QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bitsanis, D. Articles by Djahanbakhch, O. Search for Related Content PubMed PubMed Citation Articles by Bitsanis, D. Articles by Djahanbakhch, O.

---

Human Nutrition and Metabolism

Arachidonic Acid Predominates in the Membrane Phosphoglycerides of the Early and Term Human Placenta^1,2

Demetris Bitsanis³, Michael A. Crawford, Therishnee Moodley, Holm Holmsen^*, Kebreab Ghebremeskel and Ovrang Djahanbakhch

Institute of Brain Chemistry and Human Nutrition, London Metropolitan University, London, UK; ^* Department of Biomedicine, University of Bergen, Bergen, Norway; Academic Department of Obstetrics and Gynaecology, Bart’s and The Royal School of Medicine at Newham University Hospital, London, UK

³To whom correspondence should be addressed. E-mail: d.bitsanis{at}londonmet.ac.uk.

	ABSTRACT

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
The aim of this study was to determine whether the high concentration of arachidonic acid (AA) in term placentae accumulates during pregnancy or is an inherent characteristic of placental lipids. We investigated the lipid content and fatty acid composition of the human placental phospholipids at 2 gestational periods, early in pregnancy (8–14 wk, n = 48) and at term (38–41 wk of gestation, n = 19). The subjects were healthy, normotensive, and free of medical and obstetric complications. The lipid concentration of placentae increased from 0.8% in early gestation to 1.4% at term (P < 0.0001). The mean proportions of AA were lower in the choline (P < 0.05), inositol (P < 0.0001), and ethanolamine (P < 0.0001) phosphoglycerides of the term compared with the early placenta. In contrast, the proportions of the immediate precursor of AA, dihomo--linolenic acid (DGLA), were higher in the term placenta, particularly in the inositol and serine phosphoglycerides (P < 0.0001). In sphingomyelin, the percentage of lignoceric acid was increased and that of nervonic acid was reduced at term (P < 0.01). The dominance of AA, particularly in the early placenta, suggests that it has an important role for placental development, i.e., organogenesis and vascularization. There was no evidence of an accumulation of AA in the placenta toward term, which might be a trigger for parturition. In contrast, the increased proportion of DGLA (precursor of the vasorelaxant and anticoagulant prostaglandin E₁) at term is more consistent with a profile favoring optimal blood flow to nourish the fetal growth spurt.

KEY WORDS: • early placenta • term placenta • arachidonic acid

The process of placentation begins with implantation of the blastocyst beneath the uterine epithelium and differentiation of trophoblast cell lineage into the embryonic and extraembryonic structures of the conceptus (1,2). This invasive behavior follows a precise chronology of vascular events during the first trimester of gestation (3). These events involve placental tissue angiogenesis, organogenesis, and progressive establishment of the 2 circulations within the placenta in preparation for the second phase of pregnancy fetal growth (3–6).

Human fetal growth and development have a unique requirement for the supply of dietary lipids. During intrauterine life, the human placenta selectively transfers arachidonic [AA,⁴ 20:4(n-6)] and docosahexaenoic [DHA, 22:6(n-3)] acids from the maternal circulation to the fetus (7,8). AA is the major essential fatty acid component of the inner cell membrane lipid in human vascular endothelium (9). DHA has a primary role in the function of retina and brain (10–12). The supply of AA and DHA to the fetus, by the placenta, depends on the maternal diet, circulating lipids, and the length of gestation (13–15).

The endothelial cell lining of the vascular system has the highest membrane to cytoplasm ratio of any cell and constitutes the largest single organ mass of the adult. Consequently it will require a high proportion of membrane lipids and hence essential fatty acids (EFA). The human placenta, as a fast growing vascular network, will also be expected to exercise a high demand for the same EFA. To assess the lipid requirements in early development and test whether the proportions of AA increase or are conserved in placental membranes throughout pregnancy, we determined the lipid content and fatty acid composition of the human placental phospholipids in early gestation (8–14 wk of age) and at term.

	SUBJECTS AND METHODS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
    Subjects and selection criteria. Placentae from healthy pregnant women (n = 67) were obtained at 2 periods of gestation, early (8–14 wk) and term (38–41 wk of age).

The mothers were nonsmokers and nonalcoholics, normotensive, and free of medical and obstetric complications. The early termination of the pregnancy was due to socio/psychological reasons. Ethical approval was granted by the East London Health Authority and a signed consent was obtained from the mothers.

    Sample collection. Placentae were collected from legally terminated pregnancies by evacuation and term vaginal or caesarean delivery from St. Andrews Hospital and Newham General Hospital, East London.

