Perinatal triglyceride and cholesterol metabolic disturbances in newborn infants

Материал и методы. Проводили анализ анамнестических данных течения беременности у 217 беременных, на основании которых выставлялся высокий риск развития интранатальной гипоксии и рождения ребенка в тяжелом состоянии. Кроме оценки состояния ребенка при рождении, новорожденным проводили определение количества холестерина и триглицеридов в центральной венозной крови сразу после рождения и на 5-е сутки жизни.


Introduction
Alterations of cholesterol (LDL) and triglycerides (TG) synthesis in neonates is a serious issue of perinatology because in the early neonatal period the imbalance of lipid level in newborns contributes to respiratory failure.Cholesterol is an important component of cell membranes and intracellular organelles.Cholesterol significantly contributes to the lateral diffusion of lipids and proteins in the phase of lung surfactant (LS) organization.Triglycerides are a component of a lung surfactant and alteration of its components affect its functions that might significantly impact the premature and morphologically immature infants [1][2][3][4][5][6].
Postnatal metabolism depends on antenatal development of the child.Each period of antenatal development is characterized by certain patterns of lipid metabolism.Normally, fatty acids are transported to the fetus through placenta by erythrocytes and serum of the mother.The fetus produces ketone bodies from acetate beginning from the gestational age of 10 weeks.Lipid oxidation in the liver of the fetus is slow, and the production of ketone bodies and glycerophospholipids is reduced, however, there are all necessary enzymes required for the synthesis of cholesterol.The active form of acetic acid is the base matter for the synthesis of fatty acids, and it is not only synthesized in the body of the fetus, but also easily crosses the placenta.Although the activity of the enzyme β-hydroxy-β-methyl-glutaryl-COA reductase is not high, the fetus implements its need for cholesterol by 80%; 20% of cholesterol comes via placenta.The transport of lipids through placenta is limited.Lipid metabolism of the fetus is characterized by low activity of lipolysis.Lipogenesis is active in the liver of the fetus.Glucose and its metabolites are used for lipid synthesis of the fetus.The accumulation of cholesterol occurs during period of myelination and increasing the body weight.By the end of intrauterine development the total level of lipids in the body of the fetus can reach 8-16%.The compow w w .r e a n i m a t o l o g y .c o m DOI:10.15360/1813-9779-2015-6-28-37го развития общее количество липидов в организме плода может достигать 8-16%.Состав жирных кислот и фосфолипидов плода определяется их содержанием в организме матери [1,2,7].На концентрацию липидов крови плода, новорожденного влияют генетические факторы, характер питания матери, эндокринная регуляция, особенности маточно-плацентарного кровотока.Образование жировой ткани происходит за счет собственного синтеза липидов, т.к.их трансплацентарный переход от матери органичен.
Alterations of placentation, transplacental blood flow affect lipid metabolism.The most frequent complications of pregnancy are threatened abortion and preeclampsia.In case of preeclampsia a partial restructuring of the uteroplacental arteries is revealed in placenta during the first and the second waves of invasion of trophoblast into spiral arteries of the uterus, as well as the dysfunction of vascular endothelium.Endothelium dysfunction, involutive-degenerative changes, destruction of syncitio-trophoblast, massive fibrin-like deposits, inflammatory changes and decrease of metabolic processes cause fetal hypoxia, retardation of intrauterine growth, prenatal damage to the fetal tissues and preterm birth [8][9][10].Preeclampsia is characterized by anatomical and functional changes of placenta, which impairs transplacental blood flow and the fetus itself.Intrauterine growth retardation, dysfunction of gastrointestinal tract, depression of central nervous system in newborns in the early period of adaptation are associated with a decreasing of total lipids in blood [11].
Postnatal alterations in newborns from women with complicated pregnancies and in preterm infants cause changes of metabolism including triglyceride and cholesterol levels that represents scientific topic of our study.
The aim of the study: to evaluate the effects of course of pregnancy and delivery on parameters of lipid metabolism in the newborns and to compare the changes of triglyceride and cholesterol levels in neonates of different groups.

Materials and Methods
The analysis of the pregnancy course and its outcome for newborns was performed.The study included 217 women.232 newborns were delivered including 31 twins and 5 triplets.Vaginal delivery occurred in 33,8% of patients.In all other cases surgical cesarean cessation was performed, which was divided into planned (PCC) and emergency (ECC) cesarean cessation.The cases of emergence surgical delivery were divided into groups depending on the causes of the delivery and complications of pregnancy.Depending on the way of delivery the newborns were divided into following groups (Fig. 1): Group 1: neonates delivered vaginally.Group 2: neonates delivered via Gusakov's cesarean cessation.
Group 3: neonates delivered via Gusakov's cesarean cessation due to placenta previa, abruption of placenta or low placentation complicated by bleeding.
Group 5: neonates delivered via Gusakov's cesarean cessation due to other obstetrical indications.
The criteria for the inclusion into the study: complicated pregnancy and expected severe neonate's condition at birth.
Exclusion criteria: congenital malformations in newborns.
The following research methods were used: 1. Analysis of anamnestic data of pregnancy, based on which a high risk of intrapartum hypoxia and delivery of a neonate in a severe condition was predicted.
