**6. Is normal pregnancy atherogenic?[80]**

60 Lipoproteins – Role in Health and Diseases

**1. Pre-eclampsia** 

**5. Prelipaemia** 

**3. Hypothyroidism 4. Hypertension** 

**Other maternal factors 1. BMI(Obesity)** 

**3. Maternal nutrition** 

factors not mentioned)

**4. Pre-pregnancy lipid levels** 

**6. Alcoholism** 

**1. Obesity** 

**Medical complications of pregnancy**

**2. Pregnancy-induced hypertension 3. Gestational diabetes mellitus** 

**Co-existing medical conditions** 

**2. Types 1 and 2 diabetes mellitus** 

**4. Intra-uterine growth restriction(retardation)** 

**5. Renal diseases, particularly nephritic syndrome** 

**2. Maternal weight gain in the index pregnancy** 

**Figure 1.** Classification of hyperlipidaemia of pregnancy

**7. Medications, eg LMWt-heparin and glucocorticoid** 

**Table 5.** Factors that can also modulate lipid and lipoprotein concentrations in pregnancy (genetic

The change in triglycerides in normal pregnancy is important in relation to lipoprotein subclasses, such as LDL. These lipoproteins contain subfractions of various sizes, densities and compositions, which differ in their ability to initiate atherogenesis [81]. One of the subfractions of LDL (LDL-3) is small, dense LDL particles which do not bind readily to the LDL receptors and therefore remain in the circulation for longer time, penetrate the arterial intima better than do larger ones[82] and are more readily oxidized, probably because they contain less vitamin E and other antioxidants[83]. Finally, their uptake into macrophages to create form cells, and initiate atherogenesis, is facilitated [84]. This may explain their identification as an independent risk factor for coronary heart disease [82-84].

Plasma triglycerides are the major determinant of small, dense LDLs, accounting for 40-60% of the variability of this fraction in the plasma [75]. VLDL represents the major precursor of LDL and reflects plasma TGs levels. Two subclasses of VLDL have been defined: a large and buoyant fraction enriched with TGs (VLDL-1) and a smaller, denser fraction(VLDL-2). It follows from the association between LDL subclasses and raised TGs that VLDL-1 may be important as a vehicle in the process of neutral lipid exchange and generation of small,

dense LDLs. Cholesterol esters are transferred from LDL and HDL to VLDL-1 by cholesterol ester transfer protein(CETP) in exchange for TGs and the increased concentration of VLDL-1, due to hypersecretion by the liver promote TG transfer into LDL during pregnancy[33]. TG-enriched LDL particles subsequently undergo a size reduction through the action of hepatic lipase, resulting in the formation of small, dense LDL subfractions. In addition Lippi[2], et al demonstrated in their study that advanced pregnancy is associated with an increased prevalence of undesirable or abnormal values for total cholesterol, LDL-C and TGs in the second trimester, and total cholesterol, LDL-C, TGs TC:HDL ratio in third trimester demonstrating that physiological pregnancy is associated with a substantial modification of lipid and lipoproteins metabolism from the second trimester, providing reference ranges for traditional and emerging cardiovascular risk predictors throughout the gestational period. Therefore, is normal pregnancy atherogenic?