Fresh early placentae were excised and washed several times in cold saline to remove all traces of blood. Representative samples of term placentae were dissected and washed similarly in cold saline. Both early and term placentae were either processed immediately or stored at –70°C until analysis.

To our knowledge, data on the nature of the placental lipids are limited. The early placentae (n = 48) were analyzed to characterize primarily the major lipid components, i.e., choline (CPG) and ethanolamine (EPG) phosphoglycerides. Subsequent analysis for inositol (IPG) phosphoglycerides, important in cell signaling, serine (SPG) phosphoglycerides, and sphingomyelin (SPM) was possible from 29 placentae due to limits of sample sizes; 19 term placentae were analyzed for comparative purposes (sample size at 95% power of detecting the difference at the 5% level for AA based upon previous studies was estimated, n > 11.7) (16).

    Lipid extraction and fatty acid analysis. Lipids were extracted by the method of Folch et al. (17) from placental homogenates in chloroform:methanol (2:1, v:v), containing 0.1% BHT (Sigma/Aldrich) as an antioxidant under N₂. The phospholipid fractions were separated by TLC on silica plates using chloroform:methanol:methylamine 40% aqueous solution (65:15:5, by vol) in 0.1% BHT as developing solvents. FAME were prepared in 15% acetyl chloride in methanol as a transesterification agent in sealed vials at 70°C for 3 h under N₂.

FAME were separated by GLC (HRGC MEGA 2 Series, Fisons Instruments) fitted with a BP20 capillary column (30 mm x 0.32 mm i.d., 0.25 µm film; SGE). Hydrogen was used as a carrier gas; the oven, injector, and detector temperatures were 183, 235, and 250°C, respectively. FAME were identified by comparison of retention times with authentic standards and calculation of equivalent chain length values. Peak areas were quantified using a computer Chromatography Data System, EZChrom (Scientific Software).

    Gravimetric determination of lipid. The total lipid extract of the placenta was removed with chloroform:methanol to a preweighed trident vial, and the solvent was evaporated under a stream of oxygen free nitrogen until the vial reached a constant weight. The difference between the final and starting weight of the vials containing the tissue lipid extract is the gross weight of the lipid and BHT. Corrections for the BHT content were made on the basis of the weight of the blank extract containing BHT only.

    Quantitation of phospholipids. The phospholipid distribution in the placenta was determined by the method of Touchstone et al. (18). An aliquot of total lipid extract in chloroform was applied directly onto TLC aluminum sheets (Merck) developed in chloroform:methanol:methylamine 20% aqueous solution (60:35:10, by vol) together with phospholipid standards for reference (Merck). The developed TLC plates were dried, sprayed with 10% cupric sulfate in 8% phosphoric acid as charring reagent, and heated at 170°C for 10–30 min with frequent inspection. Subsequently, they were scanned with a Canon 5000F onto a Dell Pentium computer; the spots were encircled and the pixels were numerated. The amounts of the individual phospholipids were interpolated from the standard curve set up by scanning (1,2,4, and 6 µg) of phospholipids.

    Statistical analysis. Data are expressed as means ± SD. Student’s unpaired t test was used to investigate differences in fatty acid composition between early and term placentae. The relative distribution of the phospholipid classes between early and term placenta were compared by Mann-Whitney U nonparametric tests. To determine the effects of age, BMI, and ethnicity on linoleate (LA), AA, and DHA of the early placenta, factorial analysis was performed with age, BMI, and ethnicity as fixed factors and LA, AA, and DHA as dependent variables. Tukey’s honestly significant difference post hoc test was used if a significant difference was indicated. Differences were considered significant at P < 0.05. All data were analyzed using the computer statistical software, SPSS for Windows (Release 10).

	RESULTS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
    Maternal characteristics. The early and term placenta were obtained at 11.9 ± 1.7 and 40.2 ± 1.0 wk of gestation, respectively. Clinical information was available on the women who terminated their pregnancy between 8 and 14 wk of gestation. They had a BMI (n = 35) of 23.6 ± 3.86 kg/m² and they were 26.5 ± 5.64 y old (n = 47, range: 17–38 y of age). The early gestation women were an extremely diverse population that differed also in religion, culture, and ethnicity (Caucasian, n = 18; African, n = 15; Asian, n = 11; Undeclared, n = 4). In contrast, the majority of the mothers who delivered at term were Asians (n = 14), whereas a small number were from other ethnic groups (African, n = 2; Undeclared, n = 3).

In the factorial analysis conducted to determine the effect of age, BMI, and ethnicity (Caucasians, Africans, and Asians) on LA, AA, and DHA of the early placenta, there were no effects or factors interaction (P > 0.05).