2. Clinical evaluation of the child at birth. 3. Measurement of lactate level in central venous blood immediately after the birth.
4. Measurement of cholesterol and triglyceride levels in central venous blood immediately after birth and on the day 5 of life.
5. Statistical data processing was performed using the program Statistica 6.0 (StatSoft, Inc.USA).Statistical processing of the data was performed using the methods of descriptive and variation statistics and non-parametric methods of estimation.The differences between groups were considered significant at P<0.01.

Results and Discussion
The mean age of the mothers was 29.4±6 years.The parity of delivery and pregnancy: the median pregnancy was 2 [1;4], the mean number of births was 1,7±0,9.All cases of pregnancy were complicated.
85.3 and 14.7% of pregnancies ended in premature birth and in-term birth, respectively.Anthropometric data of the newborns is presented in Table 1.The table shows, that the newborns of the 4th group 4 were premature.The newborns of the group 2 were close to full-term.They were delivered by planned cesarean cessation.The neonates born from mothers with placental abruption, preeclampsia and eclampsia were characterized by significantly lower gestational age and weight at birth (P<0.01)(groups 3 and 4).No significant differences in the first minute of life Apgar scale score were observed (P>0.01).Newborns at a high risk of respiratory distress syndrome (RDSN) were treated by surfactants Curosurf or Aveofact 3-5 minutes after birth.The average dose of Curosurf did not differ significantly between groups (P>0.01).The mean dose of Alveofact was 50 mg/kg.76 newborns (8 multiple pregnancies) were delivered as a result of vaginal delivery.Premature or early rupture of membranes, fast and swift delivery, delivery with uterine scar were observed in 57%, 7.1% and 2.9% of pregnant women, respectively.Cases of delivery in women with bicornuate or saddle uterus and in women with alcohol intoxication were also observed.The deliveries were complicated by retention of placenta parts; defects of the placenta were diagnosed in 15.7% of patients.In 85.5% and 14.5% of women clear amniotic fluid and meconium amniotic fluid, respectively, was observed.The distribution of newborns into groups by gestational age and body weight was as follows: full-term infants -23.7%, prematurity -76,3%.Twenty-six percent of newborns had a very low weight at birth (VLBW).Ninety-two percent of newborns had signs of acute intrapartum hypoxia at birth; they received full com-O r i g i n a l I n v e s t i g a t i o n s Преэклампсия и эклампсия (группа 4) остаются одной из актуальных проблем акушерства и гинекологии.Удельный вес данной нозологии в нашем исследовании составляет 17,6%.Все пациентки получали стационарное лечение, направленное на нормализацию артериального давления, биохимических показателей и гомеостаза матери, улучшение маточно-плацентарного кровотока, внутриутробной гемодинамики плода.Длительность лечения зависела от тяжести состояния пациентки, ответа на лечение и гемодинамического профиля плода.Относительная стабили-plex of initial resuscitation including intubation and mechanical lung ventilation (MLV) in the delivery room.Taking into account the high risk of ARDS development, 42% of preterm infants received surfactant replacement therapy in the delivery room.
Planned cesarean cessation was performed in 5 patients.The indications for surgical delivery included the scar on the uterus, the retention of intrauterine development with impaired transplacental blood flow, multiple pregnancy (triplets, in vitro fertilization).Seven infants were born.Three of them were born with severe respiratory insufficiency as an indication for MLV.Its duration was significantly shorter (P<0.01)compared to the newborns of other groups.
Placental abruption was the third place within the structure of complications.More than a half of the patients were taken into hospital due to placenta previa and other abnormalities of placentation.Placenta abruption was observed in 46.2% of women with normal placentation.Bleeding was the indication for early emergency delivery.Amniotic fluid contaminated with blood was observed in 59% of newborns.As a result, 44 pre-term deliveries including 4 twins and 1 triplet occured.A quarter of newborn were born with VLBW.Severe respiratory disorders, impaired oxygen status and altered metabolism were observed in 90.9% of neonates, whichwere under MVL..In 22.5% of cases high-frequency oscillator MVL was performed.Taken into account the high risk of RDSN, 54.5% of preterm infants were treated by replacement surfactants.
Preeclampsia and eclampsia remain among the most important challenges in obstetrics and gynecology.These diagnoses comprized 17.6% of all cases in this study.All patients received inpatient treatment in order to normalize blood pressure, biochemical parameters, and homeostasis of the mother, improve transplacental blood flow and intrauterine fetal hemodynamics.The duration of the treatment depended on the severity of patient's condition, response to treatment and hemodinamic profile of the fetus.Relative stability of the indicators allowed to prolong the pregnancy, however, all the newborns were delivered prematurely via emergency cesarean cessation.As a result, 41 premature infants, including 4 twins and 2 triplets, were born.In 39% of these newborns VLBW was diagnosed.In all cases the amniotic fluid was clear.Surfactant replacement therapy was conducted in 53,7% of the newborns.MLV was required in 70.7% of newborns.The main mode of lung ventilation was the controlled one.In 6,9% the newborns condition required high-frequency lung ventilation (HFLV) that was performed as needed.
