Gestational Diabetes During and After Pregnancy

11. Lipids in Gestational Diabetes: Abnormalities and Significance

Robert H. Knopp, Elizabeth Chan¹  , Xiaodong Zhu, Pathmaja Paramsothy and Bartolome Bonet

(1)

Northwest Lipid Research Clinic, Division of Metabolism, Endocrinology and Nutrition, Division of Cardiology, University of Washington, Seattle, WA, USA

Elizabeth Chan

Email: gkuroishi@pcamailbox.com

Abstract

Dyslipidemia in gestational diabetes (GDM) consists of an ∼50 mg/dL increase in triglyceride, an ∼4 mg/dL decrease in high density lipoprotein (HDL), and generally lower low density lipoprotein (LDL) levels by ∼30mg/dL, more small dense LDL, and greater susceptibility of LDL to oxidation. Predictors of increased birth weight are the postprandial hyperglycemia of GDM and elevated triglyceride. Predictors of diminished birth weight are lower HDL, lower apo-A-I, higher apo A-II and increased oxidative stress, typified in pre-eclampsia. Birth weight in an individual GDM pregnancy is likely a function of these competing trends. A therapeutic approach to the management of GDM is needed for the hyperglycemia and hypertriglyceridemia, but also for the heightened oxidative stress which may be propagated by abnormalities of LDL and HDL function.

11.1 Introduction and Overview

Cholesterol and essential fatty acids are required for fetal development. In mammals, this requirement is met in the mother by an increase in all lipoprotein fractions under the influence of estrogen. Plasma triglycerides and low density lipoprotein (LDL) increase in proportion to gestational age, while high density lipoprotein (HDL) peaks in midgestation and then declines. As a generalization, gestational diabetes (GDM) exaggerates the triglyceride increase and decreases HDL, but without an increase in LDL cholesterol. The dyslipidemia of GDM affects fetal and maternal health in at least four ways: (1) triglyceride increases are associated with increased birth weight, (2) hyperlipidemia in pregnancy predicts elevated maternal lipids in later life, just as GDM predicts diabetes, (3) GDM is associated with increased susceptibility of LDL to oxidative stress, and (4) elevated triglycerides are associated with occurrence of preeclampsia. Clinical management focuses on excellent diabetes management, with consideration of a moderate allowable fat diet and omega-3 fatty acid supplements. Triglyceride elevations exceeding 1,000 mg/dL justify high dose fish oil or fibric acid treatment to prevent pancreatitis, the major therapeutic priority of lipid management in pregnancy. Further research is needed to determine the extent to which the dyslipidemia of GDM drives lipoprotein oxidation, inflammation, preeclampsia, divergent effects on birth weight, malformations, and transmission of acquired traits to the next generation, and to what extent altering lipid levels can modify these predispositions. Devising dietary and pharmacologic therapies for disorders linked to dyslipidemia in GDM are challenges for the future.

11.2 Lipid Metabolism in Normal Pregnancy

Hyperlipidemia in pregnancy is a physiological adaptation to the altered hormonal milieu of pregnancy. The progression of maternal lipid elevations is predominately regulated by estrogen, which stimulates the production of very low density lipoprotein (VLDL), inducing hypertriglyceridemia in proportion to the growth of the placenta (Fig. 11.1).1 Trig lyceride levels rise gradually to a maximum 2–4-fold (Fig. 11.2). Likewise, the levels of LDL cholesterol at term increase 25–50% above baseline.2, 3 Concomitantly, the activity of lipoprotein lipase (LPL) to remove triglyceride by maternal tissues is reduced, especially in the third trimester4 while placental LPL activity increases.5 The net effect is to favor lipid delivery, and especially chylomicron triglyceride fatty acid delivery, to the placenta. The importance of essential fatty acid supply to the fetus is underscored by the positive association of placental fatty acid transport protein (FATP) mRNA expression with maternal, placental, and umbilical cord blood phospholipid docosahexanoic acid (DHA).6 In addition, reduced fetal growth has been observed in mothers with an adverse fatty acid profile including increased trans-, arachidonic, and most n-6 fatty acids, and decreased n-3 fatty acids.7 In addition, the incidence of small for gustational age (SGA) was increased twofold among the 7% of mothers with the most adverse fatty acid profile.7

Fig. 11.1

Adaptations in lipid metabolism in pregnancy. Broader arrows indicate greater traffic; dashed arrow indicates diminished traffic. Modified from reference1 with kind permission of Springer Science+Business Media

Fig. 11.2

Plasma triglyceride and cholesterol in normal pregnancy: 10th median and 90th percentile values. Reproduced from Heart 92, 1529-1534, 2006 with permission from BMJ Publishing Group Ltd

