Plasma fatty acids of neonates born to mothers with and without gestational diabetes

ARTICLE IN PRESS

Prostaglandins, Leukotrienes and Essential Fatty Acids 72 (2005) 335–341 www.elsevier.com/locate/plefa

Plasma fatty acids of neonates born to mothers with and without gestational diabetes B.A. Thomasa,, Kebreab Ghebremeskela, Clara Lowyb, Brigid Offley-Shoreb, Michael A. Crawforda a

Institute of Brain Chemistry and Human Nutrition, London Metropolitan University, TB 9/4, 166-220 Holloway Road, London N7 8DB, UK b Endocrine and Diabetic day Centre, Guy’s and St Thomas’ Hospital Trust, London SE1 7EH, UK Received 31 August 2004; accepted 7 January 2005

Abstract Women with gestational diabetes mellitus (GDM) and their neonates have lower levels of arachidonic (AA) and docosahexaenoic (DHA) acids in red cell membranes. It is not clear if this abnormality is restricted to red cells or is a generalised problem. We have investigated plasma fatty acids of neonates (venous cord) of GDMP (n ¼ 37), and non-diabetic (n ¼ P31) women. The GDMs had lower levels of dihomogamma-linolenic (20:3n-6, DHGLA) acid, n-6 metabolites, DHA and n-3 metabolites (po0:05) in choline phosphoglycerides (CPG). They also had lower levels of AA (4.5%), adrenic acid (22:4n-6, 13%), osbond acid (22:5n-6, P 7%) and n-6 (2.5%). There was a similar pattern in triglycerides (TG) and cholesterol esters (CE). Mead acid, a marker of generalised shortage of derived and parent essential fatty acids, was higher in CPG and TG of the GDM group by 73% and 76%. The adrenic/osbond acid (22:4n-6/22:5n-6) ratio, a biochemical marker of DHA insufficiency, was reduced in CPG (4.5%), TG (63%) and CE (75%) of the GDM group. These findings, which are consistent with the previous red cell data, suggest that the neuro-visual and vascular development and function of the offspring of GDM women may be adversely affected if the levels of AA and DHA are compromised further by other factors, pre- or post-natally. Studies are required to elucidate the underlying mechanism for the reduction of the two fatty acids and to evaluate the developmental and health implications. r 2005 Elsevier Ltd. All rights reserved.

1. Introduction There is evidence that the fetus and neonates have the ability to synthesise arachidonic (AA) and docosahexaenoic (DHA) from their respective parent compounds linoleic (LA) and alpha-linoleic (ALA) acids [1–3]. However, the rate of synthesis is not fast and is unlikely to meet the high fetal and neonatal requirement for growth and development. Hence, the fetus and neonates will have to rely on other sources, specifically the mother, for optimal supply of AA and DHA. Indeed, selective and preferential transfer of AA and DHA from maternal to fetal circulation is a consequen-

Corresponding author. Tel.: +44 207 753 3165; fax: +44 207 753 3164. E-mail address: [email protected] (B.A. Thomas).

0952-3278/$ - see front matter r 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.plefa.2005.01.001

tial decline of these fatty acids in maternal blood and has been reported in several studies [4–6]. In fetal plasma and red cells, the relative level of ALA is almost undetectable and LA is nearly half that of the mother. In contrast, the proportions of AA and DHA are significantly higher in the fetus. Women of childbearing age have a greater capacity for synthesising DHA [7,8] and possibly AA, as both AA and DHA share the same synthetic pathway. Regardless of this ability, women with diabetes [9], and those from developing countries where the first gestation occurs at a very young age, followed by successive pregnancies at short birth spacing, are unlikely to provide sufficient amounts of these fatty acids that are required for optimal pre- or post-natal development. We have previously found lower levels of AA and DHA in women with insulin dependent diabetes, and

ARTICLE IN PRESS 336

B.A. Thomas et al. / Prostaglandins, Leukotrienes and Essential Fatty Acids 72 (2005) 335–341

their neonates at birth [10,11]. Likewise, it has been shown that neonates of gestational diabetics have reduced proportions of AA and DHA in red cell phospholipids [12] and choline phosphoglycerides [13]. The latter two studies did not provide plasma fatty acid data. Hence, it is unclear whether the lower level of red cell AA and DHA in neonates of gestational diabetics [12,13] was a reflection of an inadequate status or impaired incorporation. In the current study, we have investigated whether or not maternal gestational diabetes mellitus has a discernable adverse effect on plasma AA and DHA of the offspring at birth.

