**2. Pathophysiology of hyperlipidaemia of pregnancy**

**Pregnancy** is a dynamic state consequent of the fact that normal fetal development needs the availability of essential nutrients such as glucose, free fatty acids(FFAs), long-chain polyunsaturated fatty acids(LCPUFAs), amino acids, minerals, vitamins, to be continuously supplied to the growing fetus despite intermittent maternal food intake[10,25]. The dynamism of the gestational period support fetal growth and development while maintaining maternal homeostasis and preparation for lactation. This is achieved by complex and continuously evolving adjustments in maternal nutrient metabolism occurring throughout gestation.

Many of these maternal adjustments occur in the early stages of pregnancy when the fetus is too small to make considerable metabolic demands of the mother, resulting in the maternal metabolism working from a different baseline compared with the nonpregnant state. This period is called the anabolic phase. In late pregnancy, however, the maternal metabolic processes become more complicated because of the two-way interaction between the mother and the developing fetus. This is caked the catabolic phase.

The changes in nutrient metabolism can be described by several general concepts[8]: (a) adjustments in nutrient metabolism are driven by hormonal changes, fetal demands and maternal nutrient supply; (b) more than one potential adjustment exists for each nutrient; (c) maternal behavioural changes augment physiologic adjustment; and (d) a limit exists in the physiologic capacity to adjust nutrient metabolism to meet pregnancy needs, which when exceeded, fetal growth and development are impaired. Subsequently, metabolic adaptations, during pregnancy are essential [26]: 1, To ensure adequate growth and development of the fetus; 2, to provide the fetus with adequate energy stores and substrates that are needed following birth; 3, and, to provide the mother with sufficient energy stores and substrates to cope with the demands of pregnancy as well as those of labour and lactation. One of the maternal metabolic adjustments during pregnancy includes accumulation of fat depots in maternal tissues[26]. During this anabolic phase, the number of insulin receptors on the adipocytes increases, culminating into increased insulin sensitivity, increase lipoprotein lipase(LPL) activity which hydrolyses circulating triglycerides for tissue uptake, enhanced lipogenesis and marked maternal fat deposition(about 3.5 to 6.0kg) which is used as energy sources for the mother so that glucose is spared for the developing fetus in the catabolic part of the pregnancy[27, 28]. Lean women increase their fat stores more than obese women per kg body weight, likely due to higher insulin sensitivity in them, in early pregnancy, promoting lipid uptake and de novo synthesis.

throughout gestation.

modulators of lipid metabolism in pregnancy.

**2. Pathophysiology of hyperlipidaemia of pregnancy** 

and the developing fetus. This is caked the catabolic phase.

promoting lipid uptake and de novo synthesis.

is that Statins, classified by FDA as category X, should be avoided in pregnancy[23, 24]. The use of lipid and lipoprotein ratios in interpreting pregnancy associated hyperlipidaemia may provide a balanced hyperlipidaemia not only in normal pregnancy but also in the other

**Pregnancy** is a dynamic state consequent of the fact that normal fetal development needs the availability of essential nutrients such as glucose, free fatty acids(FFAs), long-chain polyunsaturated fatty acids(LCPUFAs), amino acids, minerals, vitamins, to be continuously supplied to the growing fetus despite intermittent maternal food intake[10,25]. The dynamism of the gestational period support fetal growth and development while maintaining maternal homeostasis and preparation for lactation. This is achieved by complex and continuously evolving adjustments in maternal nutrient metabolism occurring

Many of these maternal adjustments occur in the early stages of pregnancy when the fetus is too small to make considerable metabolic demands of the mother, resulting in the maternal metabolism working from a different baseline compared with the nonpregnant state. This period is called the anabolic phase. In late pregnancy, however, the maternal metabolic processes become more complicated because of the two-way interaction between the mother

