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Obstetrics & Gynecology 2005;106:345-351
© 2005 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Increased Low-Density Lipoprotein Susceptibility to Oxidation in Pregnancies and Fetal Growth Restriction

Isabel Sánchez-Vera, PhD, Bartolomé Bonet, MD, PhD, Marta Viana, PhD, Amalia Quintanar, RN and Antonio López-Salva, MD, PhD

From the School of Medicine, Universidad San Pablo-CEU, Madrid, Spain; and the Departments of Pediatrics and Neonatology and of Obstetrics and Gynecology, Fundación Hospital Alcorcón. Madrid, Spain.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Objective: Atherosis and placental infarction have been observed in pregnancies complicated by fetal growth restriction (FGR). Low-density lipoprotein (LDL) oxidation plays a central role in the pathogenesis of atherosclerosis; therefore, it could be involved in the placental alterations observed in FGR. The aims of the present study were to estimate LDL susceptibility to oxidation in pregnancies complicated by FGR and to evaluate their relationship with fetal growth and placental hormone secretion.

Methods: A cohort prospective study was carried out in 50 women with uncomplicated pregnancies and 55 women with FGR. Blood was drawn at 15, 24, and 32 weeks of gestation. Low-density lipoprotein oxidation was initiated by the addition of CuCl2 and formation of conjugated dienes was monitored. Cholesterol, triglycerides, vitamin E, estradiol, progesterone, and placental lactogen were determined.

Results: Women with FGR showed a lag phase (minutes from addition of CuCl2) similar to the control group in the first trimester of pregnancy (85.3 ± 3.3 versus 81.3 ± 5.6). But in the second and third trimester, they showed a lower lag phase than the control group: 69.6 ± 3.6 versus 84.4 ± 3.5 (P < .05) and 69.9 ± 3.4 versus 95.6 ± 3.4 (P < .001). During the third trimester, pregnancies complicated with FGR showed lower levels of estradiol, progesterone, and human placental lactogen than those in the control group. In the third trimester, a positive correlation was found between the lag phase and the birth weight (P = .001) and with the plasma levels of estradiol (P = .002).

Conclusion: Fetal growth restriction is associated with an increased LDL susceptibility to oxidation, a process that could damage the placenta, leading to alterations in placental endocrine function and fetal weight. Pregnancies complicated by fetal growth restriction show an increased LDL susceptibility to oxidation, a process that may lead to placental dysfunction and growth delay.

Level of Evidence: II-2

Fetal growth restriction (FGR) is one of the most common complications of pregnancy.1,2 The etiology of FGR is multifactorial and includes congenital malformations, chromosomal alterations, and placental dysfunction.1,2 Placental dysfunction results in a decreased supply of oxygen and nutrients to the fetus and subsequent growth delay. A large number of these malnourished fetuses will not achieve a growth catch-up and will never reach the predicted parental height.

Atherosis in the decidual placental blood vessels and placental infarction are relatively common findings in placentas from pregnancies complicated by FGR.6,7 This condition may affect the transfer of oxygen and nutrients toward the fetus. Women with pregnancies complicated by FGR also have an increased rate of mortality, secondary to cardiovascular diseases,8,9 suggesting a common mechanism for both placental damage and atherosclerosis. Low-density lipoprotein (LDL) oxidation is a key step in the development of atherosclerosis and vascular diseases.10,11 During this process there is a generation of free radicals, lipid peroxides, and toxic compounds that may lead to vascular dysfunction, increased cholesterol uptake, foam cell formation, and cell toxicity. Studies performed in a placental cell culture model have shown that LDL oxidation is cytotoxic for placental cells, leads to cholesterol ester accumulation in both placental macrophages and trophoblast,14,15 and decreases the secretion of progesterone.15 Therefore, oxidized LDL in women with FGR may participate in the placental and vascular alterations observed under this condition and later on in life, leading to development of atherosclerosis and cardiovascular diseases. The aims of the present study were to estimate the LDL susceptibility to oxidation in pregnancies complicated by FGR and to evaluate the relationship between LDL oxidation and placental hormone secretion and fetal growth.


   MATERIALS AND METHODS
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ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The study was carried out from July 2000 to July 2003. During this time all women attending the obstetrics clinics of the Foundation Hospital Alcorcón were asked to participate in the study. Because in our institution we also follow emigrant women and because most of them do not speak Spanish fluently, only white women who spoke Spanish fluently were included in the study. In our institution under regular conditions, blood test are performed on all pregnant women at weeks 15, 24, and 32 of pregnancy when, respectively, the triple screening test, the O'Sullivan test, and different serologic determinations are obtained. A 15-mL sample of blood in ethylenediaminetetraacetic acid (EDTA, 1 mg/mL) was obtained from each women who volunteered to participate in the study, at least during one trimester of the pregnancy. The blood was drawn at the time of the regular laboratory test, so the study did not cause extra clinical visits or vein punctures in participating women. Plasma was separated by centrifugation at 3,500 revolutions per minute for 10 minutes and was divided into different aliquots. To preserve the LDL structure, one aliquot was stored in tubes containing sucrose, final concentration 0.5%, and used for LDL isolation. The remaining plasma was stored without any further treatment until the different metabolic and hormonal parameters were analyzed. All samples were stored at –40°C.