HDL protects against oxidative8 and inflammatory stress9,10 as well as accomplishing reverse cholesterol transport.11 Very little study has gone into the effects on the placenta in normal pregnancy. What is known is that the buoyant subfraction of HDL, HDL₂, can both deliver cholesterol for progesterone synthesis12 and facilitate the removal of cholesterol from tissues, primarily by the ABC-A1 and ABC-G1 transporter proteins.13–15 Descriptively, HDL cholesterol reaches a peak at midgestation that is about 25 mg/dL higher than nonpregnant baseline (about 80 mg/dL) and then declines in the second half of gestation to about half of the midterm increase (about 65 mg/dL). It is speculated that the midterm HDL peak is estrogen driven while the partial decline in the second half of gestation is related to the contra-insulin hormones of gestation which peak in late gestation. Notably, apoproteins (apo) A-I and A-II levels do not fall like HDL cholesterol in the last half of gestation. Apo A-I may help to maintain the anti-oxidant, progesterone secretory, and reverse cholesterol transport functions of HDL, despite the fall in HDL cholesterol.9,10

11.3 Placental Lipid Transport in Normal Pregnancy

The metabolism of lipids by the placenta is illustrated in Fig. 11.3. Triglyceride is metabolized to free fatty acids (FFAs) and transported across the placenta with chylomicron triglyceride metabolized more rapidly than VLDL triglyceride. Cholesterol can enter the placenta from VLDL remnants, the classical LDL receptor, or select fractions of HDL, probably by the scavenger receptor, SR-B1.12 Cholesterol is most likely transferred to fetal HDL by ABC-A1 and G1 cholesterol transporters residing on the placental endothelium on the fetal surface of the placenta.15 Apo B is made by the placenta16 but its role in cholesterol transfer to the fetus has not been demonstrated.13 It appears that the supply of cholesterol to the placenta and fetus is conserved and redundant.

Fig. 11.3

Transplacental lipid transport. Modified from reference1 with kind permission of Springer Science+Business Media

Essential fatty acid transport to the fetus is among the most important lipid metabolic functions of the placenta. It was shown long ago that polyunsaturated fatty acids cross the subhuman primate placenta more rapidly and in proportion to chain length17 than do saturated fatty acids. This property is likely due to the greater fluidity of the polyunsaturates and would specifically favor transplacental transport of the omega-3 series and particularly docosahexanoic acid (DHA) (22:6), important for central nervous system development and in particular, vision.

Other proteins control placental fatty acid transport as in other tissues, including fatty acid binding protein18 and the fatty acid transport proteins FATP-1 and FATP-4. FATP-4 is especially correlated with DHA concentrations in cord blood phospholipids.6,19 Finally, placental LPL activity is threefold elevated at term compared to the first trimester, thereby augmenting placental provision of fatty acids from lipoproteins including essential fatty acids from chylomicrons during rapid fetal growth.5

11.4 Effects of Maternal Lipids and Lipoproteins on Birth Weight in Normal, Unselected Pregnancies

We examined the relationship of birth weight in healthy pregnancy to fuels and hormones, including fasting glucose, insulin, FFAs, progesterone, estradiol, estriol, and human placental lactogen (HPL). Only HPL was significantly associated (p<0.01) with birth weight ratio and birth length,20 possibly due to its contrainsulin effect or as a barometer of placental size. Birth weight variation explained by other categories of predictors (R²) was 14% for lipoprotein lipids, 8% for apoproteins, and 33% for maternal characteristics.20

VLDL triglyceride was a positive but not significant weight predictor (p = 0.14) in this healthy cohort of subjects20 (mean 36-week triglyceride was 209 mg/dL, 10th to 90th percentile confidence interval 146–341 mg/dL).2More surprising was the negative association of apo A-II with birth weight and length.20 Apo A-II is primarily associated with HDL_3; it associates with enhanced and pro-inflammatory HDL in transgenic models21 and accelerates apo A-I catabolism.22 Conversely, the positive association of apo A-I with birth weight and length underscores the positive effects of HDL in pregnancy, including cholesterol transport to the fetus, support of placental progesterone synthesis,12 anti-inflammatory and anti-oxidative effects in the maternal circulation and possibly in the placenta,8,9 and support of innate immunity.10

In a later study, the association of triglyceride to birth weight ratio was maximal at a triglyceride level of 200 mg/dL (∼80th percentile at 36 weeks) and a birth weight ratio of 1.08 (Fig. 11.4).23 Unexpectedly, higher triglyceride concentrations were associated with progressively lower birth weight ratios (Fig. 11.4). This hyperbolic trend was superimposable in normal and positive glucose screen, negative GTT pregnancies.23 This relationship suggests a toxic effect of major hypertriglyceridemia on fetal growth and development in late gestation, even in otherwise healthy pregnancies. Possible mechanisms include the toxicity of diabetic VLDL to vascular endothelium,24 the association of elevated triglyceride levels with preeclampsia25 and oxidative stress from obesity and the metabolic syndrome,26 for which triglyceride is a marker.

Fig. 11.4

Relationship of birthweight ratio to plasma triglycerides. Copyright 1992 American Diabetes Association from Diabetes Care^®, Volume 15, 1992; 1605–1613. Modified with permission from The American Diabetes Association

11.5 Dyslipidemia in Pregnancy

Because the hyperlipidemia of pregnancy is a normal adaptation, normal reference values are useful to judge degrees of abnormality as a function of gestational age. The 90th percentile values are provided in Table 11.1.2, 3 A greater than 90th percentile value for triglyceride approaches 400 mg/dL in late gestation and the triglyceride elevations of gestational diabetic pregnancy can be interpreted in this light.