2.3. Dietary assessment

2. Patients and methods

2.4. Demographic data and sample collection

2.1. Recruitment of diabetic and non-diabetic mothers

Detailed anthropometric and clinical data of the babies of the GDM (n ¼ 37) and non-diabetics (n ¼ 31) women were obtained at birth. Venous cord blood, about 5 ml, was also collected in a heparinised tube. Plasma was separated by cold centrifugation (4 1C) at 2000 rpm for 15 min, flushed with nitrogen and stored at 70 1C until analysis.

Thirty-seven women with gestational diabetes mellitus (GDM) and uncomplicated singleton pregnancy were recruited during the third trimester (weeks 28–32) from St. Thomas’ Hospital, London, UK. Also, non-diabetic women (n ¼ 31) aged X16 years and without a family history of diabetes, high blood pressure and other chronic disorders were enrolled. Ethical approval from the Ethics Committee of Lambeth & Southwark Health Authority and written consent from the subjects were obtained. 2.2. Diagnosis and treatment The diagnosis of gestational diabetes was based on the standard criteria of the European Association for the Study of Diabetes [14]. High-risk women—those with a history of GDM, stillbirth, macrosomia, and a prepregnancy BMI 426 were screened for diabetes with an oral glucose tolerance test (OGTT). After an overnight fast, the women were given a 75 g glucose load and their blood glucose concentration monitored at 60 and 120 min. If blood glucose concentration at 60 min was greater than 8 mmol/l, a second sample was taken at 120 min. GDM was diagnosed if the second reading was equal to or exceeded 9 mmol/l. At diagnosis, the GDM women were referred to a dietitian for individual dietary advice. During the initial consultation, information was obtained on dietary habits, lifestyle, health, knowledge of food and nutrition and general attitude to nutrition and health. Basic explanation was provided about nutrient composition, specifically fat, carbohydrate and protein, of the food and food products that were commonly consumed by the individual expectant mother. If it was deemed necessary, the GDM women were advised to reduce calorie, total fat, saturated fat and refined carbohydrates and increase complex carbohydrate and fibre consumption.

Nutrient intake of the two groups of women was assessed by the use of a 4-day dietary questionnaire that has been validated in a previous pregnancy study [15]. All of the dietary records were taken between weeks 2 and 3 after the dietary advice. A nutritional programme FOODBASE 2000 Version 3.0 (Institute of Brain Chemistry and Human Nutrition) was used to calculate the daily nutrient intake. Coding, assessment of portion size and interpretation of the food diaries was carried out by one individual, in order to eliminate interpersonal variability.

2.5. Fatty acid analysis Total lipids were extracted by the method of Folch et al. [16] by homogenising 1 ml plasma in 45 ml chloroform:methanol (2:1 v/v) containing 0.01% butylated hydroxytoluene (BHT) under nitrogen. Choline phosphoglycerides (CPG), triglycerides (TG) and cholesterol esters (CE) were separated with chloroform:methanol:water (60:30:4 v/v) and petroleum spirit:ether:formic acid:methanol (85:15:2:5:1 v/v) containing BHT, respectively, on silica gel plates. The lipid bands were detected by spraying with a methanolic solution of 2, 7dichloroflurescein (0.01% w/v) and identified by the use of authentic standards. Fatty acid methyl esters (FAME) were prepared by heating the plasma lipid fractions scraped from the silica plate with 15% acetyl chloride in methanol in a sealed tube at 70 1C for 3 h under nitrogen. The FAME were esterified through a number of washing steps using 4 ml 5% sodium chloride (saline), 2 ml petroleum spirit (40–60 1C), 2 ml 2% potassium bicarbonate and 100–200 mg pre-dried anhydrous granular sodium sulphate. The concentrated FAME was taken up in 1 ml heptane with BHT and stored at 4 1C. FAME were separated by gas chromatograph (HRGC MEGA 2 series, Fisons Instruments, Milan, Italy) fitted with a capillary column (25 m  0.32 mm ID, 0.25 m film, BP20). Hydrogen was used as a carrier gas, and the injector, oven and detector temperatures were 235, 210 and 260 1C. The FAME were identified by comparison of retention times with authentic standards (Sigma-Aldrich Co. Ltd., UK) and interpretation of equivalent chain length values. Peak

ARTICLE IN PRESS B.A. Thomas et al. / Prostaglandins, Leukotrienes and Essential Fatty Acids 72 (2005) 335–341

areas were quantified by the use of a computer chromatography data system (EZChrom Chromatography Data System, Scientific Software Inc., San Ramon, CA, USA), using a formula based on normalized percentage of the peak area. The calculation represents the percentage of total fatty acids (calculation of area % is assumed to be equal to wt%). 2.6. Statistical analysis The continuous variable data are expressed as means and standard deviations (mean7SD). Unpaired Student’s t-test was used to investigate for a significant difference between the levels of the continuous variables of the two groups of mothers, and their respective neonates. Differences between the discrete (binary) variable values were analysed with chi-squared test. All the calculations were performed by the use of SPSS for Windows, Release 10 (SPSS UK Ltd, Woking, Surrey, UK).