During this period, 6,082 women delivered in our institution, and we obtained one blood sample each from 1,152 of these women during one trimester. After delivery, the medical records of all women participating in the study were reviewed. Fifty-five of the women who volunteered to participate in the study during at least one trimester of pregnancy delivered a newborn with FGR, defined as birth weight below the 10th percentile for gestational age, according to the Spanish standard birth weight tables.16 Women with pregnancies that were complicated by gestational diabetes or preeclampsia or who gave birth to newborns with congenital malformations were excluded from the present study. Of the 55 women delivering a newborn with FGR, the diagnosis for 20 of them was performed before delivery during the prenatal ultrasound examination; 5 were considered type II FGR (asymmetrical) and 15 were type I FGR (symmetrical). In the remaining 35, the diagnosis was performed after birth. As a control group, we used 50 women who also participated in the study for all 3 trimesters of gestation and delivered healthy newborn infants with appropriate weight for gestational age and who did not present any complications during pregnancy or delivery. The study was approved by the Foundation Hospital Alcorcón Ethics Committee, and all the women participating in the study gave written informed consent at the time of blood extraction.

Low-density lipoproteins were isolated from EDTA-treated plasma obtained by ultracentrifugation following methods previously described in our laboratory17 and passed through an Econo-PacR 10-DG column (BioRad, Madrid, Spain) to remove EDTA and sucrose. Low-density lipoprotein concentration was determined immediately using the Lowry procedure,18 and aliquots of 0.1 mg of LDL protein/mL were incubated with CuCl2 (2.5 µM). The formation of conjugated dienes was determined as described by Esterbauer et al.19 In short, 1 mL of the LDL solution was incubated in a quartz cuvette at 37°C. Absorbance was read at 234 nm in a Beckman DU-640 spectrophotometer (Beckman Instruments, Fullerton, CA) every 10 minutes for a maximum of 4 hours or until the rapid phase of LDL oxidation reached a plateau. The lag phase was estimated as the incubation time corresponding to the intersection of 2 lines drawn from the changes in optical density: one through the initial, slowly rising curve, which corresponds to the utilization of the endogenous antioxidants, and the other, a subsequent, rapidly rising curve, which corresponds to the propagation phase of the LDL oxidation.19 The lag phase was expressed as minutes from the addition of CuCl2. The slope was determined by a linear regression and was expressed as µmol of conjugated dienes generated per minute.

Because most of the chemicals commonly used in the laboratory, including phosphate buffered saline, may contain metal ions as contaminants, all the solutions used in the experiments were treated with Chelex (iminodiacetic acid chelating resin; Sigma, Barcelona, Spain) to remove any metal traces. Triacyl-glycerol and cholesterol in plasma were measured using a commercial kit (Triglycerides Enzymatic Trinder Method; Menarini Diagnostics, Florence, Italy). The inter- and intra-assay coefficients of variation (CV) for all lipid measures were less than 3%. Estradiol and progesterone were determined by using the Vitros Auto Analyzer (Johnson & Johnson, Skillman, NJ). The inter- and intra-assay CV were less than 7% and less than 5%, respectively. Human placental lactogen (hPL) was determined by immunoenzymometric assay. The inter- and intra-assay CV were less than 8%. The detection limit of the assay was 0.15 µg/mL. Vitamin E in plasma was determined by high performance liquid chromatography, following methods previously described in our laboratory.17

Results are expressed as the mean ± standard deviation. The significance of the difference between the means of normal pregnancies and pregnancies complicated by FGR was obtained by using the Student t test. The difference among the 3 trimesters of the pregnancy was estimated by repeated measures of analysis of variance (ANOVA) in each group. Among the parameters that could affect LDL susceptibility to oxidation, such as cholesterol, triglycerides, and vitamin E, or among parameters that could be affected by the LDL oxidation, such as birth weight, the coefficient of linear regression was determined. In contrast, among the parameters that could affect the LDL susceptibility to oxidation or could be affected by oxidized LDL, the Pearson correlation coefficient was determined. Statistical analysis was performed with SPSS 11.5 (SPSS Institute, Paris, France).