Table 11.1

Upper limits of normal for plasma total triglyceride, total cholesterol and LDL-C in normal pregnancy

	90th Percentile			10th Percentile
Gestational week	Triglyceride	Cholesterol	LDL-C	HDL-C
0	115	225	140	40
10	140	230	143	50
20	210	275	165	62
27	265	290	180	61
30	300	295	186	58
33	315	300	192	52
36	340	300	200	46
39	370	300	204	45

A clinical indication for triglyceride-lowering is a triglyceride level above 1,000 mg/dL, as it is in nonpregnant individuals, on the rationale of preventing pancreatitis, usually due to LPL deficiency or uncontrolled diabetes.27Severe pancreatitis and at the extreme, hemorrhagic pancreatitis in pregnancy can be lethal for the fetus and a potential cause of long-term disability in the mother if it becomes chronic and recurrent. Fortunately, cases usually do not reach this level of severity, but present with gradual onset of abdominal pain rather than sudden, acute pancreatitis. A slower onset allows time for triglycerides to be checked and treatment to be initiated. An immediate clue to severe hypertriglyceridemia is lipemic plasma at the time of blood draw or in the lab report. Typically, the lipemia interferes with measurements in aqueous plasma, causing reductions in electrolytes and lower than expected or even normal amylase levels.

A first choice for treatment of hypertriglyceridemia is high dose omega-3 fatty acids on the order of 8–10 g/day and avoidance of dietary fat. An example of this treatment for recurrent pancreatitis is given in Table 11.2. This 28-year-old nondiabetic woman was having low-grade mid-abdominal pain radiating to the back, similar to but less severe than that experienced in her first pregnancy. Ascending doses of fish oil extract containing EPA and DHA to 10 g/day resulted in a 57% decrease in triglyceride levels between weeks 30 and 38 and resolution of the abdominal pain between 30 and 34 weeks. Fibrates and low fat diet are two other choices for triglyceride management.27 This complication is more often due to LPL deficiency than GDM or overt diabetes.27

Table 11.2

Effects of ω-3 fatty acids in severe hypertriglyceridemia*

Weeks gestation	20–26	30	34	35	36	37	38
Triglyceride (mg/dL)	2,152–4,040	6,480	4,860	4,904	3,480	3,147	2,791
ω-3 fatty acids (g/d)a	0	0	2	4	6	8	10

^aSemipurified fish oil extracts; courtesy Virginia Stout, PhD, NOAA, Seattle, WA

*28-year-old, pancreatitis in first pregnancy with triglycerides ∼10,000 mg/dL, delivered at 38 weeks; patient had gnawing abdominal pain at week 30

Heterozygous familial hypercholesterolemia and LDL elevations 2–4 times normal are not associated with decreased reproductive efficiency as far as we are aware. However, maternal hypercholesterolemia is associated with cholesterol and fatty streak deposition and monocyte and oxidation markers in fetal, newborn, and childhood aortae, even in the absence of offspring hypercholesterolemia.28,29 Whether the dyslipidemia of GDM (see below) has similar association with perinatal and childhood vasculopathy has not been studied to our knowledge.

A final reason to obtain plasma lipid levels in pregnancy is that they provide a clue to the existence of disordered lipid metabolism post-partum, just as GDM predicts the evolution to overt diabetes in about 50% of subjects postpartum.3,30

11.6 Lipoprotein Lipids in GDM

Effects of GDM on lipid and lipoprotein levels compared to normal pregnancy are reviewed in Table 11.3. In the first trimester, triglycerides were 14 gm/dL higher at 15 weeks gestation in one study.31Second trimester elevations were 101, 38, 43, 35 mg/dL (mean of 54 mg/dL in four studies).31–33 Third trimester elevations were 42, 18, 42, 47, 77, 59, and 35 mg/dL (mean of 48 mg/dL in seven studies).23,31–37 The unweighted grand mean triglyceride level in GDM in the third trimester is 232 mg/dL (Table 11.3). This elevation is ∼50 mg/dL compared to both second and third trimester non-GDM comparators (Table 11.3) and 23 mg/dL above the 36 week median,2,37 but this reference group did not exclude GDM and diabetes.2 The triglyceride distribution in GDM is shifted generally upward compared to all deciles of the triglyceride distribution in normal pregnancy (see horizontal axis, Fig. 11.4).

