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American Journal of Clinical Nutrition, Vol. 70, No. 1, 53-61, July 1999
© 1999 American Society for Clinical Nutrition

Original Research Communications

Maternal plasma phospholipid polyunsaturated fatty acids in pregnancy with and without gestational diabetes mellitus: relations with maternal factors1,2,3,4

Vasuki Wijendran, Robert B Bendel, Sarah C Couch, Elliot H Philipson, Kate Thomsen, Xuefei Zhang and Carol J Lammi-Keefe

1 From the Departments of Nutritional Sciences and Animal Sciences, University of Connecticut, Storrs, and the Department of Obstetrics and Gynecology, Hartford Hospital, Hartford, CT.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The fatty acids arachidonic acid (AA; 20:4n-6) and docosahexaenoic acid (DHA; 22:6n-3) are essential for fetal growth and development, but their metabolism may be altered in insulin resistance.

Objectives: The objectives were to determine maternal plasma phospholipid polyunsaturated fatty acid concentrations in pregnant women receiving dietary therapy for gestational diabetes mellitus (GDM) and to identify maternal factors associated with plasma phospholipid AA and DHA concentrations in the third trimester.

Design: Fasting plasma phospholipid fatty acids were determined in women with GDM (n = 15) receiving dietary therapy only and in healthy, pregnant women without GDM (control group, n = 15) at 27–30, 33–35, and 36–39 wk gestation.

Results: Maternal plasma phospholipid (as % by wt of total fatty acids and mg/L) linoleic acid (18:2n-6), AA, and 22:5n-6 concentrations did not differ significantly between women with GDM and control subjects. The other n-6 long-chain polyunsaturated fatty acids (% by wt) were lower in GDM subjects than in control subjects. Plasma phospholipid (expressed as % by wt and mg/L) linolenic acid (18:3n-3) and summed precursors of DHA were lower and DHA (% by wt and mg/L), adjusted for dietary DHA intake, was 13% higher in GDM subjects than in control subjects. Maternal blood hemoglobin A1C was inversely related to plasma phospholipid AA (% by wt) (r = -0.56, P = 0.03) in control subjects and positively associated with plasma phospholipid AA (% by wt) in women with GDM (r = 0.76, P = 0.001). Pregravid body mass index was negatively associated with plasma phospholipid DHA (% by wt) in control subjects (r = -0.55, P = 0.04) and in women with GDM with a body mass index (in kg/m2) <30 (r = -0.76, P = 0.007).

Conclusions: This is the first report documenting alterations in maternal plasma phospholipid PUFAs in pregnant women receiving dietary therapy for GDM. In pregnant woman, both with and without GDM, maternal glycemic control and pregravid BMI appear to be significant predictors of plasma phospholipid AA and DHA, respectively, during the third trimester. Additionally, dietary DHA significantly affects phospholipid DHA concentrations.

Key Words: Docosahexaenoic acid • arachidonic acid • insulin resistance • gestational diabetes mellitus • pregnancy • glycemic control • body mass index • long-chain polyunsaturated fatty acids • phospholipids • women


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The n-6 and n-3 long-chain polyunsaturated fatty acids (PUFAs) are essential for optimum fetal growth and development. Arachidonic acid (AA, 20:4n-6) influences fetal (1, 2) and preterm infant (3) growth. Docosahexaenoic acid (DHA, 22:6n-3), a major component of the developing central nervous system, is essential for cognitive and visual functions (4–6).

During the perinatal period, maternal supplies of AA and DHA are likely the major source of long-chain PUFAs (7, 8), determining fetal essential fatty acid and long-chain PUFA accretion. Holman et al (9) reported that pregnant women in North America had lower plasma phospholipid PUFAs (% by wt) at term and delivery than did nonpregnant women. Further, a trend for lower plasma phospholipid AA and DHA values (% by wt) during the third than during the first trimester was reported for pregnant women in the Netherlands (10). Although these studies (9, 10) provide evidence for compromised PUFA status in pregnancy, there is limited information on the maternal factors that influence essential fatty acid metabolism during gestation. Presumably, maternal dietary intake of long-chain PUFAs, particularly AA and DHA, is an important determinant of maternal fatty acid status in pregnancy (2). However, data on the usual intake of n-6 and n-3 long-chain PUFAs by pregnant women in North America are limited (11).