3. Results 3.1. Anthropometric, demographic and clinical characteristics 3.1.1. Mothers Clinical, demographic and demographic data of the two groups of mothers are given in Table 1. The mean age (Po0:05), body weight (Po0:0001), body mass index (Po0:0001), and systolic (Po0:05) and diastolic (Po0:05) blood pressure of the GDM women were significantly higher compared with those of the nondiabetics.

337

Table 1 Anthropometric, demographic and clinical variables of women with and without gestational diabetes Characteristics

Non-diabetic (n ¼ 31) GDM (n ¼ 37)

Age (years) 27.775.3 Height (m) 1.6470.1 Pre-pregnancy wt. (kg) 60.1710.8 22.373.3 Pre-pregnancy BMIa Weight at recruitment (kg) 71.5712.8 BMI at diagnosis 27.5774.52 Systolic blood pressure 114.9712.9 Dystolic blood pressure 69.179.4 Glucose at 0 min (mmol/l) 4.270.3 Glucose at 60 min (mmol/l) 6.071.2 Glucose at 120 min (mmol/l) — HbA1Cb (%) 4.570.21

31.075.0* 1.6470.1 74.8720.3*** 27.877.1*** 88.8718.4*** 32.8776.15*** 119.9715.3* 75.6710.8* 5.771.8*** 12.273.1*** 10.972.5 5.770.7***

Parity (n) 0 1 X2 Information not given

20 8 3 —

17 10 10 —

Smoker (n) Never In the past Current Information not given

19 4 7 1

24 5 5 3

*Po0.05; **Po0.01; ***Po0.001. Mean is significantly different from corresponding control values. The data are expressed as mean7SD. a BMI (Body Mass Index) weight (kg)/height (m)2. b HbA1C, glycosylated haemoglobin; GDM, gestational diabetes mellitus.

difference in intakes of LA, ALA and AA between the two groups (P40:05). 3.2. Plasma fatty acids of the neonates (cord)

3.1.2. Neonates Anthropometric and clinical data of the babies are given in Table 2. 9.7% and 40.5% (Po0:05) of the babies of the non-diabetics and diabetics, respectively, were delivered by elective caesarian. The neonates of the GDM women were heavier (Po0:05), had a shorter gestational age (Po0:01) and higher prevalence of hypoglycemic episode (Po0:001) at birth. In addition, the female neonates of the diabetics had a higher mean birth weight (Po0:05). 3.1.3. Dietary energy, macronutrients and fatty acids The mean daily intake of energy, protein, carbohydrate and fat of the two groups of women are given in Table 3. Compared with the non-diabetics, the GDM women had lower intakes of energy (Po0:05), total fat and total sugar (Po0:0001), and higher dietary fibre (Po0:05). In addition, the GDM group consumed less saturates, monounsaturates and trans fatty acids (Po0:0001), and more DHA (Po0:05). There was no

3.2.1. Choline phosphoglycerides (CPG) Mean fatty acid composition of plasma CPG of the two groups of neonates is given in Table 4. The neonates of the GDM women had lower levels of arachidic (20:0; Po0:001) and Pdihomogamma-linolenic P(20:3n-6, DHGLA) acids, n-6 metabolites, DHA, n-3 and P n-3 metabolites (Po0:05) and higher palmitic (16:0) and mead (20:3n-9, Po0:05) acids compared with the corresponding non-diabetics. In addition, the levels of AA (4.5%), adrenic acid P (22:4n-6, 12%), osbond acid (22:5n-6, 7%) and n-6 (2.5%) were lower in the GDM group (P40:05). 3.2.2. Triglycerides (TG) Fatty acids of plasma triglycerides of the neonates of the GDM and non-diabetic women are given in Table 5. The GDM group had levels of eicosaenoic (20:1nPlowerP 9), ardrenic acids, n-6, n-6 metabolites (Po0:05) and ALA (Po0:01) and higher levels of palmitic and

ARTICLE IN PRESS 338

B.A. Thomas et al. / Prostaglandins, Leukotrienes and Essential Fatty Acids 72 (2005) 335–341

Table 2 Anthropometric data of neonates of women with and without gestational diabetes Non-diabetic (n ¼ 31) Gestational age at delivery (wks) Gender Male Female Birthweight (kg) Male Female