   RESULTS
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ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Characteristics of the study subjects are shown in Table 1. No differences were observed in maternal age or the number of smokers between the group women with pregnancies complicated by FGR and the control group. The average number of cigarettes smoked per day ranged between 6 and 10. Early delivery was observed more often in women with FGR pregnancies than in the control group (Table 1). As expected, the birth weight was significantly lower in the FGR group. When the birth weight ratio was calculated according to gestational age and gender, the birth weight ratio in newborns from pregnant women complicated by FGR remained lower than in the control group (Table 1). We did not find any differences between the birth weight and the birth weight ratio in newborns with FGR, whether they were diagnosed in utero or after delivery. The group of women with FGR showed a higher number of female newborns than the control group.


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  		Table 1. Characteristics of Study Subjects

 

The initial body weight and the body mass index in women delivering a newborn with low birth weight was lower than in the control group (Table 2). The differences between both groups remained and increased throughout the pregnancy (Table 2) because the weight gain during the pregnancy was lower in the FGR group than in the control group (Table 2).


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  		Table 2. Comparison of Obstetric-Gynecological Factors Between Patients and Controls

 

In the first trimester of pregnancy, no differences in the plasma levels of cholesterol and triglycerides were observed between women with FGR and those in the control group (Table 3). Both groups showed the same increase in cholesterol and triglycerides throughout pregnancy. During the first trimester, women with FGR showed lower plasma levels of vitamin E than those in the control group. These differences disappeared in the following trimesters of gestation (Table 3). An increase in the plasma levels of estradiol, progesterone, and hPL was observed during pregnancy in both groups (Table 3). However, pregnancies complicated with FGR showed lower levels of estradiol, progesterone, and hPL during the second and third trimester than did those in the control group (Table 3).


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  		Table 3. Plasma Levels of Cholesterol, Triglycerides, Vitamin E, and Placental Hormones in the Study Subjects

 

In the first trimester of pregnancy, the lag phase in the formation of conjugated dienes was similar between women in the group with FGR and those in the control group (Fig. 1). In contrast, during the second and third trimester, marked differences were observed between both groups. In the control group, a trend toward a higher lag phase was observed as gestational age increased. But pregnancies complicated by FGR showed a decrease in lag phase as pregnancy advanced, reaching statistically significant differences between both groups during the second and third trimester (Fig. 1).



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  		Fig. 1. Lag phase in low-density lipoprotein oxidation in pregnant women with uncomplicated pregnancies (white bars) and complicated by fetal growth restriction (black bars). Values are expressed as the mean ± standard deviation. * Denotes differences between the control group and pregnancies complicated by fetal growth restriction (* P < .05; *** P < .001).

Sánchez-Vera. Oxidized LDL and Fetal Growth Restriction. Obstet Gynecol 2005.

 

When the lag phase was studied, dividing the women between nonsmokers and smokers, we did not find any differences in lag phase in LDL susceptibility to oxidation during the 3 trimesters of the study, either in the control group or in the FGR group (data not shown).

During the 3 trimesters of pregnancy, a negative correlation was observed between cholesterol levels and lag phase (r: 0.266, 0.391, and 0.328 during the first, second, and third trimesters, respectively, with P < .01 in the 3 trimesters). During the third trimester, a positive correlation was observed between lag phase and both estradiol (r: 0.433; P < .001) and progesterone (r: 0.415; P < .001). A positive correlation was found between lag phase and birth weight (r: 0.448; P < .001; Fig. 2) and the placental lactogen (r: 0.294; P < .05).



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  		Fig. 2. The linear regression between the lag phase in the low-density lipoprotein oxidation and the birth weight ratio is shown (r = 0.448; P < .001).

Sánchez-Vera. Oxidized LDL and Fetal Growth Restriction. Obstet Gynecol 2005.

 


   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Present results show an increased LDL susceptibility to oxidation during the second and third trimester in pregnancies complicated by FGR. A positive correlation has also been found between the lag phase of the LDL oxidation and birth weight. An enhanced LDL susceptibility to oxidation may increase LDL oxidation in the slow-flow, low-pressure circulation of the placental arteries and intervillous space, creating the optimal conditions for the LDL oxidation. This process may be involved in the placental and vascular alterations seen in pregnancies complicated by FGR because oxidized LDL may lead to cholesterol ester accumulation in the blood vessels of the decidua and to placental cytotoxicity.