Additionally, factors that regulate the synthesis of long-chain PUFAs from the precursors linoleic acid (LA;18:2n-6) and {alpha}-linolenic acid (LNA; 18:3n-3) also influence maternal PUFA status in gestation. Some studies have shown that insulin sensitivity and adiposity are independent factors influencing enzyme activities that regulate essential fatty acid metabolism (12, 13). In pathologies characterized by insulin resistance, hyperglycemia, or both—eg, type 1 diabetes (14, 15), obesity (13), and cardiovascular disease (16)—impaired {Delta}5-desaturase, {Delta}6-desaturase, and elongase activities are evident.

Gestational diabetes mellitus (GDM) is a pathologic condition in which abnormal glucose tolerance is recognized for the first time in pregnancy (17). It affects up to 5% of all pregnancies (17). GDM is associated with poor perinatal outcome (18) and for the mothers it is a risk factor for development of type 2 diabetes later in life (19).

Decreased insulin sensitivity combined with insufficient insulin secretion in GDM result in exaggerated glucose intolerance and alterations in lipid metabolism (20). Hyperglycemia and hyperlipidemia, predominantly elevated VLDL triacylglycerol and increased plasma fatty acids, are common symptoms in the third trimester of pregnancies complicated with GDM (20–22). Therefore, it is suggested that GDM is a component of the syndrome of insulin resistance (20). Insulin resistance coupled with perturbations in general lipid metabolism in GDM may affect essential fatty acid metabolism. This could have important implications for fetal growth and central nervous system development.

The objectives of the present study were to 1) describe alterations in maternal plasma phospholipid PUFAs in the third trimester in pregnant women with or without GDM, and 2) identify maternal factors associated with plasma phospholipids long-chain PUFAs, especially AA and DHA, during gestation.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
Women with GDM (n = 15) and healthy pregnant women (n = 15) were recruited from the Department of Obstetrics and Gynecology at Hartford Hospital. The protocol was approved by the University of Connecticut and Hartford Hospital Human Subject Approval committees and written, informed consent was obtained from all subjects. In accordance with the usual procedure followed at Hartford Hospital, all subjects underwent a screening test for GDM between 24 and 30 wk gestation, which involved an oral challenge with 50 g glucose. A positive screening result (1-h plasma glucose concentration >=7.77 mmol/L) was followed by a 3-h oral-glucose-tolerance test. Women with GDM were identified according to the oral-glucose-tolerance test criteria of O'Sullivan and Mahan (23) and the recommendations of the National Diabetes Data Group (17). Briefly, women with positive screening results were administered 100 g of an oral glucose load and then fasting and 1-, 2-, and 3-h plasma glucose concentrations were determined. GDM was diagnosed in women who had >=2 plasma glucose concentrations that met or exceeded the following criteria (17, 23): 5.83 mmol/L (fasting), 10.55 mmol/L (1 h), 9.16 mmol/L (2 h), and 8.05 mmol/L (3 h), Healthy, pregnant women with negative screening test results (plasma glucose <7.77 mmol/L) were recruited as control subjects. Women with hypertension, hyperlipidemia, renal or liver diseases, thyroid disorder, multiple gestations, or parity >5 and women with GDM who required drugs or insulin therapy to achieve glycemic control were excluded from the study. Women with GDM in this study were treated with diet only. Control subjects and women with GDM were enrolled in the study between 27 and 30 wk gestation.