39.371.4

19 12 3.3270.44 3.3970.48 3.2070.36

GDM (n ¼ 37)

38.571.1**

20 17 3.6170.46* 3.6470.55 3.5770.33*

Length (cm) Male Female

50.5073.17 50.9673.07 49.7673.31

51.1672.73 51.1872.37 51.1673.18

Head circumference (cm) Male Female Hypoglycaemiaa (n)

34.5671.23 34.7671.25 34.2371.18 2

34.8371.37 34.8471.42 34.8371.36 17***

Mode of delivery Vaginal Caesarean

28 3

22 15

*Po0.05, **Po0.01, ***Po0.001. Mean is significantly different from corresponding control values. The data are expressed as mean7SD. a Hypoglycemia defined as blood glucose concentration p2 mmol/l.

mead acids, and total saturates (Po0:05) compared with the corresponding non-diabetics. The proportions of P AA (23.4%) and n-6 metabolites (18.7%) were lower in the neonates of the GDM women (P40:05). 3.2.3. Plasma cholesterol esters (CE) Mean proportions of eicosaenoic acid and DHGLA were reduced (Po0:01), and palmitic acid (Po0:05) increased in the cord of the GDM than in the nondiabetics (Table 6). The levels of AA (8.2%), ardrenic acid (40%), ALA (54.6%), DHA (16.7%) and P n-3 (24.5%) were lower in the GDM group (P40:05).

4. Discussion and conclusions The investigation indicates some of the plasma n-6 and n-3 fatty acids of neonates may be adversely affected by pregnancy-induced maternal diabetes. The levels of AA were reduced by 4.5%, 23.4% and 8.2% in the plasma CPG, TG and CE respectively. The corresponding decrease in DHA was 14.4%, 4.2% and 16.7%. These findings mirror the reduction in the levels of the two fatty acids previously reported in red cell phospholipids [13] and red cell choline and ethanolamine phosphoglycerides [17].

Table 3 Mean estimated dietary intake and % contribution to energy in women with gestational diabetes during third trimester Nutrients

Control

Energy (kcal/d) 2213 Protein (g/day) 81.08723.2 % Energy 14.5473.5 91.02727.2 Total fata (g/day) % Energy 37.2575.3 Total carbohydrate (g/day) 282.30775.1 % energy 47.4876.09 % energy from starch (complex 150.40738.41 CHO) % energy from sugar (refined 127.4749.3*** CHO) Fibre (NSP) 12.2574.9 Saturated fatty acids 32.57712.23 Monounsaturated fatty acids 26.7978.97 Polyunsaturated fatty acids 13.5575.57 18:2n-6 11.7175.18 20:4n-6 0.1270.07 P 11.9275.20 Pn-6 n-6 metabolites 0.2170.13 18:3n-3 1.3370.56 20:5n-3 0.1170.22 22:6n-3 0.1370.14 P n-3 1.6370.66 P n-3 metabolites 0.3070.38 Trans fatty acids 2.6771.60

GDM 1955* 84.9728.8 17.6474.05*** 69.7725.1 *** 31.9075.9*** 260.99787.5 50.3076.12* 175.0775.4 82.8743.2*** 14.976.1* 19.8978.56*** 21.1878.20** 14.2977.15 12.2176.59 0.1370.08 12.4176.62 0.2070.13 1.4270.77 0.1670.25 0.2070.17* 1.8870.94 0.4670.45 1.4070.85***

*Po0.05, **Po0.01, ***Po0.0001. Mean is significantly different from corresponding control values. For other abbreviations see Table 1. a Intakes are g/day unless otherwise stated, CHO, carbohydrate; NSP, non-starch polysaccharide. P saturates ¼ 12:0+14:0+16:0+18:0+20:0+22:0+24:0; P monoenes ¼ 14:1+16:1+18:1+20:1+22:1+24:1; P n-6 ¼ 18:2+18:3+20:2+20:3+20:4+22:4+22:5; P Pn-6 metabolites ¼ 18:3+20:2+20:3+20:4+22:4+22:5; Pn-3 ¼ 18:3+20:5+22:5+22:6; n-3 metabolites ¼ 20:5+22:5+22:6; Trans ¼ 16:1t+18:1t+20:1t+22:1t+18:2tt+18:3ct.

