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Fetal and Maternal Lipoprotein Metabolism in Human Pregnancy Complicated by Type I Diabetes Mellitus¹

Department of Fetal Medicine, Birmingham Womens Hospital, University of Birmingham (M.D.K), Birmingham B15 2TG; Department of Medicine, Manchester Royal Infirmary (M.I.M, P.N.D), Manchester, M13 9WL; and Department of Chemical Pathology, North Staffordshire Hospital (R.H.N), Stoke-on-Trent, ST4 6SD, United Kingdom

Address all correspondence and requests for reprints to: R. Neary, Consultant Clinical Biochemist, Clinical Pathology Block, North Staffordshire Hospitals, Keele University, Stoke-on-Trent, ST4 6SD, United Kingdom.

	Abstract

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Serum lipid, apolipoprotein concentration, and lipoprotein composition were determined in maternal and umbilical venous cord blood at delivery by elective Cesarean section (CS) in 10 singleton, full-term pregnancies with maternal insulin-dependent diabetes mellitus (type I DM), which predated pregnancy, and in 22 nondiabetic pregnancies. The objectives of the study were to determine the influence of maternal type I DM, and hence potential fetal overnutrition on fetal lipid metabolism. There were no significant differences in gestational age, fetal weight, or fetal serum insulin concentration between the type I DM group and those with nondiabetic pregnancies, although fetal venous cord blood glucose was 3.4 mmol/L (3.0–4.5 mmol/L) (median and 25th–75th percentiles) and 2.9 mmol/L (2.0–3.4 mmol/L), respectively, and maternal Hemoglobin A1c [9.6% (8.2–10.7%) and 6.8% (6.3–7.8%), respectively], was significantly greater in the type I DM subjects (P < 0.02 and 0.002 respectively). Plasma nonesterified fatty acid (NEFA) concentrations were lower in the type I DM mothers [0.85 mmol/L (0.56–2.31 mmol/L) compared with 1.14 mmol/L (0.88–1.24 mmol/L] in nondiabetic pregnancies; P < 0.0001). Serum high-density lipoprotein phospholipids (HDL-PL) were increased in type I DM mothers because of elevated HDL₂ phospholipid [0.39 mmol/L (0.27–0.48 mmol/L) compared with 0.12 mmol/L (0.06–0.21 mmol/L), respectively, P < 0.01). The maternal HDL cholesterol (C) concentration was not significantly different in the uncomplicated and type I DM pregnancies. However, in the umbilical venous cord blood, serum levels of NEFA [0.49 mmol/L (0.33–1.29 mmol/L) in type I DM compared with 0.13 mmol/L (0.06–0.33 mmol/L) in nondiabetics;P < 0.02)], total cholesterol (TC) [2.87 mmol/L (1.65–4.86 mmol/L) in type I DM compared with 1.65 mmol/L (1.46–1.87 mmol/L) in nondiabetics; P < 0.02], free cholesterol (FC) [0.97 mmol/L (0.60–1.26 mmol/L) in type I DM compared with 0.62 mmol/L (0.37–0.75 mmol/L) in nondiabetics; P < 0.05), and cholesteryl ester (CE) [1.90 mmol/L (1.44–3.33 mmol/L) in type I DM compared with 1.01 mmol/L (0.83–1.24 mmol/L) in nondiabetics; P < 0.02), triglyceride (TG) (1.06 [0.50–1.91) mmol/L in type I DM compared with 0.29 [0.25–0.36] mmol/l in nondiabetics; P < 0.001), phospholipid (PL) (2.52 [1.73–3.03) mmol/L in type I DM compared with 1.34 [1.27–1.48] mmol/L in nondiabetics; P < 0.01], and the apolipoproteins A-I and B had significantly higher concentrations in type I DM. In umbilical venous cord blood, ratios of HDL-TC and HDL-PL to apo AI, reflecting the lipid content of HDL, were reduced when the mother had type I DM during pregnancy (P < 0.02 and P < 0.0001, respectively).

These results indicate that maternal type I DM may lead to a fetal serum lipoprotein composition more closely resembling that seen in the adult. In type I DM, maternal TG and PL and fetal TC, TG, PL CE, and FC were correlated to NEFA levels (P < 0.05), but not to glucose, insulin secretion, or maternal control of type I DM. These data suggest that the enhanced supply of NEFA to the fetus in type I DM pregnancies may drive the synthesis of cholesterol as well as TGs and PLs.