    Placenta lipid concentration and fatty acid composition of the individual phospholipids. Total lipid (mg/g dry tissue) was elevated at term (14.00 ± 0.98, n = 19) compared with the early placenta (8.29 ± 1.30, n = 48; P < 0.0001). The relative percentage distribution of the phospholipid classes (% total phospholipids) did not differ between early and term placentae (P > 0.05; Table 1). The distribution of the major fatty acids (% total fatty acids) of the individual phospholipids at the 2 time points in gestation are presented in Tables 2, 3, 4, 5, 6. Supplemental Tables 1–4 present comprehensive versions of Tables 2, 3, 4, 5.

However, CPG and EPG differed in their monounsaturated and (n-3) fatty acid content. At term, the proportions of palmitoleate (C16:1), oleate (C18:1), and total monounsaturates (mono) were increased in EPG (Table 3) and decreased in CPG (Table 2). Moreover, the relative amounts of docosapentaenoic acid (n-3) [DPA (n-3); 22:5(n-3)], total metabolites (n-3) [met (n-3)] and total n-3 [(n-3)] were elevated in EPG (Table 3) in term placenta compared with earlier in gestation. Although the proportions of 22:5(n-6) and DHA did not differ at the 2 time points, the ratio 22:5(n-6):DHA decreased in CPG at term (Table 2).

    Inositol (IPG) and serine (SPG) phosphoglycerides. The term placental IPG had higher proportions of C16 and lower AA and AA:LA ratio compared with earlier in gestation (Table 4). SPG had also a lower AA:LA ratio (Table 5); unlike IPG, however, this was due to the increase in LA rather than changes in AA content.

Of the (n-3) fatty acids, the proportions of DHA were lower in IPG (Table 4) and higher in SPG (Table 5) at term compared with earlier in gestation. As a result, the 22:5(n-6):DHA ratio was increased in IPG and decreased in SPG at term. Despite the decrease in DHA, the IPG of the term placenta had higher proportions of eicosapentaenoic acid [EPA, 20:5(n-3)] and DPA (n-3) (Table 4). In SPG, the increase in the percentage of DHA and DPA (n-3) resulted also in an increase in met (n-3) and (n-3) at term (Table 5).

DGLA, the immediate precursor for AA, was increased significantly at term in all phosphoglycerides (Table 2, 3, 4, 5), but particularly in IPG and SPG. Consequently, the term placentae had a higher ratio of total AA precursors:AA compared with earlier in gestation (Tables 2, 3, 4, 5).

    Sphingomyelin (SPM). The SPM of the term compared with the early placenta had greater proportions of SFA due to increases in behenic (C22) and lignoceric (C24) acids (Table 6). On the other hand, the proportions of nervonic (C24:1) acid and mono were decreased at term (Table 6).

    The dominance of AA. In the different polar phosphoglycerides, AA ranged from 17 to 36% of the fatty acids and was present in higher proportions than any other unsaturated fatty acid in all but the serine phosphoglycerides. AA was substantially greater than the total of long-chain (n-3) fatty acids even in the serine phosphoglycerides, which are usually reported to be concentrated in DHA rather than AA.

	DISCUSSION

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
    Comparison with other data. This is the first study to compare the fatty acid composition of human placental membrane phospholipids at the beginning and end of gestation. Membrane phospholipids and fatty acids influence the physiological and morphological properties of the human placenta (4,19). Because the phospholipid molecular species contain essential and nonessential fatty acids, they are the cellular component that is susceptible to host nutrition. It was reported that 77–88% (19,20) of placental lipids are made up of phospholipids, 50–60% of which are EPG and CPG (19).

Information about the early placenta is limited. Nikolasev et al. (19) investigated the fatty acid composition of CPG, EPG, IPG, and SPM from 5 pregnancies (5 and 12 wk of gestation) in Szeged. They defined the early membranes as predominantly saturated. They reported AA at 1.0%, which we suspect was due to a methodological error.

Our data on term placentae, in agreement with other term data (20–23), demonstrate that AA is quantitatively an important placental membrane constituent (Table 7). Moreover, the study of Powell et al. (24) on the fatty acid composition of the microvillous (n = 8) and basal (n = 8) membranes suggested that the AA content is relevant to the syncytiotrophoblast membranes that comprise the epithelial barrier to transport across the human placenta. The above studies, with the exception of Nikolasev et al. (19), demonstrated a high preference of AA for the placental membranes. However, these studies had a small sample size or focused only on the total phospholipids.