The lower AA and DHA in neonates of the GDM women was intriguing, since the nutrients are selectively transferred from maternal to fetal circulation [4–6,18]. Moreover, as compared to the non-diabetics, the GDM women consumed more DHA and the same amount of AA. In addition, there is evidence to indicate that, AA and DHA are elevated in plasma phospholipids of GDM women [10,19]. The influx of the n-6 and n-3 fatty acids from the mother to the fetus is dependent on maternal status and placental efficiency. Consequently, it appears that the reduced levels of AA and DHA in the neonates of the GDM women were the reflection of impaired placental transfer. The uptake of the longchain polyunsaturated fatty acids (LCPUFA) by the placenta is thought to be mediated by membrane bound cytosolic fatty acid binding proteins (FABPs) [20], and the rate of flux is primarily dependent on the abundance of the available binding sites [21]. Recent evidence demonstrates that the membrane protein CD36 (fatty

ARTICLE IN PRESS B.A. Thomas et al. / Prostaglandins, Leukotrienes and Essential Fatty Acids 72 (2005) 335–341

339

Table 4 Mean percent fatty acid composition of plasma choline phosphoglycerides of neonates of gestatational diabetics and non-diabetics at delivery (mean %7SD)

Table 5 Mean percent fatty acid composition of plasma triglycerides of neonates of gestational diabetics and non-diabetics at delivery (mean %7SD)

Fatty acids

Non-diabetic

GDM

Fatty acids

Non-diabetic

GDM

14:0 16:0 18:0 20:0 P Saturates 16:1n-7 18:1n-9 20:1n-9 P Monoenes 18:2n-6 18:3n-6 20:2n-6 20:3n-6 20:4n-6 22:4n-6 22:5n-6 P n-6 P n-6 metabolites 18:3n-3 20:5n-3 22:5n-3 22:6n-3 P n-3 P n-3 metabolites

0.1670.08 28.7172.47 15.1771.12 0.0870.03

0.2070.81 29.9671.95* 14.7771.60 0.0570.03**

1.5870.45 27.2272.62 4.6971.61 0.8970.05

1.6270.53 29.3173.47* 5.1371.81 0.0970.06

44.5072.94 0.8970.26 9.8871.74 0.1170.06

45.5571.63 1.0170.28 10.5671.39 0.1270.07

11.0171.82 8.0171.18 0.1070.03 0.5570.38 5.5271.06 17.3072.30 0.6570.16 0.9570.54 33.0772.44

12.2371.62 8.7372.50 0.0970.03 0.5170.42 4.9970.81* 16.5572.65 0.5770.19 0.8870.54 32.3272.43

14:0 16:0 18:0 20:0 P Saturates 16:1n-7 18:1n-9 20:1n-9 P Monoenes

34.1674.04 6.3771.39 29.2174.84 0.3470.15 36.0874.95

36.7674.74* 6.3371.89 29.5774.20 0.2570.10* 36.5275.02

25.0672.29 0.0670.03 0.4370.21 0.5470.30 6.6071.87 7.6372.23 7.5672.23

23.6073.00* 0.0870.06 0.4770.27 0.4970.23 5.6571.27* 6.6971.47* 6.6171.47*

18:2n-6 18:3n-6 20:2n-6 20:3n-6 20:4n-6 22:4n-6 22:5n-6 P Pn-6 n-6 metabolites

11.8773.13 0.3370.16 0.5970.40 0.6970.29 3.1371.98 1.5271.43 1.6971.80 20.3774.40 8.5173.26

10.5973.03 0.2670.12 0.4070.33 0.6170.31 2.4071.03 0.7970.53* 2.3572.19 17.5173.49* 6.92720.7

18:3n-3 20:5n-3 22:5n-3 22:6n-3 P n-3 P n-3 metabolites

0.5670.32 0.3670.19 0.3470.21 1.6771.05 3.3171.74 2.7571.63

0.3770.15** 0.3270.15 0.3470.22 1.6071.08 3.0871.54 2.6771.49

0.4170.26

0.7170.56*

20:3n-9

0.4270.31

0.7470.30*

20:3n-9

*Po0.05, **Po0.001. Mean is significantly different from corresponding control values. For abbreviations see Table 3.