In noncomplicated pregnancies, LDL susceptibility to oxidation decreases during the third trimester, despite the elevation of plasma levels of cholesterol to values associated with increased LDL susceptibility to oxidation in other conditions20,21 and to a high risk of cardiovascular diseases secondary to atherosclerosis. These results suggest that the pro-oxidant effects of hypercholesterolemia are blunted by other conditions. Estradiol is a powerful antioxidant, and plasma levels are markedly increased during pregnancy, reaching the highest values during the third trimester. In vitro, we have shown that estradiol antioxidant effects are dose-dependent,23 and present results show a positive correlation between plasma levels of estradiol and the lag phase of the LDL oxidation. Therefore, the decreased LDL susceptibility to oxidation observed during the third trimester of pregnancy could be secondary to the high plasma levels of estradiol. An imbalance between the pro-oxidant effects of hypercholesterolemia and the antioxidant effects of estradiol could be responsible for the increased LDL susceptibility to oxidation found in pregnancies complicated by FGR, where plasma levels of estradiol are lower than in the control group. A similar situation could be found during menopause, where the decreased levels of estradiol may be linked to a higher LDL susceptibility to oxidation and increased cardiovascular diseases secondary to atherosclerosis.

Present results suggest that the increased LDL susceptibility to oxidation observed in pregnancies complicated by FGR could be responsible for the placental dysfunction present in these pregnancies, as shown here by a decrease in plasma levels of estradiol, progesterone, and hPL. Previously, in a placental cell culture model, we have shown that cholesterol from oxidized LDL, despite being taken up by the placental trophoblast, is not used for progesterone hormone synthesis.15 However, what is even more relevant is that the placental damage caused by an increased LDL oxidation may also affect fetal growth. In fact, we have observed a positive relationship between the lag phase and newborn birth weight, suggesting a relationship between both processes.

Epidemiological studies have shown that women with pregnancies complicated by FGR have a higher risk of mortality, secondary to cardiovascular diseases.8 Low-density lipoprotein oxidation plays a central role in the development of atherosclerosis and cardiovascular diseases. Therefore, it is attractive to speculate that, in these women, under a stress condition, such as pregnancy hypercholesterolemia could be, LDL is more susceptible to oxidation and, therefore, to the development of atherosclerosis and cardiovascular diseases. In the present study, during the first trimester of gestation when the plasma levels of cholesterol were within the normal range, LDL susceptibility to oxidation was similar to that in the control group. In contrast, during the second and third trimester of gestation, when cholesterol levels show the highest levels, LDL susceptibility to oxidation increased in pregnant women with FGR, but not in those in the control group. This suggests that this group of women is more sensitive to the effects of hypercholesterolemia in the LDL oxidation process.

In the present study, we cannot rule out the possibility that a hypoxic-ischemic event resulting from other conditions may occur in the placenta, generating free radicals that induce LDL damage and increase LDL susceptibility to oxidation, as we show occurring in pregnant women delivering newborns with FGR. However, the fact that the increased LDL oxidation was already observed in the second trimester, before the diagnosis of FGR, suggests that LDL oxidation may occur first and that the damage produced by these process could be the cause of the placental damage and the FGR, rather than a consequence. It is possible that an initial hypoxic-ischemic event could damage the placenta and decrease the placental secretion of estradiol and progesterone, a phenomenon that will increase the LDL susceptibility to oxidation, exacerbating the hypoxic-ischemic event, and leading to a vicious cycle.

There is evidence that fetuses with FGR are at a higher risk for developing cardiovascular diseases later on in life.25 Maternal factors, such as hypercholesterolemia, can increase the risk of developing fatty streaks in the fetus26,27 and accelerated progression of atherosclerosis during childhood.26 A maternal increased LDL oxidation may lead to the fetal transfer of lipid peroxides, which may play a role in the development of fatty streaks and to in utero programming for changes that could later on facilitate the development of cardiovascular disease. In fact, lipid peroxide products have been shown in human fetal arteries,28,29 suggesting a role for oxidative stress in this process. Therefore, the maternal LDL oxidation may not only damage the placenta, but also the fetal arteries, with potential consequences later on in life.

In summary, our results show that pregnancies complicated by FGR have an increased LDL susceptibility to oxidation that may lead to placental dysfunction and growth delay. Therefore, LDL oxidation should be included among the different etiologies of FGR. Pregnancies complicated by FGR might have consequences later on in life, both for the mother and the fetus, increasing the risk of developing cardiovascular diseases. If present results are confirmed in larger studies, the administration of antioxidants may constitute a new therapy for the treatment and prevention of FGR and the associated complications.


   Footnotes
 
This work was supported by Grants From the Spanish Ministry of Health (FIS 00/0304 and 02/1731) and the University San Pablo-CEU (14/01).

The authors thank Elena Arranz, Mercedes Page, and José Manuel Gasalla for their technical assistance.

Corresponding author: Dr. Bartolomé Bonet, Department of Pediatrics and Neonatology, C/ Budapest 1. Alcorcón 28922, Madrid, Spain; e-mail: bbjbonet{at}fhalcorcon.es.

doi:10.1097/01.AOG.0000171112.95083.86


   REFERENCES
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ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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