Study design
The study was longitudinal in design. In accordance with the standard clinical protocol at Hartford Hospital, women with GDM were referred to the Diabetes Lifecare Center at Hartford Hospital for dietary counseling. The dietary recommendations were those of the American Diabetes Association for normal pregnancy (24): {approx}45% of the daily energy intake was from carbohydrate, {approx}22% was from protein, and {approx}33% was from fat, divided among 3 meals and 3 snacks over the day. Maintaining a consistent state of euglycemia (a fasting blood glucose concentration <=5.27 mmol/L and a 2-h postprandial glucose concentration <=6.66 mmol/L) was the goal of the dietary therapy. Antepartum glucose control was monitored by measuring glucose in finger-prick capillary blood samples.

All subjects were scheduled for 3 antenatal visits during the third trimester at 27–30, 33–35, and 36–39 wk gestation. Maternal plasma phospholipid fatty acid, fasting plasma insulin, and blood glycated hemoglobin (Hb A1C) concentrations were determined at each visit. Data on dietary PUFA intake and maternal body weight were also collected at each visit.

Data collection
Antenatal study visits were scheduled in the morning after an overnight fast. At each visit, maternal fasting blood ({approx}5 mL) was collected from the antecubital vein into EDTA-containing tubes. Plasma was separated by centrifugation (1500 x g at 4°C for 10 min), portioned, and stored at -80°C until analyzed for phospholipid fatty acids and plasma insulin.

Three 24-h dietary recalls were obtained from all subjects to estimate the intake of macronutrients and individual fatty acids during the third trimester. At each visit, a complete record of all foods consumed by the subjects on the previous day, as recalled by the subjects, was obtained. The repeated recalls were coded and analyzed by using the University of Minnesota NUTRITION DATA SYSTEM (NDS 2.91; Minneapolis).

Maternal body weight was measured at each visit, with subjects wearing light clothing and no shoes, with a digital 5005 Stand-On-Scale (Scale-Tronix, Inc, White Plains, NY). Prepregnancy weights, maternal heights, and fasting blood glucose concentrations during the third trimester of gestation were obtained from the hospital records. For control subjects, fasting blood glucose values were available only at 27–30 wk gestation.

Sample analysis
All solvents used in the analysis of plasma phospholipid fatty acids contained 0.01% butylated hydroxytoluene. Total lipid was extracted from plasma by a modified Folch procedure (25, 26) by using 2:1 (by vol) dichloromethane:methanol and washed with 0.6% NaCl to remove impurities. The extract was dried under vacuum, dissolved in a minimum amount of dichloro-methane, and applied to thin-layer silica gel plates. Plates were developed in 90:30:2 petroleum ether:diethyl ether:acetic acid (by vol) to separate phospholipids, fatty acids, triacylglycerols, and cholesteryl esters. The phospholipid band at the point of origin was scraped and eluted with 2:1 dichloromethane:methanol. Fatty acid methyl esters (FAMEs) were prepared by transesterification with 2 mol KOH/L in methanol. Before the methylation of phospholipid PUFAs, 10 µL of 17:0 standard (2 g/L heptane) was added as an internal standard to determine the absolute concentration (mg/L) of plasma phospholipid fatty acids. FAMEs were separated with a Hewlett-Packard 6890 gas chromatograph (Wilmington, DE) equipped with an Omegawax 250 capillary column (30 m x 250 mm x 25 µm; Supelco, Bellefonte, PA). The oven temperature was programmed from 190 to 210°C at a rate of 2°C/min with a final hold of 10 min to separate 12:0 to DHA FAMEs. The injector and detector temperatures were maintained at 250 and 280°C, respectively. Helium flow was maintained at 1.0 mL/min and the inlet split ratio was maintained at 1:50. External standards (containing FAMEs 12:0 to DHA; Matreya Inc, Pleasant Gap, PA) were run with each set of samples. Plasma phospholipid FAMEs were identified by comparison with external standards and expressed as relative weight (% by wt) and absolute concentration (mg/L).

Fasting plasma samples were analyzed in duplicate for insulin by using the ultrasensitive human insulin radioimmunoassay kit (Linco Research, Harvester, MO). Blood Hb A1C was determined at the clinical chemistry laboratory at Hartford Hospital by using the Diamat Analyzer System (BioRad, Hercules, CA), an automated HPLC assay.

