Maternal first and second trimester lipid levels in patients with different glucose tolerance

Objective

Fetal growth is a diverse process affected by genetic, demographic and metabolic factors. In diabetic patients strict glycemic control does not always prevent macrosomia. This suggests that fuels other than glucose such as lipids and aminoacids also contribute to fetal weight gain. The purpose of this study was to determine maternal lipid levels in patients with different glycemic status.

Methods

This prospective study was conducted at Adana Research and Application Hospital of Başkent University between December 2009 and July 2011. Blood samples were drawn to measure fasting blood glucose, serum triglycerides, cholesterol, VLDL, LDL, HDL and hemoglobin at the first and second trimesters. When 50 g oral glucose intake was 135 mg/dl or above, the patients had a 100 g oral glucose tolerance test. The patients were divided into three groups as normal glucose tolerance (NGT, n=333), impaired glucose tolerance (IGT, n=115), and gestational diabetes mellitus (GDM, n=156).

Results

In the first trimester, triglycerides (NGT, 104.5±54.2; IGT, 104.6±43.5; GDM, 128±63), cholesterol (NGT, 170.2±37.9; IGT, 171.6±32.4; GDM, 180.2±37.2) and VLDL (NGT, 21.4±12.8; IGT, 20.8±8.7; GDM, 25.8±12.7) were higher in GDM group when compared to NGT and IGT groups (p<0.05).

Conclusion

This study revealed that lipid levels can be different depending on differences in glucose tolerance.

Keywords

Diabetes, glucose tolerance, lipid, pregnancy.

Introduction

Fetal growth is a diverse process affected by genetic, demographic and metabolic factors.[1] Impaired glucose metabolism has been proven to affect fetal growth in a linear fashion.[2,3] Even minor degrees of impaired glucose tolerance, as demonstrated by single elevated level of glucose in 100 g glucose tolerance test, are associated with macrosomia.[4] Although poor glycemic control is commonly associated with accelerated fetal growth,[5,6] strict glycemic control does not always prevent macrosomia, particularly in overweight women.[7] This suggests that fuels other than glucose such as lipids and aminoacids also contribute to weigh gain.[8]
Pre-pregnancy body mass index (BMI), weight gain during pregnancy, glucose tolerance and triglycerides are reported to be associated with infant birth weight.[9] These variables are also interrelated. They affect each other.
The purpose of this study was to determine maternal lipid levels during first and second trimesters in patients with different glycemic status.

Methods

This prospective study was conducted at Başkent University Adana Research and Application Hospital between December 2009 and July 2011. Women with singleton pregnancies were approached at the first antenatal visit in first trimester. Smoking women, women with pre-gestational diabetes, thyroid and hypertensive disorders, lupus and anti-phospholipid syndrome, multiple pregnancies, and pregnancies with structural fetal abnormalities, or aneuploidy were excluded in order to eliminate the influence of these conditions or diseases on lipid metabolism and infant birth weight. There were no women using anti-lipidemic drugs. Written informed consent was obtained from patients prior to the enrollment. The study was approved by the local ethics committee.
At the first admission, after an overnight fast, blood samples were drawn to measure fasting blood glucose, serum triglycerides, cholesterol, very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), high density lipoprotein (HDL) and hemoglobin. During 24th-28th weeks of gestation, a fasting blood was drawn for the same parameters and the patients had 50 g oral glucose challenge test. When blood samples taken one hour after 50 g oral glucose intake showed glucose of 135 mg/dl or above, the patients had a 100- g oral glucose tolerance test (OGTT). Carpenter- Coustan criteria were used to diagnose gestational diabetes mellitus (GDM).[10]
When two or more of the plasma glucose measurements met or exceeded the following thresholds, the diagnosis of GDM was confirmed: fasting plasma glucose=95 mg/dl, one hour plasma glucose=180 mg/dl, two hour plasma glucose=155 mg/dl and three hour plasma glucose=140 mg/dl. When the patients had 50 g OGTT <135 mg/dl, they were included in normal glucose tolerance (NGT) group. When the patients had 50 g OGTT ≥135mg/dl, but the 100 g OGTT glucose levels were normal, or when they had a single elevated glucose level at 100 g OGTT, they were included in impaired glucose tolerance group (IGT). Blood glucose, triglycerides, cholesterol and HDL were determined by enzymatic calorimetric assay (oxidase). VLDL and LDL cholesterol were calculated by Friedewald formula: LDL-C= (total-C)-(HDL-C)-(VLDL-C) VLDL-C (mg/dl) = triglyceride (mg/dl)/5. All tests were performed by Hitachi 912 analyzer (Roche Diagnostics, Mannheim, Germany).
Gestational age was calculated on the basis of the last menstrual period and was confirmed by the measurement of crown rump length (CRL) in the first trimester. Obstetricians performed sonographic evaluations using Voluson 730 (GE healthcare, Milwaukee, WI, USA) equipped with abdominal transducers of 5-9 MHz. CRL was measured during 11th-14th gestational weeks. The calibers were placed starting from the most cephalic to the most caudal pole. This was converted to the gestational weeks by Hadlock et al.’s formula.[11] The difference between measured and expected fetal ages was expressed in gestational weeks as delta CRL (∆ CRL). BMI was calculated based on the self-reported pre-pregnancy weight and height. Weight gain was calculated by subtracting weight before pregnancy from weight before delivery. All patients were followed up until delivery and delivered at our institution. Data regarding the birth weights were derived from the hospital records.
Maternal hyperlipidemia was defined as a value higher than the 75th percentile of each lipid concentration. Women with gestational diabetes were followed up with endocrinology clinic. Patients were put on a diet and exercise program was recommended. Patients were called 3 weeks later and insulin was commenced according to the fasting and postprandial blood sugar level. All patients were regularly followed up until delivery and insulin doses were adjusted according to the blood sugar.
Numerical variables were evaluated for normality of data by using Kolmogorov-Smirnov test. One way analysis of variance (ANOVA) or Welch ANOVA was performed to compare the differences between the groups. Welch ANOVA was used when homogenity of variance was not satisfied. Chi-square test was used for the analysis of categorical variables. Power analyses were made to detect differences in lipid levels between the glucose tolerance groups by using NCSS-PASS 2007 program for this study. Power of the study was found to be 75%. Data were expressed as means ± standard deviation (SD) or percentages where appropriate. p<0.05 was considered statistically significant. SPSS for Windows (version 17.0; SPSS, Inc., Chicago, IL, USA) was used for statistical analyses.

