IUGR) lipid and lipoprotein concentration would not be elevated in women with IUGR without preeclampsia. Indeed, in confirmation of our hypothesis, we observed comparable median triglyceride, VLDL₁, and HDL concentrations in IUGR and controls. Unexpectedly, however, median cholesterol and LDL-cholesterol concentrations were significantly lower in IUGR cases (P < 0.01). In addition, median total VLDL₂, IDL, and LDL concentrations were also significantly lower in women with IUGR (P < 0.01). Importantly, with respect to LDL-cholesterol and total LDL mass, there was little or no overlap in the ranges of concentrations measured between cases and controls.

What are the potential mechanisms for lower cholesterol (LDL-cholesterol) concentrations in IUGR? Information on booking first-term lipid levels was not available; so, it is possible that women destined to develop IUGR have lower starting cholesterol values. Alternatively, there may be a failure of an appropriate rise in LDL concentrations in pregnancies complicated by IUGR. In normal pregnancy, total cholesterol concentrations increase by around 60%, between 10 and 35 weeks of gestation (12). This failure for LDL to rise could be the result of increased LDL catabolism and/or a reduction in synthesis. Because VLDL₂ and IDL are the synthetic precursors to LDL in the circulation (13), their significantly lower median concentrations imply that a failure of appropriate LDL synthesis is the more likely option. We may speculate that, to maintain energy supply (most efficiently delivered via triglycerides) to the growing fetus, triglyceride synthesis (in the form of VLDL₁) is maintained at the expense of cholesterol in the form of VLDL₂, IDL, and (in particular) LDL. To explore this possibility, further investigations are needed to examine potential alterations in liver pathways responsible for hepatic assembly and secretion of VLDL₁ and VLDL₂ particles. Current evidence would suggest that insulin and insulin resistance are important in regulating hepatic VLDL₁ synthesis (13), whereas estrogens impact upon hepatic synthesis of both VLDL₁ and VLDL₂ particles (14, 15). Whatever the mechanism, if our results are confirmed in larger, longitudinal investigations, then LDL-cholesterol measurements (when LDL-cholesterol fails to rise appropriately or is low in the third trimester) may be of use in identifying mothers with, or at risk of, a pregnancy complicated by IUGR.

In conclusion, the results of this study suggest that LDL levels, which normally increase by around 60% in uncomplicated pregnancies, fail to rise appropriately in pregnancies complicated by IUGR and, as a result, may play a role in the pathogenesis of growth retardation.

	Footnotes

 
¹ This work was supported by Research Grant G9500819 from the Medical Research Council/Chief Scientist Office/Scottish Office Home and Health Department (SOHHD) and Grant K/MRS/50/C2256 from the (SOHHD).

Received August 27, 1998.

Revised October 9, 1998.

Accepted October 13, 1998.

	References

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