	Introduction

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THE relationship between abnormal levels or composition of blood lipoproteins and cardiovascular disease in adults is well established in both epidemiological and prospective studies. Although high levels of circulating low-density lipoprotein (LDL) increase cardiovascular risk, a raised level of high-density lipoprotein (HDL) confers protection (1). Raised cholesterol in young adults has recently been linked with coronary heart disease in later life (2) and, as shown in the Bogalusa Heart Study, levels of HDL and LDL tend to track from childhood to adult life (3). Recently, it has been suggested that the antecedents of this relationship may extend back into intrauterine life, because raised levels of LDL cholesterol in adults are inversely associated to abdominal girth at birth (4). Thus, those with at-risk lipoprotein profiles early in life may well be predisposed to later coronary heart disease. Although recent interest has focused on the relationship between fetal undernutrition (5) and cardiovascular disease caused by an increase in risk factors for the adult, cardiovascular mortality appears related to birth weight (6, 7).

During the course of normal pregnancy, plasma triglyceride (TG) and cholesterol concentrations rise by at least 200% and 25%, respectively (8, 9, 10). Few data exist for the corresponding fetal lipoprotein concentrations and composition. We recently reported our comprehensive findings of fetal venous cord blood lipoprotein composition in uncomplicated pregnancies and demonstrated a markedly less atherogenic lipid profile in fetal blood compared with the adult (11). The fetal lipid profile was not only characterized by substantially lower lipid levels as shown by others (12, 13), but also by lipid-enrichment of HDLs and lipid-depletion of atherogenic very low density lipoproteins (VLDL) and LDL. These changes were explained by a reduction in cholesterol esterification on HDL and its subsequent transfer to VLDL and LDL by cholesteryl ester transfer protein (CETP). This may explain why fetal lipoprotein composition is analogous to animal species without CETP that are resistant to developing atherosclerosis (14).

The lipoprotein profiles of nonpregnant subjects with type I diabetes mellitus (type I DM) vary, probably dependent on control (15, 16). However in pregnancy, with chronic exogenous insulin administration achieving moderately good glycemic control, lipoprotein patterns comprise an increased serum HDL cholesterol and low TG and total cholesterol (TC) concentrations in one study (17). However, others have not demonstrated such changes, and although total TGs, VLDL/LDL, HDL cholesterol increased with gestation in those with insulin-dependent diabetes, there was no significant difference from gestationally matched controls (18, 19). It is of note that the study groups were a heterogenous ethnic mix and White’s classification severity, which may alter lipoprotein metabolism (20). The effect of maternal type I DM may be to provide the fetus with abundant substrates for energy provision and an altered metabolic environment. However, the consequences reported of type I DM for fetal lipid metabolism have varied with increased LDL cholesterol, serum cholesterol, and reduced HDL cholesterol in venous cord blood (21, 22, 23). Again, such studies have examined a heterogenous ethnic group and venous cord bloods of babies born by varied routes of delivery, all of which may alter lipoprotein concentrations. The aim of this study was to investigate the effect of preexistent type I DM, apparently well controlled in pregnancy, on lipoproteins in the fetoplacental circulation of babies born by elective Cesarean section.

	Materials and Methods

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Subjects

Ten caucasian women with a diagnosis of type I DM (established before pregnancy) were studied together with 22 healthy, caucasian pregnant subjects. Pregnant women who smoked or were taking drugs known to affect lipid metabolism (other than insulin) were excluded. No subjects were hypertensive, had macroalbuminuria, or other pregnancy-related complication. All subjects were delivered by elective Cesarean section (under epidural anesthesia) for indications unconnected with any complication of the current pregnancy (i.e. previous Cesarean delivery, breech presentation). All fetuses were appropriately grown, with birth weights between the 5th-95th centile for gestational age (Table 1). All subjects with type I DM were seen before their pregnancies. Preconceptually, seven initially presented with ketoacidosis, two with polydipsia and weight loss, and one had been identified by routine screening (i.e. glucosuria). The median duration since diagnosis of type I DM was 10 yr (range 4–21 yr), and the median preconceptual insulin dose was 24 IU/day (range 15–32 IU/day). The nondiabetic pregnancy group had no glucosuria detected in pregnancy or any past medical history consistent with glucose intolerance during pregnancy. None of the fetuses was macrosomic (>4500 g).