Emergency cesarean cessation.The indications for emergency surgical delivery included abnormalities in the positon of the fetus, the primary weak-ness of labor contractions, discoordination of labor activity, and multiple pregnancy.As a result, 64 neonates were delivered including 13 twins and 2 triplets.VLBW was diagnosed in 12,5% of neonates at birth.Clear and meconium amniotic fluid was observed in 90.6% and 9.4% of patients, respectively.Only 15.6% of neonates did not require MLV, the rest of them (84.4%) received MLV in the mode of controlled ventilation (77.8%) and HFLV ( 22.2%).Surfactant replacement therapy was performed in 34.4% of the neonates.
Another important aim of perinatology is to provide professional care to newborns and most comfortable postnatal adaptation, especially in newborns of risk groups.Lipid metabolism, along with other kinds of metabolism, affects early and late postnatal adaptation of a newborn.The dynamics of triglycerides and cholesterol levels in studied groups of infants is shown in Fig. 2.
The newborns of groups 3 and 5 were characterized by significantly lower level of perinatal synthesis of triglycerides in plasma compared to the newborns groups 1, 2 and 4 (P<0.01),presumably due to the influence of antenatal hypoxia and metabolism disorders.In 38,6% of infants of group 3 triglyceride level was lower than 0,19 mmol/l.In two cases only trace quantity of triglycerides was observed.Each third child of group 5 possessed low concentration of triglyceride in plasma with a threshold concentration of 0.2 mM/l and lower.Correlation analysis demonstrated the following regression equations: • direct correlation of medium strength between the gestational age and the level of triglycerides in plasma at birth: r=0.48;P=0,00005; y=-0,666941249 + 0,0297279329*x.
By the 5 th day of life triglycerides synthesis in newborns of groups 3 and 5 did not differ significantly from the neonates of other groups and corresponded to physiological age values.Further research showed that triglyceride level in plasma of infants from group 1 was 0.44±0.3mM/l.The most critical indicators of triglyceride synthesis were observed in neonates with gestational ages 22-29 weeks and ELBWnot exceeding 0.01-0.2mmol/l.A significant increase of triglyceride level in blood occurred by day 5 of postnatal life.The rate of its growth in infants of this group significantly varied with a median of increase by 2.57 mmol/l [1,7; 4,7].The highest increase in triglyceride production in early neonatal period was observed in extremely premature new-born with ELBW compared to the mean values.The production of TG in the blood of these neonates was increased 5.1-9.9-fold.
The mean value of triglycerides in plasma at birth was 0.52±0.2and 0.51±0.4mmol/l in neonates of the groups 2 and 4, respectively, which was higher (P<0.01 compared to the neonates of groups 3 and 5 (P<0.01).At the end of the early neonatal period, the production of triglycerides increased significantly (P<0.01).The mean value of the indicator reached 0.98±0.4and 0.88±0.3mmol/l, respectively.The postnatal production of triglycerides in plasma is affected by gestational age.The smaller the gestational age was, the lower the triglycerides blood levels were as determined at birth and on day 5 of life.The data was confirmed with a correlation analysis.A direct correlation of medium strength between the gestational age and the concentration of triglycerides in plasma on day 5 of life was revealed.The following regression equation was obtained: r=0.6040;P=0.0132; y=-3.04448276+ 0.125734355*x.The body weight at birth is an important parameter.There цфs a direct correlation between body weight and the production of triglycerides in newborns in postnatal period (Fig. 3).
The levels of cholesterol at birth was significantly lower in infants of group 1 compared to the neonates of other groups (P<0.01) (Fig. 2).The amount of cholesterol increased significantly by day 5 of life(P<0.01)and reached physiological values.Cholesterol level in plasma at birth in children of the other groups did not vary significantly and was stable.Cholesterol synthesis increased significantly by day 5 of life (P<0.01).
Several common features were typical for all neonates and mothers included in the study.They included complications during pregnancy, prenatal and intrapartum hypoxia affect fetal and postnatal production of cholesterol and triglycerides.Perinatal synthesis of triglycerides was reduced in all neonates and depended on the way of delivery, gestational age, body weight at birth.The lowest triglyceride level at birth was typical of the newborns with ELBW, placenta previa and placental abruption.Placental insufficiency causes fetal hypoxia and the appearance of tissue degradation products in the bloodstream that possesed effect of endotoxins.These products of cell damage are capable to affect the endothelium of blood vessels of the placenta and fetus and worsen the alterations of blood circulation, metabolism, and hypoxia of the fetus [5,9].From the early gestational ages, the feto-placental complex plays an essential role in transferring steroid hormones from the mother's body to the fetus.Progesterone and estrogens are synthesized from cholesterol and phospholipids.Synthesized by the placenta from phospholipids and triglycerides, progesterone partially enters the adrenal glands of the fetus, as an intermediate stage of estriol and estrone formation.This process supports the synthesis of progestins, which ensure the prolongation of pregnancy [8,12].Alteration of placentation at early geststational ages causes an imbalance of lipid metabolism and synthesis of hormones, which increases the risk of premature birth.