Table 11.3

Mean lipoprotein lipids in normal (Nl) and GDM pregnancy and postpartum

		Weeks
		15		24–27		32–39		12–14 post
Year [Reference]		Nl	GDM	Nl	GDM	Nl	GDM		Nl	GDM
1972 37	(n) Triglyceride Cholesterol					(14) 186 278	(11) 228 193
1977 34	(n) Triglyceride Cholesterol					(38) 189 211	(22) 207 209
198035	Fasting glucose (n) Triglyceride Cholesterol LDL-C Non-HDL-C HDL-C					≤85 (327) 232 266 155 202 64.1	≥85 (23) 274 255 136 191 63.8
1982 32	(n) Triglyceride Cholesterol LDL-Ca Non-HDL-C HDL-Ca			(21) 185 251 165 183 68	(5) 286 241 145 189 52	(21) 224 259 162 204 55	(5) 271 224 130 172 52		(21) 82 204 145 153 51	(5) 148 208 147 163 45
1992 23	(n) Triglyceride					(521) 165c	(96) 203
1992 Unpub- lished data (Bonet B Knopp RH)	(n) Triglyceride Cholesterol LDL-C Non-HDL-C HDL-C					(9) 143 247 151 180 67	(7) 220 197 97 142 55
1998 36	(n) Triglyceride Cholesterol VLDL-C LDL-C Non-HDL-C HDL-C					(20) 178 232 72 101 162 70	(20) 237 221 50 96 150 71
2005 33	(n) Triglyceride Cholesterol LDL-C Non-HDL-C HDL-C			(121) 176 245 155 180 65	(36) 219 255 151 193 62
		15		24–27		32–39		12–14 post
Year [Reference]		Nl	GDM	Nl	GDM	Nl	GDM		Nl	GDM
2007 31	(n) Triglyceride Cholesterol	(45) 70 163	(62) 94 198	(45) 106 190	(62) 141 220	(45) 150 224	(62) 185 274
Grand	(n)	(45)	(62)	(1461)	(199)	(474)	(150)		(21)	(5)
Means	Triglyceride Cholesterol	70 163	94 198	158 229	212 239	186 238	232 225		82 204	148 205
Reference Valuesb, 2
b, 2	Triglyceride	98 (50–180)		140 (100–250)		209 (146–341)			77 (54–137)
	Cholesterol	195 (140–250)		235 (190–280)		243 (161–254)			200 (161–254)

( ) denotes numbers of subjects; Nl normal

^aValues estimated from figure in reference32

^bMean (10–90th percentile ranges) extrapolated, GDM or diabetes not excluded, from reference3

^c1-h post glucose screen triglyceride measurement; excludes GDM or screen (+), GTT (−)

Regarding cholesterol levels, first trimester values are higher in GDM compared with non-GDM (33 mg/dL in one study), slightly higher in the second trimester (10 mg/dL in three studies), but slightly lower in the third trimester (13.4 mg/dL in seven studies). In contrast, LDL-C levels are lower in GDM in the second trimester by 20 and 4 mg/dL and more so in third trimester GDM by 19–54 mg/dL (mean of 27.5 mg/dL in four studies (Table 11.3).

Because cholesterol carried in LDL is shifted to VLDL in hypertriglyceridemic states, LDL can be an inexact measure of atherogenic lipoprotein levels. To quantify this shift, the sum of VLDL and LDL cholesterol (calculated as non-HDL-C) is a more accurate measure of atherogenicity in hypertriglyceridemia. Non-HDL-C is higher in GDM by 6 and 13 mg/dL (two studies) in the second trimester (Table 11.3), but lower in the third trimester, 11–38 mg/dL in four studies (mean 23 mg/dL). The higher non-HDL-C value in second trimester GDM is potentially important, as vascular lesions in the second trimester fetus are linked to maternal hypercholesterolemia 28,29. An additional atherosclerotic effect of hypertriglyceridemia is an increase in small dense LDL, conferring additional atherogenicity in GDM.38

HDL-C is antiatherogenic by its reverse cholesterol transport, anti-oxidant and anti-inflammatory effects. Typically, levels are reduced in hypertriglyceridemia and diabetes. In GDM, second trimester HDL-C levels were lower by 16 and 3 mg/dL in two studies. In third trimester, HDL-C levels were −0.3, −3, −12 and 1 mg/dL in GDM (mean of −3.6 mg/dL in four studies (Table 11.3).

The separate effects of obesity and GDM on the dyslipidemia of GDM have been addressed by Sanchez-Vera et al.31 GDM is consistently associated with elevated triglyceride, even in the absence of obesity. On the other hand, triglyceride elevations associated with obesity diminish as gestation proceeds, indicating that the hypertriglyceridemia of GDM is more related to the GDM than to obesity.

11.7 Placental Lipid Metabolism in GDM

There is little research on placental lipid metabolism in GDM, though it is relevant to the relationship of maternal nutrient excess, including effects of maternal hypertriglyceridemia on fetal growth and development and macrosomia. In an abstract report of obesity, GDM or type 2 diabetes in pregnancy with maternal hypertriglyceridemia and cord blood hypertriglyceridemia, placental villi had increased levels of FFAs, but reduced triglycerides and no enhancement of villous droplets or lipid droplet associated proteins.39 The data suggest that that the placenta adapts to the maternal hypertriglyceridemia with increased transport of fatty acids without becoming triglyceride enriched. These observations in GDM differ from type 1 diabetic pregnancy where placental triglyceride content increases.40

Another example of the maintenance of placental transport function relates to arachidonic and DHAs which are decreased in infants of GDM pregnancy compared with normal pregnancy.41 However, when umbilical arterial and umbilical venous arachidonic acid (AA) and DHA levels in GDM pregnancy were compared with normal pregnancy, venous plasma levels were normal but arterial values were reduced.41 These results indicate that fetal AA and DHA levels are reduced by fetal consumption and not deficiency of placental transport, consistent with adaptations to enhance DHA transplacental transport discussed above.6, 19