All mothers gave informed consent and ethical approval was granted by the South Birmingham District Ethical Committee, U.K.

Collection of blood samples

All Cesarean sections were elective and performed between 0830–1100 h. The mothers had fasted from approximately 2300 h the previous evening. All mothers had 30 mL of blood collected from the antecubital fossa without venous stasis just before anesthesia. Maternal blood glucose during delivery was maintained by iv dextrose (500 mL of 5% over 4 h) infusion together with insulin given to maintain the blood glucose between 3–6 mmol/L. At delivery a blood sample (20 mL) was obtained from the umbilical vein before placental separation.

Methods

Preparation of blood, lipid, and lipoprotein assays. The samples were taken into plain and EDTA-containing tubes on ice. Following centrifugation, serum and plasma were separated and stored frozen, although an aliquot of serum was removed before freezing for precipitation of the apolipoprotein B (apo B)-containing lipoproteins. The resulting supernatants containing HDL and HDL₃ were subsequently frozen and stored at -20 C before lipid analyses.

Laboratory methods. Insulin concentrations were measured by RIA (Coat-a-Count, Diagnostic Products Corp., Los Angeles, CA). Hemoglobin A1c (HbA1c) was assayed by ion-exchange chromatography with a previously normal range determined in pregnancy described as 4.5–7.2% (Glycomat, Ciba-Corning Diagnostics Ltd., Halstaad, U.K.). Serum levels of TGs, phospholipids (PL), TC, and FC were measured by enzymatic methods (Boehringer Mannheim, Lewes, Sussex, U.K.) on an automated discrete random access analyzer (Axon, Bayer Diagnostics, New York, NY). The cholesteryl ester (CE) was estimated by the difference between TC and FC. Supernatants containing total HDL or the HDL₃ subfraction were obtained by precipitation of the other lipoproteins with buffered polyethylene glycol (Quantolip, Immuno Ag, Vienna, Austria). The lipid determinations were made on the supernatants and increased assay sensitivity was achieved by a 3-fold increase in sample volume and the addition of tribromo-hydroxybenzoic acid in a concentration of 0.5 g/L in the assay reagent (24). This method has undergone extensive evaluation in our laboratory. Nonesterified fatty acids were measured by a manual enzymatic method (Randox Laboratories Ltd., Co Antrim, Northern Ireland, U.K.). Apolipoproteins AI (apo AI) and B (apo B) were measured by rate immunonephelometry (Beckman Instruments, Brea, CA).

Data analysis

Statistical analysis was performed using the NCSS package (J. Hintzee, Kaysville, UT). Because the sample size was relatively small and Gaussian distribution could not be assumed, results are expressed as median and 25th–75th percentiles with nonparametric tests used for comparison. Continuous variables were compared between groups using the Mann-Whitney U test and categorical variables with the Fischer-Exact test. Correlations were performed using Spearman’s rank coefficient of correlation.

	Results

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Baseline characteristics of mothers and fetuses with type I DM and nondiabetic pregnancies

At delivery there was no significant difference in gestational age or fetal weight between the two groups (Table 1). Furthermore, there were no differences in maternal age, parity, or body mass index. HbA1c was significantly higher in the mothers with type I DM (P < 0.0025), although glycemic control was strictly monitored throughout pregnancy by regular blood glucose monitoring, and control perceived as optimal. Fetal glucose levels in umbilical venous cord blood were significantly greater in type I DM pregnancies (P < 0.02). Fetal serum insulin [13.2 pmol/L (11.5–17.5 pmol/L); median and (25th–75th percentiles)] in type I DM pregnancies did not, however, differ significantly from that of nondiabetic pregnancies [11.5 pmol/L (10.2–12.2 pmol/L)].

Maternal lipoprotein profile in type I DM and nondiabetic pregnancies

At delivery serum levels of nonesterified fatty acid (NEFA) were significantly lower in the type I DM mothers [0.85 pmol/L (0.56–2.31 pmol/L)] compared with nondiabetic mothers [1.14 pmol/L (0.88–1.24 pmol/L); P < 0.0001] (Table 2). There were no differences in the serum levels of FC, TG, CE, PL, or apo AI. However, the lower level of apo B in the type I DM mothers approached statistical significance [1.45 g/L (1.01–1.86 g/L)] compared with nondiabetic mothers [1.87 g/L (1.52–2.17 g/L; P = 0.052]. In maternal HDL (Table 3), the concentration of PL was higher in type I DM mothers because of an increase in the HDL₂ PL subfraction [0.71 pmol/L (0.54–0.94 pmol/L)] compared with nondiabetic mothers [0.24 pmol/L (0.12–0.27 pmol/L); P < 0.0001]. Although a similar trend was seen in the cholesterol component of HDL₂, this was not significant. No differences were seen in the HDL₃ subfraction (Table 3).