Statistical analysis
All statistical analyses were performed by using SAS software (27). Variables that were not normally distributed were log transformed to approximate normality by the Shapiro-Wilk test (P >= 0.05). Student's t tests were used to determine significant differences between the group means for the descriptive data, age, parity, pregravid body mass index (BMI; in kg/m2), fasting blood glucose, and mean dietary fatty acid intake. A two-factor repeated-measures analysis of variance (ANOVA) using PROC GLM was used to assess group differences in weight gain during pregnancy, fasting plasma insulin, and Hb A1C. A two-factor repeated measures ANOVA, using the PROC GLM and PROC MIXED procedures, was used to determine group and time effects on fatty acids. Because the study had a repeated-measures design, with correlated observations corresponding to the 3 time points for each subject, a test of sphericity was run to verify that the assumptions of equal variance and equal correlations were satisfied (P >= 0.05). Group and time effect means were estimated by using the least-squares means procedure in PROC GLM. SEs were obtained with the PROC MIXED procedure.

The repeated-measures analysis of covariance (ANCOVA) was performed to compare the group and time effect means after adjustment for the covariates. Potential covariates were identified by using Pearson correlation analysis to assess the association between fatty acids and covariates and by using a Student's t test and a two-factor repeated-measures ANOVA to compare covariate group means. The association of mean maternal fatty acid intake with mean maternal phospholipid fatty acids was estimated by Spearman rank correlation. Hb A1C, pregravid BMI, fasting plasma insulin concentration, and mean dietary PUFA intake were identified as significant covariates. The assumptions of linearity and homogeneity between the groups for the covariates were checked by the plot of residuals versus covariates and by the test of homogeneity of slopes between the groups. Simple and multiple (forward stepwise) regression analyses were performed to study the association of independent maternal factors with maternal long-chain PUFA concentrations. The effect of prepregnancy BMI on fatty acids was studied further by categorizing women into 4 BMI classes (28) and by using a three-factor repeated-measures ANOVA, in which BMI and group were the between-subject factors and time was the within-subject factor.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Maternal characteristics
Maternal characteristics of the study population are given in Table 1Go. Women with GDM were significantly older and gained less weight than did the control subjects. Mean fasting plasma insulin and Hb A1C concentrations were significantly higher in women with GDM than in control subjects during the third trimester of gestation. Hb A1C increased significantly between 27–30 and 36–39 wk gestation in both groups.


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  		TABLE 1. Maternal characteristics of the study population1,
 
Plasma phospholipid fatty acids in women with GDM and control subjects
Maternal plasma phospholipid fatty acids (% by wt and mg/L) are given in Table 2Go and summed plasma phospholipid fatty acids and indexes in control subjects and women with GDM during the third trimester of gestation are shown in Table 3Go. The major n-6 PUFAs (>=18 carbons) in phospholipids, LA and AA (% by wt and mg/L), did not differ significantly between the 2 groups. The n-6 long-chain PUFAs (>=20 carbons)—namely 20:2 (% by wt and mg/L), 20:3 (% by wt), and 22:4 (% by wt)—were lower in women with GDM than in control subjects. The product-precursor ratio of AA to 20:3n-6, as an indirect measure of {Delta}5-desaturase activity, showed a trend to be higher in women with GDM than in control subjects (Table 3Go; P = 0.09).


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  		TABLE 2. Plasma phospholipid fatty acids in control subjects (C) and in women with gestational diabetes mellitus (GDM) at 27–30, 33–35, and 36–39 wk gestation1,
 

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  		TABLE 3. Plasma phospholipid fatty acids and indexes in control subjects (C) and in women with gestational diabetes mellitus (GDM) at 27–30, 33–35, and 36–39 wk gestation1,
 