11.8 Dyslipidemia of GDM and Birth Weight

The importance of triglyceride elevations to increased birth weight can be judged by comparison to other predictors of birth weight. Triglyceride is positively associated with birth weight, up to a triglyceride level of 200 mg/dL in normal pregnancy, approximately 80th percentile in healthy women and then becomes negative, suggestive of a negative or toxic effect of higher triglycerides on birth weight.23 Among second trimester, screen (+), GTT (−) women (most of whom have triglycerides OR TGs < 200 mg/dl TGs <200 mg/dL), plasma triglycerides 1-h after a 50-g glucose load are as strong a predictor of birth weight (r = 0.13), as 2-h glucose concentration (r = 0.15) or the sum of glucose increments (r = 0.13) after a 100-g glucose tolerance test (all <0.05) in screen (+), GTT (−) women (n = 264).23 Triglyceride was not a statistically significant correlate in GDM (r = 0.11) possibly due in part to GDM’s association with triglyceride levels above 200 mg/dL (Fig. 11.4). The association between triglyceride and birthweight was strongest was strongest in the combined group of positive screened, negative GTT and GDM subjects (r = 0.16) (p < 0.01, n = 360) compared with negative screenees (r = 0.09) (p < 0.05, n = 511).

Couch et al confirmed an association of triglyceride with birth weight in normal women, along with HDL₂ (p < 0.05).36 Surprisingly, this association was not seen in GDM subjects, although the sample sizes were equal, 20 in each group. Kitajima et al also found a positive association of late second trimester fasting plasma triglyceride levels with birth-weight ratio in 146 subjects with a positive 1-h screening test but a negative 75-g oral glucose tolerance test (r = 0.22, p = 0.009).42 Among measured maternal lipids, only triglyceride was associated with birth-weight in univariate analysis. Associations with maternal prepregnancy body mass index (BMI) and fasting glucose were less, r = 0.18 and 0.17, respectively (p = 0.04 in both instances). In logistic regression, fasting triglyceride was a predictor of large for gestational age (LGA) infants, independent of prepregnant BMI, maternal weight gain, and maternal glucose levels. Di Cianni et al performed a similar analysis in 83 women with positive screening test but with negative oral glucose tolerance tests (GTTs).33 The R² association of triglyceride with birth weight was 0.09, meaning that this measure accounted for 9% of the birth weight association, while the glucose R² was 0.044, both p < 0.05. In step-wise regression, only triglycerides and prepregnancy BMI remained independently associated with birth weight (F tests 4.07 and 7.26 respectively) (p < 0.01 in both instances).

Most recently, Schaeffer-Graf et al found that maternal FFA as well as triglycerides were significantly associated with fetal abdominal circumference (AC) at 28 weeks gestation (FFA p < 0.02 and triglyceride p < 0.001).43 This study also examined the cord blood lipids and found lower cord triglyceride levels in LGA babies and cord triglyceride inversely associated with birth weight and neonatal fat mass. Separately, Bomba-Opon et al found elevated FFA levels in late gestation GDM women and a positive association of FFA with birth weight.44

In conclusion, triglycerides are predictors of birth weight across all categories of GDM screening status and among several studies. The most consistent association is in (+) screen, (−) GTT non-GDM women. In GDM, a weaker association of TG and birth weight may be due to the larger number of GDM women with triglycerides >200 mg/dL and a negative, possibly toxic, association of higher triglycerides with birth weight.

11.9 Oxidative Stress in GDM

Because of the known association of inflammation with metabolic syndrome, GDM, and diabetes,45–47 it is of interest to assess the role of oxidative stress in GDM, including lipoprotein susceptibility to oxidation. Sánchez-Vera et al measured LDL oxidation in 45 nondiabetic subjects and 62 women with GDM by measuring the time for LDL oxidation to begin under oxidizing conditions (lag phase).31 A shortened lag phase reflects diminished antioxidant defense against oxidative stress due to prior antioxidant consumption in vivo. Lag phase was shortened in GDM compared to healthy pregnant women by 32, 31, and 24 % across the 3 trimesters (<0.001). These data indicate that GDM increases the susceptibility of LDL to oxidative stress by one third. LDL from non-obese GDM women were less sensitive to oxidative modification especially in the third trimester whereas obese GDM women were more-so.

Additional evidence of heightened oxidative stress and diminished antioxidant defense has been detected in GDM (see review48). Vitamin C levels and total antioxidant capacity levels were reduced in GDM, though oxidized lipids measured as malonyldialdehyde (MDA) and lipid hydroperoxides were unchanged. However, evidence of lipid oxidation has been found in maternal tissues and placenta in the form of lipid hydroperoxides, 8-isoprostanes and MDA with compensatory antioxidant enzyme activity including elevated activity of superoxide dismutase and glutathione peroxidase. Surprisingly, the ability of the placenta to respond to inflammatory stress was impaired with a reduced capacity to form 8-isoprostane, TNFα, and NF-kappa B.49 Oxidative stresses can injure the placenta as seen in trophoblast cytotoxicity from oxidized LDL in primary tissue culture.50 Also of interest is that lag phase for the oxidation of LDL is shortened in type 1 diabetic pregnancy (B Bonet and RH Knopp, unpublished observations). Enhanced oxidative stress is a well known cause of congenital malformations in animal models of diabetes.51