Results

During the study period 2383 women delivered at our institution between December 2009 and July 2011. Among these patients the incidence of GDM was %6.5. Because our hospital is a reference hospital seven hundred and ninety-three women admitted to our clinic at the first trimester had all the data thus were included in the study. Seventy-eight women had abortion [spontaneous abortions (53), fetal anomaly (8), intrauterine exitus (17)] and 56 women were lost to follow up. Fifty-five women were excluded because of hypertension [preeclampsia (23), pregnancy induced hypertension (32)]. Thus a total of 604 women were studied. Data about 333 patients with NGT, 115 patients with IGT, and 156 patients with GDM were analyzed.
Maternal and fetal characteristics and data regarding the first trimester scan and maternal serum markers are given in Table 1. Mean maternal age, pre-pregnancy BMI and weight gain during pregnancy were similar in NGT and IGT groups. However, the patients were significantly older (p<0.05), pre-pregnancy BMI was significantly higher (p<0.05) and weight gain was lower in GDM group (p<0.05). The distribution of nulliparity was similar in all groups. The mean CRL, NT, free b-hCG and PAPP-A MoMs were similar in all groups. Gestational age at delivery was similar in IGT and GDM groups and was significantly lower than the NGT group (p<0.05).
Fasting blood glucose and serum lipid levels in patients with different glucose tolerance are given in Table 2. In the first trimester fasting blood glucose were similar in NGT and IGT groups and significantly higher in GDM group (p<0.05). Fasting blood glucose was similar in all groups in the second trimester. In the first trimester, triglycerides were higher in GDM group when compared to NGT and IGT groups (p<0.05). In the second trimester, triglycerides were similar in IGT and GDM groups and significantly increased when compared to NGT group (p<0.05). In the first trimester, cholesterol levels were higher in GDM group (p<0.05) when compared to NGT and IGT groups. In the second trimester, cholesterol levels were similar in all groups. In the first trimester, VLDL levels were higher in GDM group when compared to NGT and IGT groups (p<0.05). In the second trimester, VLDL levels were similar in all groups. In the first trimester, LDL levels were similar in IGT and GDM groups and were significantly higher in NGT group than in the other groups (p<0.05). In the second trimester, LDL levels were similar in all groups. In the first trimester, HDL levels were similar in all groups. In the second trimester, HDL levels were significantly lower in GDM group than in NGT and IGT groups (p<0.05). The distribution of hyperlipidemia according to glucose tolerance is given in Table 3. The frequency of having hypercholesterolemia was similar for all groups in first and second trimester. In the first trimester, hypertriglyceridemia was significantly more common in GDM group when compared to IGT (p<0.05). IGT group also had significantly higher levels of triglycerides than NGT (p<0.05). In the second trimester, GDM and IGT groups had significantly more frequent hypertriglyceridemia when compared to NGT group (p<0.05). In the first trimester, VLDL and LDL levels in the upper quartile were significantly more common in GDM group than in NGT (p<0.05). The frequencies of VLDL and LDL hyperlipidemia in the upper quartile were similar in all the groups in the second trimester. The frequency of HDL hyperlipidemia in the upper quartile was similar in first and second trimesters in all groups.