All pregnant women develop a transient hyperlipidaemia associated with hypertriglyceridaemia, and subsequent formation of small, dense LDL particles, both of which are an independent risk factor for CHD, and by 3rd trimester most women have a lipid profile which would be considered highly atherogenic in the non-pregnant state[13]. Increased prevalence of angina, cholesterol gallstone, and obesity in postmenopausal women who have had several pregnancies has been observed [85]. Yet the long-term consequences of multiple pregnancy, gestational diabetes or maternal obesity in LDL subfractions and lipid profile are unknown. Further studies are recommended to determine if certain women are at increased risk of CVD in later life because of effects on their lipid profile during pregnancy. In contrast, increasing suggestions are that maternal hypercholesterolaemia during pregnancy even when temporary and limited to pregnancy triggers pathogenic events in the fetal aorta, greatly enhanced fatty streak formation and that may influence atherogenesis later in life[14,15]. Fetal plasma cholesterol levels are high and are proportional to the maternal cholesterol levels [14] in second trimester, decline with increasing fetal age[14] and are even lower at term birth. This is supported by the fact that lipid levels observed in umbilical cord blood(UCB) from normal pregnancy were significantly lower than those found in maternal blood with exception of HDL-C, and that LDL:HDL ratio in neonate of normal pregnancy are much lower than the value in normal pregnant mothers[16]. The high HDL levels and a lower LDL:HDL ratio in UCB suggest that the fetus of a normal pregnancy is protected against atherogenic lipoprotein[16]. Despite these findings, studies at autopsy demonstrated that atherosclerosis progresses much faster in offsprings of hypercholesterolaemic mother than in offsprings of normocholesterolaemic mothers[86]. Same studies observed that at each time point, offsprings of hypercholesterolaemic mothers had 1.5 to 3-fold larger lesions than offsprings of normocholesterolaemic mothers, and they suggested that, pathogenic programming in utero increases the susceptibility to atherogenic risk factors later in life and maternal intervention with cholesterol-lowering agents reduce postnatal lipid peroxidation and atherosclerosis in their offsprings[87]. A registry study by Toleikyte,[22] *et al*, of heterozygous familial hypercholesterolaemic(FH) mothers observed that: the serum levels of cholesterol in the nonpregnant, nontreated women were 370mg/dl(9.59mmol/L); no maternal cardiovascular deaths were observed; the children of mothers with FH were no more likely than the general population to be born prematurely, have low birth weight, or have congenital malformations; and that no congenital malformations were observed in the 19 pregnancies associated with the use of lipid-lowering drugs during pregnancy. However, the current trend is that Statins, classified by FDA as category X in pregnancy, should be avoided in pregnancy [23,24]. Although there are observations for and against the maternal hyperlipidaemia being atherogenic to the fetus and increasing tendencies of future atherosclerosis, a long-term follow-up studies of offsprings of mothers with FH who did not inherited the disease is recommended. The result will demonstrate evidence of effects of maternal hyperlipidaemia on fetal atherosclerosis and or predisposition to future atherosclerosis in these offsprings.

#### **6.1. Fetal lipoproteins in pre-eclampsia**

62 Lipoproteins – Role in Health and Diseases

dense LDLs. Cholesterol esters are transferred from LDL and HDL to VLDL-1 by cholesterol ester transfer protein(CETP) in exchange for TGs and the increased concentration of VLDL-1, due to hypersecretion by the liver promote TG transfer into LDL during pregnancy[33]. TG-enriched LDL particles subsequently undergo a size reduction through the action of hepatic lipase, resulting in the formation of small, dense LDL subfractions. In addition Lippi[2], et al demonstrated in their study that advanced pregnancy is associated with an increased prevalence of undesirable or abnormal values for total cholesterol, LDL-C and TGs in the second trimester, and total cholesterol, LDL-C, TGs TC:HDL ratio in third trimester demonstrating that physiological pregnancy is associated with a substantial modification of lipid and lipoproteins metabolism from the second trimester, providing reference ranges for traditional and emerging cardiovascular risk predictors throughout the

All pregnant women develop a transient hyperlipidaemia associated with hypertriglyceridaemia, and subsequent formation of small, dense LDL particles, both of which are an independent risk factor for CHD, and by 3rd trimester most women have a lipid profile which would be considered highly atherogenic in the non-pregnant state[13]. Increased prevalence of angina, cholesterol gallstone, and obesity in postmenopausal women who have had several pregnancies has been observed [85]. Yet the long-term consequences of multiple pregnancy, gestational diabetes or maternal obesity in LDL subfractions and lipid profile are unknown. Further studies are recommended to determine if certain women are at increased risk of CVD in later life because of effects on their lipid profile during pregnancy. In contrast, increasing suggestions are that maternal hypercholesterolaemia during pregnancy even when temporary and limited to pregnancy triggers pathogenic events in the fetal aorta, greatly enhanced fatty streak formation and that may influence atherogenesis later in life[14,15]. Fetal plasma cholesterol levels are high and are proportional to the maternal cholesterol levels [14] in second trimester, decline with increasing fetal age[14] and are even lower at term birth. This is supported by the fact that lipid levels observed in umbilical cord blood(UCB) from normal pregnancy were significantly lower than those found in maternal blood with exception of HDL-C, and that LDL:HDL ratio in neonate of normal pregnancy are much lower than the value in normal pregnant mothers[16]. The high HDL levels and a lower LDL:HDL ratio in UCB suggest that the fetus of a normal pregnancy is protected against atherogenic lipoprotein[16]. Despite these findings, studies at autopsy demonstrated that atherosclerosis progresses much faster in offsprings of hypercholesterolaemic mother than in offsprings of normocholesterolaemic mothers[86]. Same studies observed that at each time point, offsprings of hypercholesterolaemic mothers had 1.5 to 3-fold larger lesions than offsprings of normocholesterolaemic mothers, and they suggested that, pathogenic programming in utero increases the susceptibility to atherogenic risk factors later in life and maternal intervention with cholesterol-lowering agents reduce postnatal lipid peroxidation and atherosclerosis in their offsprings[87]. A registry study by Toleikyte,[22] *et al*, of heterozygous familial hypercholesterolaemic(FH) mothers observed that: the serum levels of cholesterol in the nonpregnant, nontreated women were 370mg/dl(9.59mmol/L); no maternal cardiovascular deaths were observed; the children of mothers with FH were no more likely than the general

gestational period. Therefore, is normal pregnancy atherogenic?