Extreme examples of oxidative stress in pregnancy are found in preeclampsia and eclampsia, where lipid hydroperoxides are in excess, the placenta is dysfunctional and newborns are SGA.52 The lipoprotein system may play a role in propagating oxidative stress in the course of scavenging oxidized lipids from the placenta and transporting them to the liver for excretion, but, in the process, causing endothelial injury and hypertension, especially in hypertriglyceridemia.25, 53 Maternal antibodies to oxidized LDL have been found in preeclampsia.54 Similarly, evidence of lipid peroxidation and altered anti-oxidant defense has been observed in maternal and cord plasma and placenta in severe hypercholesterolemia.55

11.10 Summary

The dyslipidemia of GDM is associated with ∼50 mg/dL increase in triglyceride at term, ∼4 mg/dL lower HDL level, lower LDL levels, and normal or reduced non-HDL- cholesterol levels. The defense of LDL against oxidation is reduced by 35% in GDM and LDL is small and dense, consistent with the hypertriglyceridemia of GDM. Increases in multiple other measures of inflammation and oxidative stress are observed in GDM pregnancy. At the extreme, the consumption of antioxidant defenses is associated with circulating lipid peroxides in preeclampsia, placental damage, endothelial injury, hypertension, and retarded fetal growth. Both hypertriglyceridemia in GDM and familial hypercholesterolemia are associated with heightened oxidative stress. Birth weight in GDM may be the result of competing effects of nutrient excess (elevated glucose and triglyceride) on the one hand, and toxic effects of enhanced oxidative stress propagated by lipid peroxidation and placental dysfunction, on the other. A challenge for the future is to understand the interplay between nutrient excess, inflammation, lipoprotein oxidation, perinatal morbidity and mortality, and to devise treatments for these pathophysiologies in GDM.

Acknowledgments

This work was supported in part by NIH grant DK 035816, Clinical Nutrition Research Unit at the University of Washington.

References

1.

Knopp R, Bonet B, Zhu X-D. Lipid metabolism in pregnancy. In: Cowett R, ed. Principles of Perinatal-Neonatal Metabolism. New York: Springer; 1998:221-258.CrossRef

2.

Knopp RH, Bergelin RO, Wahl PW, Walden CE, Chapman M, Irvine S. Population-based lipoprotein lipid reference values for pregnant women compared to nonpregnant women classified by sex hormone usage. Am J Obstet Gynecol. 1982;143:626-637.PubMed

3.

Knopp R, Paramsothy P. Part 2. Management of diabetic/medical complications in pregnancy: management of hyper/dyslipidmias. In: Kitzmiller J, Jovanovic L, Brown F, Coustan D, Reader D, eds. Managing Preexisting Diabetes and Pregnancy: Technical Reviews and Consensus Recommendations for Care. Alexandria: American Diabetes Association; 2008:355-374.

4.

Alvarez JJ, Montelongo A, Iglesias A, Lasuncion MA, Herrera E. Longitudinal study on lipoprotein profile, high density lipoprotein subclass, and postheparin lipases during gestation in women. J Lipid Res. 1996;37:299-308.PubMed

5.

Magnusson-Olsson AL, Hamark B, Ericsson A, Wennergren M, Jansson T, Powell TL. Gestational and hormonal regulation of human placental lipoprotein lipase. J Lipid Res. 2006;47:2551-2561.PubMedCrossRef

6.

Larque E, Krauss-Etschmann S, Campoy C, et al. Docosahexaenoic acid supply in pregnancy affects placental expression of fatty acid transport proteins. Am J Clin Nutr. 2006;84:853-861.PubMed

7.

van Eijsden M, Hornstra G, van der Wal MF, Vrijkotte TG, Bonsel GJ. Maternal n-3, n-6, and trans fatty acid profile early in pregnancy and term birth weight: a prospective cohort study. Am J Clin Nutr. 2008;87:887-895.PubMed

8.

Banka CL. High density lipoprotein and lipoprotein oxidation. Curr Opin Lipidol. 1996;7:139-142.PubMedCrossRef

9.

Vaisar T, Pennathur S, Green PS, et al. Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL. J Clin Invest. 2007;117:746-756.PubMedCentralPubMedCrossRef

10.

Grunfeld C, Feingold KR. HDL and innate immunity: a tale of two apolipoproteins. J Lipid Res. 2008;49:1605-1606.PubMedCrossRef

11.

Oram JF. The ins and outs of ABCA. J Lipid Res. 2008;49:1150-1151.PubMedCrossRef

12.

Lasuncion MA, Bonet B, Knopp RH. Mechanism of the HDL2 stimulation of progesterone secretion in cultured placental trophoblast. J Lipid Res. 1991;32:1073-1087.PubMed

13.

Woollett LA. Maternal cholesterol in fetal development: transport of cholesterol from the maternal to the fetal circulation. Am J Clin Nutr. 2005;82:1155-1161.PubMed

14.

Schmid KE, Davidson WS, Myatt L, Woollett LA. Transport of cholesterol across a BeWo cell monolayer: implications for net transport of sterol from maternal to fetal circulation. J Lipid Res. 2003;44:1909-1918.PubMedCrossRef

15.