*Po0.05, **Po0.01. Mean is significantly different from corresponding control values. For abbreviations see Table 3.

acid translocase), which is a facilitator in the transport of the long chain fatty acids, is deficient in a rat model of human metabolic syndrome X [22]. It conceivable, that pregnancy-induced diabetes may have an adverse effect on the binding capacity of FABPs. Haggarty et al. [21] have postulated that placental FABP polymorphisms may affect the processes involved in the selective transfer of LCPUFA. The other possibility is that the two fatty acids may be taken up by the placenta and retained instead of being transferred to the fetus. Indeed, recent data from our laboratory [23], revealed that the placenta of gestational diabetic women had enhanced levels of AA and DHA, and seems to lend some support to this proposition. The levels of mead acid (20:3n-9) in the cord CPG and TG of the GDM women were 73% and 76% higher than the non-diabetics. Mead acid is a marker of a generalised shortage of derived and parent essential fatty acids. An elevated level of mead acid in cord blood is suggestive of maternal and fetal EFA insufficiency [6,24]. Similarly, the adrenic/osbond acid (22:4n-6/ 22:5n-6) ratio, a biochemical marker of DHA deficiency,

was reduced in the cord CPG (4.5%), TG (63%) and CE (75%) of the GDM group. The above data indicate that the non-diabetic neonates born to the gestational diabetic women had a ‘‘relative’’ insufficiency of plasma AA and DHA, which are vital structural components of neuro, vascular and visual systems. This finding is significant since experimental and epidemiological evidence demonstrate that nutritional constraint in utero is associated with impaired post-natal development and increased risk of chronic diseases in adults. It has been shown that a three-fold increase in AA and DHA occurs in human cerebrum and cerebellum during the third trimester. Intrauterine growth restricted neonates [25] and those with low birth weight and small head circumference [26] have reduced levels of AA and DHA at birth. Moreover, Zang et al. [27] have demonstrated that treatment with LA and ALA increases biparietal diameter and weight in intrauterine restricted fetus. In addition, it has been shown that a higher intake of n-3 fatty acids during pregnancy is related to gestational length and cerebral maturation in the newborn [28].

ARTICLE IN PRESS 340

B.A. Thomas et al. / Prostaglandins, Leukotrienes and Essential Fatty Acids 72 (2005) 335–341

Table 6 Mean percent fatty acid composition of plasma cholesterol esters of neonates of gestational diabetics and non-diabetics at delivery (mean %7SD) Fatty acids

Non-diabetic

GDM

14:0 16:0 18:0 20:0 P Saturates

0.6670.17 20.3773.13 3.6071.42 0.2270.21 25.8673.90

0.7470.31 22.8773.70* 3.4471.26 0.1370.12 27.8673.96

16:1n-7 18:1n-9 20:1n-9 P Monoenes

7.9271.86 28.9674.97 0.1870.10 37.1175.65

8.4371.95 27.5274.38 0.0970.06** 36.1775.74

18:2n-6 18:3n-6 20:2n-6 20:3n-6 20:4n-6 22:4n-6 22:5n-6 P Pn-6 n-6 metabolites

19.1173.47 0.5370.19 0.4470.45 1.2870.32 9.2673.91 0.1570.12 0.3470.31 30.9776.51 11.8674.27

18.4171.39 0.5270.18 0.3870.31 1.0770.25** 8.5073.28 0.0970.09 0.8571.36 29.6474.54 11.2373.27

18:3n-3 20:5n-3 22:5n-3 22:6n-3 P n-3 P n-3 metabolites

0.9771.38 0.2770.19 0.0870.10 0.6670.40 1.8471.40 0.9870.51

0.4470.78 0.2870.19 0.0670.04 0.5570.63 1.3970.87 0.9770.53

20:3n-9

0.4670.44

0.4170.38

*Po0.05, **Po0.01. Mean is significantly different from corresponding control values. For abbreviations see Table 3.

The current investigation, consistent with previous studies on red cells [12,29], reveals an abnormal essential fatty acid status in healthy newborn babies of gestational diabetic women. Because of the importance of these nutrients, this abnormality may have adverse effects on fetal growth and development as well as health in adulthood. There is evidence of speech and reading impairments, sub-optimal performance on developmental tests, and lower IQ in babies of pregestational and gestational diabetic women [30–33]. There is also evidence that intrauterine exposure to diabetes is a positive determinant of the development of insulin resistance and early onset of Type 2 diabetes in the offspring [34,35]. There is a need for further studies to understand the underlying mechanism for this abnormality and its developmental and health implications.

Acknowledgements The financial support of the Diabetes UK, March of Dimes Birth Defect Foundation, the Mother and Child

Foundation and Shida Kanzume Co. Ltd. is gratefully acknowledged. We also thank all the women who participated in the study.