There were significant differences in n-3 fatty acids between control subjects and women with GDM. LNA, 22:5n-3, and the sum of LNA, eicosapentaenoic acid (20:5n-3), and 22:5n-3 (% by wt and mg/L) were significantly lower in women with GDM (22.5%, 16.5%, and 15.9% lower on average, respectively) than in control subjects. In contrast, plasma phospholipid DHA was significantly higher by {approx}19% (% by wt and mg/L) in women with GDM than in control subjects. The mean plasma phospholipid DHA (% by wt), adjusted for mean dietary DHA intake, was {approx}13% (P = 0.03) higher on average in women with GDM than in control subjects. When the mean maternal dietary intake of DHA and prepregnancy BMI were included as covariates, phospholipid DHA (% by wt and mg/L) was no longer significantly different between the 2 groups. The DHA sufficiency index [ratio of DHA to 22:5n-6; (29); Table 3Go], was significantly higher in women with GDM than in control subjects.

The saturated fatty acids (SFAs) 12:0 (% by wt and mg/L) at all time points and 16:0 (% by wt) at 27–30 and 33–35 wk gestation were 33% and 5.1% higher, respectively, and the monounsaturated fatty acids (MUFAs) 16:1n-7 and 18:1n-9 (% by wt) were lower by 21.1% and 11.3%, respectively, in women with GDM than in control subjects (Table 2Go). The ratio of SFAs to MUFAs was significantly higher in the women with GDM than in control subjects (Table 3Go).

Plasma phospholipid fatty acid patterns in the third trimester of gestation
Maternal plasma phospholipid fatty acids and total fatty acids and indexes from early in the third trimester to 36–39 wk gestation are presented in Tables 2 and 3GoGo, respectively. For all fatty acids, the effect of time was not significantly different between the 2 groups. There was a significant time effect for most of the PUFAs expressed as % by wt. The n-6 long-chain PUFAs 20:3, 20:4 and 22:4 decreased significantly from 27–30 to 36–39 wk gestation (by 7.9%, 12.4%, and 10.5%, respectively) in control subjects. In contrast, docosapentaenoic acid (22:5n-6) increased between 27–30 and 36–39 wk by {approx}20%. All the n-3 fatty acids (% by wt) were significantly lower at 33–35 and 36–39 wk gestation than at 27–30 wk gestation. The DHA sufficiency index and the ratio of AA to 20:3n-6 (Table 3Go) decreased during the third trimester.

All the phospholipid fatty acids (Table 2Go) and summed fatty acids (Table 3Go) expressed as a concentration (mg/L) increased with gestation during the third trimester, except for LNA and 20:5n-3, which did not vary significantly with time.

Maternal factors related to plasma phospholipid PUFAs during the third trimester of gestation
Maternal mean estimated dietary intakes of macronutrients and fatty acids during the third trimester of gestation are presented in Table 4Go. The pattern of macronutrient intake differed significantly between women with GDM and control subjects. Women with GDM had a higher intake of protein and a lower intake of carbohydrates than control subjects. Additionally, protein and fat contributed significantly more, and carbohydrate significantly less, to total energy intake in women with GDM than in control subjects.


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  		TABLE 4. Mean estimated dietary intakes in control subjects and in women with gestational diabetes mellitus (GDM) during the third trimester1,
 
The mean estimated intake of the precursor fatty acids LA and LNA was not significantly different between the 2 groups. Women with GDM had a significantly higher intake of AA, 20:5n-3, and DHA than control subjects. Mean estimated dietary intakes of fatty acids did not show significant associations with respective mean maternal plasma phospholipid fatty acids in either control subjects or women with GDM during the third trimester. However, at 27–30 wk gestation, significant positive associations were observed between the mean intake of total SFAs and plasma phospholipid total SFAs (% by wt) in control subjects (r = 0.57, P = 0.03) and between the mean intake of LA and plasma phospholipid LA (% by wt) in control subjects (r = 0.61, P = 0.02) and women with GDM (r = 0.59, P = 0.03). Furthermore, dietary AA showed a weak positive trend for association with mean plasma phospholipid AA (% by wt) during the third trimester in control subjects (r = 0.40, P = 0.15). The correlation coefficients for the association between dietary LNA (% by wt) and mean plasma phospholipid LNA (% by wt) were as follows: r = 0.34 (P = 0.24) and r = 0.44 (P = 0.12) in control subjects and women with GDM, respectively. The correlation coefficients for the association between mean dietary DHA and mean plasma phospholipid DHA (% by wt) were r = 0.16 (P = 0.60) and r = 0.32 (P = 0.25) in control subjects and women with GDM, respectively.