In the venous cord blood serum of pregnancies complicated by type I DM, a significantly increased concentration of NEFA was noted [0.49 pmol/L (0.33–1.29 pmol/L)] compared with nondiabetic pregnancies [0.13 pmol/L (0.06–0.33 pmol/L); P < 0.02]. There were markedly higher levels of serum TC, FC, CE, PL, and apo B and AI in the venous cord blood of type I DM pregnancies (Table 4). There was, however, no statistically significant difference in the concentration of LDL cholesterol. Among HDL, differences between the groups were seen only in the HDL₂ subfraction in which increased concentrations of TC and PL were observed (P < 0.05 and P < 0.01, respectively) (Table 5). The fetal HDL-TC/apo AI and HDL-PL/apo AI were significantly greater than the corresponding ratio in maternal plasma (Table 6).

The umbilical venous cord blood serum concentrations of TC, FC, CE, PL, TG, and apo B and AI were all significantly lower than in the mother (Tables 2 and 4). In the nondiabetic group, the maternofetal differences were generally greater than in the type I DM group caused by the higher fetal lipid levels in the latter. In venous cord blood, HDL lipids more closely approached those of the mothers than total serum lipid levels as we have previously reported in nondiabetic pregnancy (Tables 2 and 4). In HDL₂, the fetal TC and PL concentration was approximately 2-fold greater than the mothers in both type I DM and control groups (Table 3 and 5).

Factors influencing lipid concentration in type I DM and nondiabetic pregnancies

Correlations were sought between blood lipid concentrations and levels of cord glucose, maternal HbA1c, fetal insulin, and maternal NEFA concentrations because these were factors that might influence lipoprotein metabolism. In the mothers with type I DM, the only significant correlations that were found were between NEFA and TG (r_s = 0.879; P < 0.05), NEFA and PL (r_s = 0.903; P < 0.05). In the fetal circulation however, TC (r_s = 0.86; P < 0.05), TG (r_s = 0.86; P < 0.05), PL (r_s = 0.98; P < 0.01), CE (r_s = 0.80; P < 0.05), FC (r_s = 0.88; P < 0.05) and apo A-I (r_s = 0.90; P < 0.05) were all significantly correlated with the serum concentrations of NEFA in type I DM. No statistically significant correlation was noted between venous cord lipoprotein parameters, insulin, or glucose in uncomplicated pregnancies. No correlation was noted between venous cord lipoprotein parameters and birth weight in either group. In particular, venous cord NEFA concentrations were not associated to birth weight in either group studied (type I DM r_s = -0.23, P = 0.4 and in uncomplicated pregnancies r_s = -0.09, P = 0.6).

	Discussion

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This study demonstrates marked differences in the concentrations and composition of fetal and maternal lipoproteins in pregnancies complicated by type I DM. Other data have previously indicated a significant increase in LDL cholesterol and decrease in HDL cholesterol in type I DM cord blood sera (23). Our own results demonstrate a similar trend of these two variables but statistical significance was not apparent, however in contrast, significant hypertriglyceridemia was noted in venous cord sera of type I DM. One explanation of the differences between these studies may be that Fordyce and colleagues (23) did not stratify their data depending on mode of delivery. All pregnant women in our data set were delivered in the morning, by elective Cesarean section (under spinal anesthesia) after at least an 8-h fast. In animal studies, analysis by proton magnetic resonance spectroscopy has noted differences in the metabolic profiles of both maternal and fetal plasma in pregnant rats whose pregnancies were complicated by diabetes (25). The differences were attributed to high concentrations of glucose, ketone bodies, and valine in the plasma of diabetic pregnant rats. Previous evidence has thus indicated that maternal diabetes may affect the metabolic components of the plasma in the fetal circulation. In this present study, maternal type I DM has been noted to exert a profound effect on some aspects of lipoprotein concentration and composition in fetal blood. In the type I DM pregnancies, venous cord blood levels of most lipid constituents including TC, FC, CE, PL, and TG were increased 2-fold compared with levels in the fetuses of nondiabetic mothers, with a more marked, 4-fold increase in NEFA. Fetal apo A-I and B were increased 2-fold in the type I DM pregnancies. These provide a marker of lipoprotein particle number and suggest a doubling in the number of both apo A-I-containing HDL particles and apo B-containing VLDL and LDL particles.