References [1] J.P. Poisson, R.P. Dupuy, P. Sand, B. Descompos, M. Narce, D. Rieu, Evidence that liver microsomes of human neonates desaturates essential fatty acids, Biochim. Biophys. Acta 1167 (1993) 109–113. [2] V.P. Carnielli, D.J.L. Wattimena, I.H.T. Luijendijk, A. Boerlage, H.J. Degenhart, P.J. Sauer, The very low birth weight premature infant is capable of synthesizing arachidonic acid docosahexaenoic acids from linoleic and linolenic acids, Pediatr. Res. 40 (1996) 169–174. [3] T.U. Sauerwald, D.L. Hachey, C.L. Jensen, H. Chen, R.E. Anderson, W.C. Heird, Intermediates in endogenous synthesis of C22:6 Omega 3 and 20:4 Omega 6 by term and preterm infants, Pediatr. Res. 41 (1997) 183–187. [4] M.D.M. Al, A.C. van Houwelingen, A.D.M. Kester, T.H.M. Hasaart, A.E.P. De Jong, G. Hornstra, Maternal essential fatty acid patterns during normal pregnancy and their relationship to the neonatal essential fatty acid status, Br. J. Nutr. 74 (1995) 55–68. [5] S.J. Otto, A.C. van Houwelingen, M. Antal, A. Manninen, K. Godfrey, P. Lopez-Jaramillo, G. Hornstra, Maternal and neonatal essential fatty acid status in phospholipids: an international comparative study, Eur. J. Clin. Nutr. 51 (1997) 232–242. [6] Y. Min, K. Ghebremeskel, M.A. Crawford, J.H. Nam, A. Kim, I.S. Lee, H. Suzuki, Maternal-fetal n-6 and n-3 polyunsaturated fatty acids gradient in plasma and red cell phospholipids, Int. J. Vitam. Nutr. Res. 71 (5) (2001) 286–292. [7] G.C. Burdge, S.A. Wootton, Conversion of a-linolenic acid to eicosapentaenoic and docosahexaenoic acids in young women, Br. J. Nutr. 88 (2002) 411–420. [8] R. Pawlosky, J. Hibbeln, Y. Lin, N. Salem Jr., n-3 fatty acid metabolism in women, Br. J. Nutr. 90 (5) (2003) 993. [9] R.R. Brenner, A.M. Bernasconi, H.A. Garda, Effect of experimental diabetes on the fatty acid composition, molecular species of phosphatidyl-choline and physical properties of hepatic microsomal membranes, Prostaglandins Leukot. Essent. Fatty Acids 63 (2000) 167–176. [10] K. Ghebremeskel, B. Thomas, Y. Min, F. Stacy, E. Koukkou, C. Lowy, Fatty acid in pregnant diabetic women and neonates: implications for growth and development, in: Riemersma et al. (Eds.), Essential Fatty Acids and Eicosanoids, Fourth International Congress, 1998. [11] K. Ghebremeskel, B. Thomas, C. Lowy, Y. Min, M.A. Crawford, Type 1 diabetes compromises plasma arachidonic and docosahexaenoic acids in newborn babies, Lipids 38 (4) (2004) 335–342. [12] V. Wijendran, R.B. Bendel, S.C. Couch, E.H. Philipson, S. Cheruku, C.J. Lammi-Keefe, Fetal erythrocyte phospholipids polyunsaturated fatty acids are altered in pregnancy complicated with gestation diabetes mellitus, Lipids 35 (8) (2000) 927–931. [13] Y. Min, K. Ghebremeskel, C. Lowy, B. Thomas, M.A. Crawford, Adverse effect of obesity on red cell membrane arachidonic and docosahexaenoic acids in gestational diabetes, Diabetologia 47 (2004) 75–81. [14] European Association for the Study of Diabetes (EASD), National Diabetes Data Group: classification and diagnosis of diabetes mellitus and other categories of glucose intolerance, Diabetes 28 (1977) 1039–1057. [15] W. Doyle, A.H.A. Wynn, M.A. Crawford, S.W. Wynn, Nutritional counselling and supplementation in the second and third

ARTICLE IN PRESS B.A. Thomas et al. / Prostaglandins, Leukotrienes and Essential Fatty Acids 72 (2005) 335–341

[16]

[17]

[18]

[19]

[20]

[21] [22]

[23]

[24]

[25]