Maternal mean Hb A1C was a significant factor related to maternal mean plasma phospholipid AA (% by wt) during the third trimester of gestation. In control subjects, mean Hb A1C was inversely associated with mean plasma phospholipid AA (% by wt) (r = -0.56, P = 0.03). In contrast, in women with GDM, a highly significant positive association was observed between maternal mean Hb A1C and mean plasma AA (% by wt) (r = 0.76, P = 0.001).

The maternal mean fasting plasma insulin concentration was positively associated with mean plasma phospholipid AA (% by wt) (r = 0.69, P = 0.004) in women with GDM. A trend for a positive association was also observed in control subjects (r = 0.51, P = 0.07).

The maternal factors Hb A1C and mean dietary intake of AA explained 38.27% of the variance in mean maternal plasma phospholipid AA (% by wt) during the third trimester in control subjects. In women with GDM, Hb A1C, fasting plasma insulin concentration, and diet explained 58.21% of the variance in mean maternal plasma phospholipid AA (% by wt) in the third trimester of pregnancy.

Maternal mean plasma phospholipid DHA (% by wt) showed a significant negative association with prepregnancy BMI in control subjects (r = -0.55, P = 0.04). In women with GDM, the association between BMI and phospholipid DHA (% by wt) was not significant (r = -0.09, P = 0.75). However, in a post hoc analysis, there was a highly significant inverse association between BMI and mean plasma phospholipid DHA (% by wt) in women with GDM with a BMI < 30 (r = -0.76, P = 0.007) .

Plasma phospholipid PUFAs (% by wt) classified according to prepregnancy BMI are shown in Table 5Go. Maternal plasma phospholipid DHA and n-3 long-chain PUFAs (% by wt) were significantly lower in overweight (BMI: >25.5 to <30) than in normal-weight (BMI >19.8 to <=25.5) subjects.


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  		TABLE 5. Plasma phospholipid fatty acids in control subjects and in women with gestational diabetes mellitus (GDM) classified according to pregravid body mass index1,
 
The mean fasting plasma insulin concentration was negatively related to mean plasma phospholipid DHA (% by wt) in control subjects (r = -0.54, P = 0.05), but not in women with GDM (r = -0.28, P = 0.31). However, in post hoc analyses, when women with a prepregnancy BMI >=30 were excluded from the analyses, plasma insulin showed a trend for a negative association with plasma phospholipid DHA (% by wt) in women with GDM (r = -0.51, P = 0.10). Maternal pregravid BMI and mean dietary DHA intake explained 35.77% and 38.11% of the variance in mean plasma phospholipid DHA (% by wt) in the third trimester of gestation in control subjects and women with GDM, respectively.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
To our knowledge the current study is the only report documenting maternal PUFA status in pregnancy complicated with GDM. Further, the present investigation identifies maternal factors that are related to plasma phospholipid AA and DHA in normal pregnancy and in GDM, with the latter providing a model of glucose intolerance and insulin resistance.

Women with GDM who received dietary therapy in the present study maintained good glycemic control as evidenced by blood Hb A1C values within the acceptable clinical range of 4–6% (17) during the third trimester of gestation. However, elevated blood Hb A1C concentrations, higher mean fasting plasma insulin concentrations, and less weight gain in the women with GDM than in the control subjects was evidence that the women with GDM who received dietary therapy were different, from a metabolic standpoint, from the women who did not have GDM.