Discussion

This study revealed that lipid levels can be different depending on differences in glucose tolerance. In all groups, triglycerides, cholesterol, and other lipoproteins increased from first to second trimester, consistent with the other studies.[12] This happens as a result of estrogen enhanced hepatic production of VLDL triglycerides,[13] increased intestinal absorption of dietary lipid, reduced clearance of triglycerides and decreased extrahepatic lipoprotein lipase activity[14] and increased insulin resistance in pregnancy.[15]
There are contradictory information in the literature about the lipid levels of pregnant patients. We found a significantly higher triglyceride concentration in GDM group compared to the other groups in first trimester. In the second trimester, triglycerides increased in IGT group more than in NGT, and were significantly higher in GDM and IGT groups compared to NGT. In GDM group compared to NGT group triglycerides are reported to be unchanged[17-21] or increased[9] in first trimester and increased in second trimester.[16,22,23] Toescu et al. reported that triglycerides start to increase at an earlier gestational age in GDM.[21] We demonstrated that in patients with GDM triglycerides start to increase as early as first trimester. Increased triglycerides in GDM group in our study may result from insulin resistance which is present even at first trimester. In diabetic pregnancies triglycerides are increased with worsening glycemic control.[24] In IGT group probably insulin resistance becomes more prominent in second trimester, causing a triglyceride level close to GDM at this gestational age. Previous studies reported cholesterol to be elevated[22] or unchanged[17-19] in first trimester or unchanged,[16,17] higher[22] or lower[23] in second trimester. In contrast, we found significantly elevated cholesterol in GDM group compared to the other two groups in first trimester. Cholesterol level was similar in the second trimester in all groups, as reported by Tarim et al. before.[16]
Very low-density lipoprotein is higher in diabetic patients with poor metabolic control compared to those with good metabolic control[21] in GDM patients when compared to NGT patients and when compared to patients with good glycemic control.[16] We demonstrated that in patients with GDM VLDL levels are increased even in the first trimester. A significantly higher LDL score is reported in diabetic women compared to the non-diabetic group.[21] Other studies reported LDL to be lower.[22,23] or unchanged[17,19] in patients with GDM. In our study, LDL was higher in IGT and GDM groups compared to NGT group in first trimester. The excess triglyceride, cholesterol, VLDL and, LDL in GDM group may result from overproduction induced by pregnancy and decreased catabolism related to deficient LPL activity because of insulin resistance.
Fasting blood glucose is significantly higher in the first trimester in the patients who are destined to develop GDM. However, it does not discriminate patients who will have NGT or IGT in the second trimester. In second trimester, fasting blood glucose of all groups was similar which may result from good glycemic control in women with GDM. There are studies which reported similar[16] or higher blood glucose[6] during second trimester in GDM compared to normal or impaired glucose tolerant women. Maternal age, pre-pregnancy BMI, and weight gain during pregnancy have potential to influence lipid levels. GDM group had a significantly greater mean maternal age. This may be due to worsening of glucose intolerance with age.[25] At the beginning of the pregnancy, BMI was higher in patients with GDM concordant with the other studies.[7,16,21] GDM group gained significantly less weight probably due to the low calorie diet they consumed.
Hypertriglyceridemia is one of the major characteristics of insulin resistance syndrome in non-pregnant adults.[26] Our study demonstrated that the frequency of having hyperlipidemia gradually increases with increasing glucose intolerance. Triglycerides, VLDL and LDL over the 75th percentile was more commonly seen in GDM group; however, among these, only hypertriglyceridemia continued to be more common in second trimester in GDM group. Fuels other than glucose such as lipids and aminoacids suggested to effect fetal weight because strict glycemic control does not always prevent macrosomia.[7] In this study, despite strict glycemic control and increased triglycerides, fetal weights were similar.
Impaired glucose tolerance and increased serum lipid levels increase future cardiovascular risk.[27] First trimester fasting blood glucose and lipids are significantly increased in patients who will develop GDM when compared to women who will remain normotolerant. First trimester LDL levels are increased in patients who will develop GDM and IGT. Patients carrying a future cardiovascular risk can be identified at the first trimester. Differences are less prominent in the second trimester. Only triglycerides are increased in patients with GDM. HDL has anti-inflammatory characteristics.[27] While HDL is similar in all groups in the first trimester, it is significantly decreased in the second trimester in patients with gestational diabetes. The decrease in HDL levels may be responsible for the increased cardiovascular risk.

Conclusion

Even minor alterations in blood glucose affect serum lipid levels. However, there are many parameters which can affect serum lipid or birth weight and cannot be controlled at all times. Normalization of blood glucose and serum lipids is the primary goal for healthy pregnancy.

References

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	File/Dsecription
	Table 1. Maternal and fetal characteristics and data regarding the first trimester scan and maternal serum markers.
	Table 2. Blood glucose and serum lipid levels in patients with different glucose tolerance.
	Table 3. Frequency of hyperlipidemia among different glucose tolerance groups.