trimester of pregnancy: a study in a London population, J. Nutr. Med. 3 (1992) 249–256. J. Folch, M. Lees, G.H. Sloane-Stanley, A simple method for the isolation and purification of total lipids from animal tissues, J. Biol. Chem. 226 (1957) 497–509. Y. Min, Ph.D. Thesis, Maternal and neonatal long chain polyunsaturated fatty acid status in normal and diabetic pregnancy, London Metropolitan University, 2000. S.R. De Vriese, C. Matthys, S. De Henauw, G. De Backer, M. Dohnt, A.B. Christophe, Maternal and umbilical fatty acid status in relation to maternal diet, Prostaglandins Leukot. Essent. Fatty Acids 67 (6) (2002) 389–396. V. Wijendran, R.B. Bendel, S.C. Couch, E.H. Philipson, K. Thomsen, X. Zhang, et al., Maternal plasma phospholipids polyunsaturated fatty acids in pregnancy with and without gestational diabetes mellitus: relations with maternal factors, Am. J. Clin. Nutr. 70 (1999) 53–61. A.K. Dutta-Roy, Transport mechanisms for long-chain polyunsaturated fatty acids in the human placenta, Am. J. Clin. Nutr. 71 (1) (2000) 315S–322S. P. Haggarty, Placental regulation of fatty acid delivery and its effect on fetal growth, Placenta 23 (Suppl A) (2002) S28–S38. T.J. Aitman, A.M. Glazier, C.A. Wallace, L.D. Cooper, P.J. Norsworthy, F.N. Wahid, et al., Identification of Cd36 (Fat) as an insulin-resistance gene causing defective fatty acid and glucose metabolism in hypertensive rats, Nat. Genet. 21 (1) (1999) 76–83. D. Bitsanis, K. Ghebremeskel, T. Moodley, O.B. Djahanbakhch, M.A. Crawford, Placental arachidonate and docosahexaenoate levels are enhanced in gestational diabetes, Sixth Congress of the International Society for the Study of Fatty Acids and Lipids 7 (2004) 91 (H4). K. Ghebremeskel, Y. Min, M.A. Crawford, J.H. Nam, A. Kim, J.N. Koo, et al., Blood fatty acid composition of pregnant and nonpregnant Korean women: red cells may act as a reservoir of arachidonic acid and docosahexaenoic acid for utilization by the developing fetus, Lipids 35 (5) (2000) 567–574. G. Vilbergsson, M. Wennergren, G. Samsioe, P. Percy, A. Percy, J.E. Mansson, et al., Essential fatty acid status is altered in pregnancies complicated by intrauterine growth retardation, World Rev. Nutr. Diet. 76 (1994) 105–109.

341

[26] A. Leaf, M.J. Leighfield, K. Costeloe, M.A. Crawford, Factors affecting long-chain polyunsaturated fatty acid composition of plasma choline phosphoglycerides in preterm infants, J. Pediatr. Gastroenterol. Nutr. 14 (1992) 300–308. [27] L. Zhang, The effects of essential fatty acids preparation in the treatment of intrauterine growth retardation, Am. J. Perinatol. 14 (1997) 535–537. [28] I.B. Helland, O.D. Saugstad, L. Smith, K. Saarem, K. Solvoll, T. Ganes, et al., Similar effects on infants of n-3 and n-6 fatty acids supplementation to pregnant and lactating women, Pediatrics 108 (5) (2001) E82. [29] Y. Min, C. Lowy, B. Thomas, K. Ghebremeskel, M.A. Crawford, B. Offley-Shore, Red cell choline phosphoglyceride fatty acid profiles in mothers and their newborns in control and gestational diabetes, 34th Annual Meeting of Diabetic Pregnancy Study Group of the EASD, 2002. Abstract OP-12. [30] T.A. Rizzo, B.E. Metzger, W.J. Burns, K. Burns, Correlations between antepartum maternal metabolism and intelligence, N. Engl. J. Med 13 (1991) 911–916. [31] T.A. Rizzo, S.L. Dooley, B.E. Metzger, N.H. Chol, E.S. Ogata, B.I. Silverman, Prenatal and perinatal influences on long-term psychomotor development of offspring of diabetic mothers, Am. J. Obstet. Gynecol. 173 (6) (1995) 1753–1758. [32] B.L. Silverman, T.A. Rizzo, N.H. Cho, B.E. Metzger, Long-term effects of the intrauterine environment, The Northwestern University Diabetes in Pregnancy Center. Diabetes Care (Suppl 2) (1998) B142–B149. [33] A. Ornoy, N. Ratzon, C. Greenbaum, A. Wolf, M. Dulitzky, School-age children born to diabetic mothers and to mothers with gestational diabetes exhibit a high rate of inattention and fine gross motor impairment, J. Pediatr. Endocrionol. Metab. 1 (2001) 681–689. [34] A. Plagemann, T. Harder, R. Kohlhoff, W. Rohde, G. Dorner, Glucose tolerance and insulin secretion in children of mothers with pre-gestational IDDM or gestational diabetes, Diabetologia 40 (9) (1997) 1094–1100. [35] B.L. Silverman, B.E. Metzger, N.H. Cho, C.A. Loeb, Impaired glucose tolerance in adolescent offspring of diabetic mothers. Relationship to fetal hyperinsulinism, Diabetes Care 18 (5) (1995) 611–617.