Stefulj J, Panzenboeck U, Becker T, et al. Human endothelial cells of the placental barrier efficiently deliver cholesterol to the fetal circulation via ABCA1 and ABCG1. Circ Res. 2009;104:600-608.PubMedCrossRef

16.

Madsen EM, Lindegaard ML, Andersen CB, Damm P, Nielsen LB. Human placenta secretes apolipoprotein B-100-containing lipoproteins. J Biol Chem. 2004;279:55271-55276.PubMedCrossRef

17.

Portman OW, Behrman RE, Soltys P. Transfer of free fatty acids across the primate placenta. Am J Physiol. 1969;216:143-147.PubMed

18.

Campbell FM, Clohessy AM, Gordon MJ, Page KR, Dutta-Roy AK. Uptake of long chain fatty acids by human placental choriocarcinoma (BeWo) cells: role of plasma membrane fatty acid-binding protein. J Lipid Res. 1997;38:2558-2568.PubMed

19.

Koletzko B, Larque E, Demmelmair H. Placental transfer of long-chain polyunsaturated fatty acids (LC-PUFA). J Perinat Med. 2007;35(suppl 1):S5-S11.PubMed

20.

Knopp RH, Bergelin RO, Wahl PW, Walden CE. Relationships of infant birth size to maternal lipoproteins, apoproteins, fuels, hormones, clinical chemistries, and body weight at 36 weeks gestation. Diabetes. 1985;34(suppl 2):71-77.PubMedCrossRef

21.

Weng W, Breslow JL. Dramatically decreased high density lipoprotein cholesterol, increased remnant clearance, and insulin hypersensitivity in apolipoprotein A-II knockout mice suggest a complex role for apolipoprotein A-II in atherosclerosis susceptibility. Proc Natl Acad Sci U S A. 1996;93:14788-14794.PubMedCentralPubMedCrossRef

22.

Kalopissis AD, Pastier D, Chambaz J. Apolipoprotein A-II: beyond genetic associations with lipid disorders and insulin resistance. Curr Opin Lipidol. 2003;14:165-172.PubMedCrossRef

23.

Knopp RH, Magee MS, Walden CE, Bonet B, Benedetti TJ. Prediction of infant birth weight by GDM screening tests. Importance of plasma triglyceride. Diabetes Care. 1992;15:1605-1613.PubMedCrossRef

24.

Arbogast BW, Lee GM, Raymond TL. In vitro injury of porcine aortic endothelial cells by very-low-density lipoproteins from diabetic rat serum. Diabetes. 1982;31:593-599.PubMedCrossRef

25.

Hubel CA, McLaughlin MK, Evans RW, Hauth BA, Sims CJ, Roberts JM. Fasting serum triglycerides, free fatty acids, and malondialdehyde are increased in preeclampsia, are positively correlated, and decrease within 48 hours post partum. Am J Obstet Gynecol. 1996;174:975-982.PubMedCrossRef

26.

Pou KM, Massaro JM, Hoffmann U, et al. Visceral and subcutaneous adipose tissue volumes are cross-sectionally related to markers of inflammation and oxidative stress: the Framingham Heart Study. Circulation. 2007;116:1234-1241.PubMedCrossRef

27.

Knopp RH. Drug treatment of lipid disorders. N Engl J Med. 1999;341:498-511.PubMedCrossRef

28.

Napoli C, D’Armiento FP, Mancini FP, et al. Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions. J Clin Invest. 1997;100:2680-2690.PubMedCentralPubMedCrossRef

29.

Napoli C, Glass CK, Witztum JL, Deutsch R, D’Armiento FP, Palinski W. Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: Fate of Early Lesions in Children (FELIC) study. Lancet. 1999;354:1234-1241.PubMedCrossRef

30.

Montes A, Walden CE, Knopp RH, Cheung M, Chapman MB, Albers JJ. Physiologic and supraphysiologic increases in lipoprotein lipids and apoproteins in late pregnancy and postpartum. Possible markers for the diagnosis of “prelipemia”. Arteriosclerosis. 1984;4:407-417.PubMedCrossRef

31.

Sanchez-Vera I, Bonet B, Viana M, et al. Changes in plasma lipids and increased low-density lipoprotein susceptibility to oxidation in pregnancies complicated by gestational diabetes: consequences of obesity. Metabolism. 2007;56:1527-1533.PubMedCrossRef

32.

Hollingsworth DR, Grundy SM. Pregnancy-associated hypertriglyceridemia in normal and diabetic women. Differences in insulin-dependent, non-insulin-dependent, and gestational diabetes. Diabetes. 1982;31:1092-1097.PubMedCrossRef

33.

Di Cianni G, Miccoli R, Volpe L, et al. Maternal triglyceride levels and newborn weight in pregnant women with normal glucose tolerance. Diabet Med. 2005;22:21-25.PubMedCrossRef

34.

Warth MR, Knopp RH. Lipid metabolism in pregnancy. V. Interactions of diabetes, body weight, age and high carbohydrate diet. Diabetes. 1977;26:1056-1062.PubMedCrossRef

35.