Successful placental development is very important for normal fetal growth, and may condition health and well being during childhood and even adulthood [88], because it forms the interface for nutrients, fluids and gas exchange between mother and fetus. Pre-eclampsia (PE), a human pregnancy specific vascular disorder, defines a pathologic condition that affects the mother and can adversely influence the feto-placental unit. PE is associated with placental dysfunction, oxidative stress[1, 89], dyslipidaemia[16,90] and endothelial cell activation, and is a major cause of maternal and fetal morbidity and mortality[88] A proatherogenic lipid profile, characterized by increased TG levels with reduced HDL concentration[90, 91] and increased small, dense LDL particles[90] has been described. In contrast other studies demonstrated a dominance of buoyant LDL-1 and a significant decreased of small, dense LDL, namely LDL-5 and LDL-6[92]. Notwithstanding, it has been suggested that an abnormal lipid metabolism may not only be a manifestation of PE, but dyslipidaemia may play an essential role in its pathogenesis

Apart from genetic predisposition, the second group of disorders associated with an increased risk of PE includes a variety of chronic conditions such as dyslipidaemia, diabetes mellitus, hypertension, renal diseases, and various thrombophilias[93]. These disorders can be convincingly grouped together based on their common association with vascular endothelial dysfunction, especially those which have been included in the proposed metabolic syndrome [93]. Ironically also all are associated with dyslipidaemia. Although PE is a multifactorial disorder, it is therefore tempting to ask, could dyslipidaemia be the central focal point linking these disorders into pathogenesis of PE? One of the abnormalities found in the abnormal placental bed is presence of acute atherosis in desidual vessels, characterized by accumulations of foam cells and perivascular mononuclear cell infiltration. Reduced placental perfusion and placental/fetal hypoxia may develop.

Catarino[16], et al, while comparing lipid and lipoproteins in normal pregnant and PE pregnant women found an enhanced physiologic hyperlipidaemia. However, the most striking difference noted in PE women was the rise TGs that almost double the median value compared to normal pregnant women. Higher TGs value has been associated with endothelial dysfunction and may therefore play an important role in the pathogenesis of PE. Considering the placental dysfunction and lipid changes occurring in PE, fetal lipid

metabolism can be affected due to an altered placental transfer of lipids. Maternal TGs does not cross the placenta. It has to be hydrolyzed by human placental LPL into FFAs which is then transported to the fetus. Fetal TG levels are therefore dependent on maternal TGs. Moreover, the placenta also contains receptors for VLDL, LDL and HDL which also transport TGs and other esterified lipid to the fetus (23)

Catarino[16],et al observed that lipid levels observed in umbilical cord blood (UCB) from normal pregnancy were significantly lower than those found in maternal blood except for HDL, which was similar. In addition, LDL:HDL ratio in neonates of normal pregnancies are much lower than the values in normal pregnant mothers. In contrast, lower values of HDL and ApoA-1 and higher TG levels were noted in neonates of PE mothers. In addition, higher LDL:HDL ratio, a decreased HDL which is more pronounced than ApoA-1, suggest that fetal loading of ApoA-1 with cholesterol is significantly less in PE. Hence fetal HDL composition is likely to be altered due possibly to enrichment with the enhanced hypertriglyceridaemia. Also observed in the PE is a significantly higher value of TGs in UCB which is parallel with significant increased TGs in maternal blood. Since hypertriglyceridaemia is considered a maternal adaptation in order to assure fetal growth in normal pregnancy, the exaggerated hypertriglycedaemia noticed in PE mothers could be a compensation pathway to face the uteroplacental hypoperfusion in order to enhance FAs transfer to the fetus. In line with this, it seems LPL expression is also enhanced in PE as was observed in IUGR [94]. Taken together, it appears lipid transfer from maternal side in PE mothers to their fetus are altered in both quantity and quality and does not seems to be protective as noticed in neonates of normal pregnancies. In support of this PE has been associated with reduced fetal birth weight [95, 96] and the expression of lipoprotein receptors are decreased in the placenta of women with PE.

PE pregnancies is associated with an enhanced hypertriglyceridaemia, which seems to have a negative impact on fetal lipid profile, as reflected by a higher atherogenic LDL:HDL ratio, decreased HDL, disproportionate decreased in HDL and ApoA-1 and enhanced hypertriglycedaemia, children born in pregnancies associated with PE deserve a closer clinical follow-up later in life.