    AA in the placentae. The compositional data reported here demonstrated that the human placental membranes from their earliest formation accumulate very high proportions of AA but not DHA. In fact, AA was the most abundant unsaturated fatty acid in the polar phosphoglycerides, with the exception of SPG. Although AA was significantly reduced at term, the proportions were substantially higher than in maternal and neonatal (cord) plasma and RBC, umbilical arteries, and brain (Fig. 1) (14,22,27–31).

View larger version (9K): [in this window] [in a new window]   FIGURE 1 The percentage AA and DHA of ethanolamine phosphoglycerides in early (gestation, n = 48) and term (n = 19) placentae, umbilical arteries (30), maternal and fetal RBC (29), and adult brain (31).

The lipid analysis of the early placentae is especially interesting. During this transient period of development, which is associated with uteroplacental vascularization and organogenesis (2,6,36–38), our data show that independent of differences in maternal origin and ethnicity, the placenta contains remarkably high amounts of AA from its inception. The embryoplacental circulation is effective by 10 wk and the first extraembryonic vessels are paired veins and arteries communicating directly with the embryonic cardiovascular system (3). The first heartbeat can be detected by highly sensitive ultrasound techniques as early as 4.5 wk of gestation (3).

    Role of the endothelium. The endothelium plays a primary role in placental angiogenesis (6) and in organogenesis (39–41). AA is the major unsaturated fatty acid in the human vascular endothelium inner cell membrane lipid (9). The remarkably high proportion of AA at 8 wk of gestation is consistent with the differentiation of the first vascular network to establish a normal fetoplacental circulation (35). The developing membranes require large amounts of AA during rapid cell division, increased trophoblast invasion, development, and growth of the fetal tissues (2). Organogenesis is completed at 11–12 wk of gestation (3). After 12 wk, the maternal arteries have become sizable and clearly delineated and the blood flow has increased substantially (5,38,42). At 14 wk of gestation, differentiation of the chorionic sac into smooth chorion and placenta is initiated (35).

There is also evidence that AA, but not EPA or DHA, induces differentiation of uterine stromal and decidual cells (43). Its turnover in nuclear membranes in stromal cells during proliferation is particularly high (44). In addition, AA but not DHA appears to act as an endothelial relaxation factor (31). The surprisingly high concentration of AA in early and term placenta taken together with the evidence mentioned above raises the speculation that AA is contributing to placental development and to organogenesis.

    Early vs. term placentae. It was proposed that the eicosanoids derived from AA constitute a part of the timing mechanism that initiates parturition (45–47). A secondary aim of this study was to test whether the AA content of the placental membranes increased toward term, consistent with increased vascularization, and reached a critical level that could initiate parturition through prostaglandins derived from arachidonic acid.

The data presented here, however, showed that the proportions of AA decreased and the only eicosanoid precursor to increase in any phosphoglyceride fraction was DGLA. The properties of the DGLA derivative prostaglandin (PGE₁) are functionally the opposite of the muscle-contracting and vascular-constrictor properties of thromboxane A₂ and PGF₂. The AA-derived PGF₂ has been used routinely as an abortifacient. The reduction in AA and increase in DGLA suggest a physiological design more relevant to muscle relaxation and the prevention of vascular occlusive events. Kuhn et al. (48) found that little or no muscle-contracting eicosanoids were produced from AA in the ex vivo perfusion of the human placental lobe. However, successive wave pressures quickly elicited prostaglandin production. By way of contrast, AA is the precursor for prostacyclin, again an antiaggregatory and vasorelaxant eicosanoid which, in the absence of trauma, would help maintain normal blood flow. Our results support Kuhn’s conclusion that the high content of AA may also be a "fail safe" mechanism rather than an initiator of parturition.

In conclusion, the remarkably high proportions of AA in early placenta raise the speculation that AA may participate in early developmental processes such as implantation, vascular growth, and hence organogenesis. The sequestering of AA and enrichment of term membranes with DGLA in normal pregnancies suggest a role for the (n-6) fatty acids favoring blood flow. With the current popular enthusiasm for (n-3) fatty acids, the importance of the (n-6) fatty acids both in relation to developmental mechanisms and the nutritional requirements for the mother and fetus warrants reevaluation.

	FOOTNOTES

 
¹ Supported by Mother & Child Foundation, Vice Chancellors’ Development and Diversity Programme, and The Worshipful Company of Innholders.

² Supplemental Tables 1–4 are available as Online Supporting Material with the online posting of this paper at www.nutrition.org.