Plasma phospholipid LA and AA concentrations were the same in control women and women with GDM. Decreased phospholipid concentrations of AA and other n-6 long-chain PUFAs have been reported in nonpregnant models of insulin resistance (14, 15, 30). Impairment in n-6 PUFA metabolism was apparent in those studies only when accompanied by acute insulin deficiency and severe hyperglycemia. Women with GDM in the present study who received dietary therapy showed no evidence of acute loss of metabolic control or severe hyperglycemia. In addition, dietary intake of PUFAs is an important factor influencing tissue phospholipid PUFA composition (2, 31). The higher dietary intake of AA in the women with GDM than in control subjects in the third trimester may have contributed to the maintenance of plasma phospholipid AA values at values similar to those in control subjects.

The lower amounts of the elongation and desaturation precursors of AA (% by wt), 20:2n-6 and 20:3n-6, in women with GDM than in control subjects, in light of no difference in LA between the 2 groups, points to a possible enhanced conversion of these metabolic precursors to AA. The data also support the notion of a lower amount of elongation of AA to 22:4n-6 in women with GDM than in control subjects. Alternatively, these long-chain PUFA intermediates may have been utilized to a greater extent.

This study showed higher maternal phospholipid DHA and lower LNA and sum of precursors of DHA in women with GDM than in control subjects. Elevated tissue phospholipid DHA was reported previously in diabetic rats (14). Increased desaturation and elongation of LNA to DHA may have been responsible for the higher DHA content and lower amount of n-3 precursors in women with GDM than in control subjects. Alternatively, increased selective oxidation of LNA (32) may have contributed to the lower content of phospholipid LNA in women with GDM than in control subjects. Higher phospholipid DHA in women with GDM than in control subjects may also have been due to enhanced release of DHA as a result of adipose tissue mobilization and perturbed metabolism and compromised placental transfer of DHA in the third trimester of pregnancy in the women with GDM.

A higher mean intake of dietary DHA in the women with GDM than in control subjects in the third trimester was likely one factor contributing to the higher maternal plasma phospholipid DHA values in the women with GDM. However, diet alone did not explain the difference in plasma phospholipid DHA between the 2 groups. Rather, prepregnancy BMI and diet together explained the group differences. These findings suggest that both alterations in maternal metabolic factors and differences in the dietary intake of DHA between the women with GDM and the control subjects may have contributed to the higher plasma phospholipid DHA values in the women with GDM.

The alterations in maternal phospholipid long-chain PUFAs documented in women with GDM in the third trimester may be clinically significant with respect to fetal PUFA requirements. In a subset of this study population (n = 13 women with GDM and 12 control subjects), fetal erythrocyte phospholipid LA, AA, and DHA (% by wt and mg/L) and differences between cord vein and artery erythrocyte phospholipid DHA (mg/L) were lower in women with GDM than in control subjects (33). It is well established that AA and DHA are normally accrued in significant quantities in the fetus in the third trimester (5, 7). Additionally, the transfer is dependent on maternal concentrations of these fatty acids. Although our data do not explain the reason for these observations, an impairment related to insulin resistance in the maternal transfer of long-chain PUFAs to the fetus in women with GDM may underlie the phenomenon.

The decrease in maternal plasma phospholipid PUFA composition (% by wt) from 27–30 to 36–39 wk gestation in control subjects and women with GDM is consistent with the findings of previous studies of normal pregnancy (9, 10). The decrease in n-6 long-chain PUFAs and n-3 PUFAs (% by wt) relative to other nonessential fatty acids likely represents a physiologic adaptation in pregnancy to meet increased fetal long-chain PUFA requirements during the third trimester of pregnancy. The decrease in the product-precursor ratio of AA to 20:3 n-6 and the ratio of DHA to 22:5n-6 (29) suggests selective maternal depletion of AA and DHA stores during the third trimester of gestation. Lower synthesis or enhanced utilization of these long-chain PUFAs than of other nonessential fatty acids may explain the decrease in these maternal long-chain PUFAs and ratios. An increase in the total phospholipid pool in the third trimester of gestation (34) likely accounts for the nonspecific increase in plasma phospholipid fatty acid concentrations.