The median maternal TC and HDL cholesterol and FC of type I DM pregnancies were all lower than those of nondiabetic pregnancies, as previously reported (17, 18, 19), but in our study did not reach statistical significance. These differences in lipoprotein levels between type I DM and healthy mothers are qualitatively similar to those observed in the nonpregnant state (11, 17) and are thus likely to be explained by the effect of exogenous insulin and type I DM per se. The observed reduction of maternal NEFA in type I DM could be explained by the relatively high concentration of insulin in the peripheral circulation of type I DM individuals potentially suppressing lipolysis in adipose tissue and thus inhibiting NEFA release (26). Insulin also induces the activity of lipoprotein lipase, which increases production of HDL precursor particles released during breakdown of TG-rich lipoproteins, perhaps explaining the high concentration (26, 27).

The increased concentration of NEFA in fetal blood of the type I DM pregnancies is probably caused by increased delivery from the maternal circulation, because an increased maternofetal gradient has been reported in diabetes (28). An abundant supply of NEFA to the fetus may be an important factor stimulating synthesis of other lipid moieties, and in this study the NEFA concentration in the fetoplacental circulation of type I DM correlated significantly with other lipids and apolipoproteins. NEFA delivery to the liver is an important factor governing TG and VLDL synthesis in adults (26). In vivo evidence using radiolabeled moieties has demonstrated an increase in production of VLDL TG and VLDL-apo B of nearly 4- and 2-fold, respectively, when the ambient NEFA concentration was doubled (29). Fetal hyperinsulinemia was not apparent in our type I DM fetuses, possibly secondary to relatively good maternal glycemic control. Had it been present, excess insulin would be expected to inhibit lipolysis in fetal adipose tissue and inhibit secretion of hepatic VLDL (26, 27). Despite maternal NEFA concentrations being lower in type I DM, at a cellular level this may have been caused by an increase in NEFA flux into cells in these subjects. Our data were compatible with the view that the influence exerted by high concentrations of NEFA was dominant in increasing fetal lipid production.

In adults, following esterification of FC on HDL, CE either remains with HDL or is transferred to VLDL in exchange for TG. Our previous report shows a reduction in this process in the mother during pregnancy with an even greater reduction in the fetus compared with healthy adults (11). This results in changes in lipoprotein composition that are particularly marked in the fetus. In some respects, fetal lipoproteins resemble those of animal species deficient in CETP activity, because in the fetal circulation, HDL composition is modified by enrichment in lipid compared with protein probably caused by diminished CETP (11, 14). In the present study, the enrichment of fetal HDL in nondiabetic pregnancies with FC was substantially greater than the fetuses from type I DM pregnancies. Thus, the fetal HDL in type I DM had a composition more closely resembling maternal HDL, possibly secondary to increased CETP activity, than in the fetus of a nondiabetic pregnancy and merits further investigation. Longitudinal studies in newborns show a fairly rapid progression to an adult lipid profile. Before birth, the switch from a fetal-type lipoprotein composition to an adult-type with relatively lipid-depleted HDL and higher levels of apo B-containing lipoproteins may occur by the end of the neonatal period (30), in part caused by feeding (31). Our present findings suggest that the influence of maternal type I DM probably mediated through increased fetal circulating NEFA appears to expedite this change, although one cannot exclude the possibility that such changes may be secondary in nature. The effect of maternal type I DM on fetal lipoprotein profile in the long term remains to be established.

	Acknowledgments

 
We express our thanks to the patients and staff of the Birmingham Women’s Healthcare National Health Service Trust for their cooperation with sample collection. The authors would like to thank Dr. Lorna Meer for her contribution in sample collection.

	Footnotes

 
¹ This work was supported by a grant for the Tommy’s Campaign (Grant No. 19/97).

Received August 19, 1997.

Revised December 5, 1997.

Accepted January 16, 1998.

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