The changes in nutrient metabolism can be described by several general concepts[8]: (a) adjustments in nutrient metabolism are driven by hormonal changes, fetal demands and maternal nutrient supply; (b) more than one potential adjustment exists for each nutrient; (c) maternal behavioural changes augment physiologic adjustment; and (d) a limit exists in the physiologic capacity to adjust nutrient metabolism to meet pregnancy needs, which when exceeded, fetal growth and development are impaired. Subsequently, metabolic adaptations, during pregnancy are essential [26]: 1, To ensure adequate growth and development of the fetus; 2, to provide the fetus with adequate energy stores and substrates that are needed following birth; 3, and, to provide the mother with sufficient energy stores and substrates to cope with the demands of pregnancy as well as those of labour and lactation. One of the maternal metabolic adjustments during pregnancy includes accumulation of fat depots in maternal tissues[26]. During this anabolic phase, the number of insulin receptors on the adipocytes increases, culminating into increased insulin sensitivity, increase lipoprotein lipase(LPL) activity which hydrolyses circulating triglycerides for tissue uptake, enhanced lipogenesis and marked maternal fat deposition(about 3.5 to 6.0kg) which is used as energy sources for the mother so that glucose is spared for the developing fetus in the catabolic part of the pregnancy[27, 28]. Lean women increase their fat stores more than obese women per kg body weight, likely due to higher insulin sensitivity in them, in early pregnancy, The important attributes of fat deposits during the anabolic phase in pregnant women are :(1) Hyperphagia, present in pregnant women and increases as gestational time advances. This progressive increase in the availability of exogenous substrates actively contributes to maternal accumulation of fat depots [29]; (2) Promotion of lipogenesis and suppression of lipolysis mediated by progressive increase in insulin and its sensitivity and enhanced by progesterone and cortisol [30]; (3) The proportional increase in adipose tissue lipoprotein lipase (LPL) activity [1,12,31) which hydrolyzes triglycerides(TGs) in form of TG-rich lipoproteins, chylomicron and very-low density lipoprotein(VLDL), which are respectively converted into remnant particles and intermediate-density lipoprotein (IDL). The hydrolytic products, non-esterified fatty acids(NEFA) and glycerol, are partially taken up by subjacent tissues [11, 12, 32, 33); (4) the unique capacity of tissue to utilize intracellularly the glycerol released during lipolysis. Under normal circumstances, the negligible glycerol kinase activity in adipose tissues hampers the utilization of glycerol for glycerol-3-phosphate synthesis and its use for the synthesis of TGs [34,35]. However, an increase in glycerol kinase activity and its subsequent capacity to metabolize glycerol has been found in rodents under condition of hyperinsulinaemia and enhanced fat accumulation, such as occurs in obesity [35, 36]. The lower lipolytic activity together with the augmented capacity of the tissues for the synthesis of glycerol-3-phosphate for uses in TG synthesis from both glucose and intracellular released glycerol results in net intracellular accumulations of TGs. Since all these pathways are stimulated by insulin, it is proposed that the enhanced insulin responsiveness [37] in the presence of an augmented response of the pancreatic β-cells to the insulinotropic stimulus of glucose that has been found in early pregnant women [38] would be the principal driving forces for the net fat depot accumulation at this stage of pregnancy. These ultimately lead to maternal fat accumulations in the anabolic phase of gestation.

The anabolic condition of adipose tissue during early pregnancy switches to a net catabolic state during the last 1/3 of gestation. The signals responsible for this switch from lipid storage to lipid mobilization are not well understood; however, placental hormones that increase with advancing gestation, known to induce maternal insulin resistance, may play a major role. Placental growth hormone, human placental lactogen, leptin, and tumour necrosis factor-α(TNF-α) are placental hormones that induce insulin resistance. The presence of high plasma levels of placental hormones, known to have lipolytic effects, human placental lipase (HPL), an augmented production of catecholamine secondary to maternal hypoglycemia [38], and the insulin-resistant condition present at this stage [39, 40], appear to be responsible for the net breakdown of maternal fat depots, consistently causing increments of plasma nonesterified fatty acids(NEFA) and glycerol levels during the 3rd trimester of gestation. The main destination of these lipolytic products released from maternal adipose tissue is the maternal liver. They are converted in the liver into their respective active forms, acyl-CoA and glycerol-3-phosphate, to become partially reesterified for the synthesis of triglycerides, which are transferred to native VLDL particles and released into the circulation. Acyl-CoA can also be converted throughout the βoxidation pathway to acetyl-CoA for energy production and ketone body synthesis, whereas glycerol may also be used for glucose synthesis. Fetal-placental glucose and amino acids

utilization rates are highest at 22 to 26weeks decreasing near term. In contrast lipid transport is maximal in the 3rd trimester coincident with rapid fetal fat accretion, this spares the mother to utilize glucose during this period. Humans are born with the highest percentage of fat (12 to 15%) compared to any species and 90% deposition occurs in the last 10weeks of gestation, exponentially increasing to 7g/day near term. The preferential use of glycerol released from maternal adipose tissue for gluconeogenesis acquire greater importance during maternal fasting period, when circulating glucose levels are lower than under nonpregnant conditions[34]. Under fed condition in early gestation, plasma ketone body values are even lower in pregnant than in nonpregnant condition [41], indicating an enhanced use of these fuels by maternal tissues as alternative substrate to glucose. However, during fasting period maternal ketogenesis become highly accelerated, as indicated by the exaggerated increase in plasma ketone bodies that occur [41]. This benefit the fetus in two ways: (1) ketone bodies are used by maternal tissues, thus, saving glucose for essential function and delivery to the fetus, (2) placental transfer of ketone bodies is very efficient, attaining the same concentration in fetal plasma as in maternal circulation[42]. In addition, ketone bodies may be used by the fetus as oxidative fuels as well as substrate for brain lipid synthesis [43].

Insulin is well known to inhibits adipose tissue lipolytic activity, hepatic gluconeogenesis and ketogenesis but to increases adipose tissue LPL activity. Thus, it is not surprising that all of these pathways change in the opposite direction which is consistent with insulin resistance occurring in later part of pregnancy. These pathways become even further modified under uncontrolled gestational diabetes mellitus(GDM), where insulin resistance is further enhanced [44].