Knopp RH, Chapman M, Bergelin R, Wahl PW, Warth MR, Irvine S. Relationships of lipoprotein lipids to mild fasting hyperglycemia and diabetes in pregnancy. Diabetes Care. 1980;3:416-420.PubMedCrossRef

36.

Couch SC, Philipson EH, Bendel RB, Wijendran V, Lammi-Keefe CJ. Maternal and cord plasma lipid and lipoprotein concentrations in women with and without gestational diabetes mellitus. Predictors of birth weight? J Reprod Med. 1998;43:816-822.PubMed

37.

Knopp RH, Warth MR, Carrol CJ. Lipid metabolism in pregnancy. I. Changes in lipoprotein triglyceride and cholesterol in normal pregnancy and the effects of diabetes mellitus. J Reprod Med. 1973;10:95-101.PubMed

38.

Qiu C, Rudra C, Austin MA, Williams MA. Association of gestational diabetes mellitus and low-density lipoprotein (LDL) particle size. Physiol Res. 2007;56:571-578.PubMed

39.

Scifres C, Chen B, Nelson D, Sadovsky Y. The influence of maternal obesity and diabetes on placental lipi trafficking. J Obster Gynec. 2008;199:S22. abstract #50.CrossRef

40.

Lindegaard ML, Damm P, Mathiesen ER, Nielsen LB. Placental triglyceride accumulation in maternal type 1 diabetes is associated with increased lipase gene expression. J Lipid Res. 2006;47:2581-2588.PubMedCrossRef

41.

Ortega-Senovilla H, Alvino G, Taricco E, Cetin I, Herrera E. Gestational diabetes mellitus upsets the proportion of fatty acids in umbilical arterial but not venous plasma. Diabetes Care. 2009;32:120-122.PubMedCrossRef

42.

Kitajima M, Oka S, Yasuhi I, Fukuda M, Rii Y, Ishimaru T. Maternal serum triglyceride at 24–32 weeks’ gestation and newborn weight in nondiabetic women with positive diabetic screens. Obstet Gynecol. 2001;97:776-780.PubMedCrossRef

43.

Schaefer-Graf UM, Graf K, Kulbacka I, et al. Maternal lipids as strong determinants of fetal environment and growth in pregnancies with gestational diabetes mellitus. Diabetes Care. 2008;31:1858-1863.PubMedCrossRef

44.

Bomba-Opon D, Wielgos M, Szymanska M, Bablok L. Effects of free fatty acids on the course of gestational diabetes mellitus. Neuro Endocrinol Lett. 2006;27:277-280.PubMed

45.

Hansel B, Giral P, Nobecourt E, et al. Metabolic syndrome is associated with elevated oxidative stress and dysfunctional dense high-density lipoprotein particles displaying impaired antioxidative activity. J Clin Endocrinol Metab. 2004;89:4963-4971.PubMedCrossRef

46.

Tesauro M, Schinzari F, Rovella V, et al. Tumor necrosis factor-alpha antagonism improves vasodilation during hyperinsulinemia in metabolic syndrome. Diabetes Care. 2008;31:1439-1441.PubMedCrossRef

47.

Kim C, Cheng YJ, Beckles GL. Inflammation among women with a history of gestational diabetes mellitus and diagnosed diabetes in the Third National Health and Nutrition Examination Survey. Diabetes Care. 2008;31:1386-1388.PubMedCrossRef

48.

Chen X, Scholl TO. Oxidative stress: changes in pregnancy and with gestational diabetes mellitus. Curr Diab Rep. 2005;5:282-288.PubMedCrossRef

49.

Coughlan MT, Permezel M, Georgiou HM, Rice GE. Repression of oxidant-induced nuclear factor-kappaB activity mediates placental cytokine responses in gestational diabetes. J Clin Endocrinol Metab. 2004;89:3585-3594.PubMedCrossRef

50.

Bonet B, Hauge-Gillenwater H, Zhu XD, Knopp RH. LDL oxidation and human placental trophoblast and macrophage cytotoxicity. Proc Soc Exp Biol Med. 1998;217:203-211.PubMedCrossRef

51.

Wentzel P, Gareskog M, Eriksson UJ. Decreased cardiac glutathione peroxidase levels and enhanced mandibular apoptosis in malformed embryos of diabetic rats. Diabetes. 2008;57:3344-3352.PubMedCrossRef

52.

Hubel CA, Roberts JM, Taylor RN, Musci TJ, Rogers GM, McLaughlin MK. Lipid peroxidation in pregnancy: new perspectives on preeclampsia. Am J Obstet Gynecol. 1989;161:1025-1034.PubMedCrossRef

53.

Clausen T, Djurovic S, Henriksen T. Dyslipidemia in early second trimester is mainly a feature of women with early onset pre-eclampsia. Bjog. 2001;108:1081-1087.PubMed

54.

Branch DW, Mitchell MD, Miller E, Palinski W, Witztum JL. Pre-eclampsia and serum antibodies to oxidised low-density lipoprotein. Lancet. 1994;343:645-646.PubMedCrossRef

55.

Liguori A, D’Armiento FP, Palagiano A, et al. Effect of gestational hypercholesterolaemia on omental vasoreactivity, placental enzyme activity and transplacental passage of normal and oxidised fatty acids. Bjog. 2007;114:1547-1556.PubMedCrossRef