The findings of the present study indicated maternal glycemic control in the third trimester as an independent maternal factor related to the plasma phospholipid AA content in normal pregnancy and in GDM. In control subjects, the moderate glucose intolerance that developed during the third trimester, as evidenced by increasing blood Hb A1C concentrations, may be one metabolic index underlying the depletion of maternal plasma phospholipid AA in the third trimester of a normal pregnancy.

In contrast, in women with GDM, impairments in glucose control and insulin resistance were associated with increased plasma phospholipid AA. There was little overlap in individual blood Hb A1C values between control subjects and women with GDM. Hence, in women with GDM with elevated Hb A1C concentrations, this positive relation with AA may reflect an impairment in transport of AA to the fetus in insulin resistance, for example.

Higher pregravid BMI and insulin resistance were associated with lower maternal DHA status in the control subjects. Dietary DHA or n-3 PUFA intakes were not related to pregravid BMI. Furthermore, in overweight women, plasma phospholipid n-3 long-chain PUFAs were lower than, whereas n-6 PUFAs were not significantly different from, those of normal-weight women (Table 5Go). On the basis of these findings, n-3 PUFA metabolism may be selectively altered in healthy pregnant women with a high prepregnancy BMI.

Obesity may be a factor underlying the alterations observed in maternal phospholipid DHA in the women with GDM. The association of prepregnancy BMI with phospholipid DHA was not apparent in the women with GDM. Obese women (n = 3), all with a diagnosis of GDM, had the highest plasma phospholipid DHA values relative to women in other BMI categories (Table 5Go). In post hoc analyses in which obese women with GDM were not included, pregravid BMI was a significant negative predictor of maternal plasma phospholipid DHA status in women with GDM (n = 12), similar to what was observed in control subjects. Furthermore, pregravid BMI, in addition to dietary DHA intake, was a confounder that explained group differences in maternal phospholipid DHA. This finding lends support to the suggestion that alterations in maternal plasma phospholipid DHA, as a metabolic response to impairment in fetal transport in insulin resistance, may be more pronounced in obese women with GDM. This finding warrants further investigation.

In summary, maternal plasma phospholipid LA and AA did not differ significantly between women with GDM who received dietary therapy and control subjects, whereas the n-6 long-chain PUFA precursors of AA and 22:4n-6 (% by wt) were lower in women with GDM than in control subjects. Maternal LNA was lower and DHA higher in women with GDM than in control subjects. On the basis of the present findings, dietary and metabolic responses to obesity and insulin resistance in the women with GDM appeared to underlie the alterations in phospholipid n-3 PUFAs in women with GDM who received dietary therapy. Maternal glycemic control was associated with plasma phospholipid AA values in control subjects (negative factor) and women with GDM (positive factor). Prepregnancy BMI was a significant negative predictor of maternal plasma phospholipid DHA status (% by wt) in control subjects and in women with GDM with a BMI <30. Further studies are needed to clarify the role of these maternal factors in the regulation of essential fatty acid metabolism and to understand the physiologic mechanisms underlying the associations reported herein.


   ACKNOWLEDGMENTS
 
We thank Patricia O'Connell and Brunnella Ibarralo from the Diabetes Lifecare Center at Hartford Hospital for their help with patient recruitment, the staff at the Department of Obstetrics and Gynecology at Hartford Hospital for their help with the research protocol, the mothers who participated in this study, and Constance M Capacchione for her help with data management.


   FOOTNOTES
 
2 Represents scientific contribution no. 1817, Storrs Agricultural Experiment Station, the University of Connecticut, Storrs.

3 Supported in part by Hartford Hospital (Hartford, CT), the Kraft/General Foods Predoctoral Fellowship Program, contract 93-37200-8876 from the US Department of Agriculture (Agricultural Research Service), and the University of Connecticut Research Foundation.

4 Address reprint requests to CJ Lammi-Keefe, Department of Nutritional Sciences, U-17, University of Connecticut, Storrs, CT 06269-4017. E-mail: clammi{at}canr1.cag.uconn.edu.

See corresponding editorial on page 3.


   REFERENCES
TOP
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 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
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