⁴ Abbreviations used: AA, arachidonic acid; C22, behenic acid; C16, palmitate; C16:1, palmitoleate; C18:1, oleate; C24, lignoceric acid; C24:1, nervonic acid; CPG, choline phosphoglycerides; DGLA, dihomo -linolenic acid; DHA, docosahexaenoic acid; DPA(n-3), docosapentaenoic acid (n-3); EFA, essential fatty acids; EPA, eicosapentaenoic acid; EPG, ethanolamine phosphoglycerides; IPG, inositol phosphoglycerides; LA, linoleate; met, metabolites; mono, monounsaturates; PG, prostaglandin; SPG, serine phosphoglycerides; SPM, sphingomyelin.

Manuscript received 14 March 2005. Initial review completed 12 April 2005. Revision accepted 4 August 2005.

	LITERATURE CITED

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 

1. Cross J. C. Formation of the placenta and extraembryonic membranes. Ann. N.Y. Acad. Sci. 1998;857:23-32.[Abstract/Free Full Text]

2. Kingdom J., Huppertz B., Seaward G., Kaufmann P. Development of the placental villous tree and its consequences for fetal growth. Eur. J. Obstet. Gynecol. Reprod. Biol. 2000;92:35-43.[Medline]

3. Kingdom J., Jauniaux E., O’Brien S. Development of the placental villous tree and its consequences for fetal growth. The Placenta: Basic Science and Clinical Practice. 1st ed. RCOG Press London, UK.

4. Page K. Development of the placental villous tree and its consequences for fetal growth. The Physiology of the Human Placenta. UCL Press London, UK.

5. Jaffe R. First trimester utero-placental circulation: maternal-fetal interaction. J. Perinat. Med. 1998;26:168-174.[Medline]

6. Dantzer V., Leach L., Leiser R. Angiogenesis and placental vasculature—a workshop report. Placenta. 2000;21:S69-S70.

7. Crawford M. A., Hassam A. G., Williams G., Whitehouse W. L. Essential fatty acids and fetal brain growth. Lancet. 1976;:452-453.

8. Crawford M. A. Placental delivery of arachidonic and docosahexaenoic acids: implications for the lipid nutrition of preterm infants. Am. J. Clin. Nutr. 2000;71:275S-284S.[Abstract/Free Full Text]

9. Crawford M. A., Costeloe K., Ghebremeskel K., Phylactos A., Skirvin L., Stacey F. Are deficits of arachidonic and docosahexaenoic acids responsible for the neural and vascular complications of preterm babies?. Am. J. Clin. Nutr. 1997;66:1032S-1041S.[Abstract/Free Full Text]

10. Anderson R. E., Maude M. B. Lipids of ocular tissues. 8. The effects of essential fatty acid deficiency on the phospholipids of the photoreceptor membrane rat retina. Arch. Biochem. Biophys. 1972;151:270-276.[Medline]

11. Crawford M. A., Sinclair A. J. Nutritional influences in the evolution of the mammalian brain. In: Lipids, Malnutrition and the Developing Brain. Elliot K. Knight J. eds. Nutritional influences in the evolution of the mammalian brain. In: Lipids, Malnutrition and the Developing Brain. A Cibe Foundation Symposium (19–21 October, 1971). :267-292 Elsevier Amsterdam, the Netherlands.

12. Uauy R., Hoffman D. R. Essential fat requirements of preterm infants. Am. J. Clin. Nutr. 2000;71:245-250.

13. van Houwelingen A. C., Puls J., Hornstra G. Essential fatty acid status during early human development. Early Hum. Dev. 1992;31:97-111.[Medline]

14. Rump P., Hornstra G. The n-3 and n-6 polyunsaturated fatty acid composition of plasma phospholipids in pregnant women and their infants. Relationship with maternal linoleic acid intake. Clin. Chem. Lab. Med. 2002;40:32-39.[Medline]

15. Haggarty P. Placental regulation of fatty acid delivery and its effect on fetal growth—a review. Placenta. 2002;23:S28-S38.

16. Kirkwood B. R. Placental regulation of fatty acid delivery and its effect on fetal growth—a review. Essentials of Medical Statistics. Blackwell Scientific Publications London, UK.

17. Folch J., Lees M., Sloane-Stanley G. H. A simple method for the isolation and purification of total lipides from animal tissues. J. Biol. Chem. 1957;226:497-509.[Free Full Text]

18. Touchstone J. C., Levin S. S., Dobbins M. F., Beers P. C. Analysis of saturated and unsaturated phospholipids in biological fluids. J. Liq. Chromatogr. 1983;6:179-192.

19. Nikolasev V., Resch B. A., Meszaros J., Szontagh F. E., Karady I. Phospholipid content of early human placenta and fatty acid composition of the individual phospholipids. Steroids Lipids Res. 1973;4:76-85.[Medline]

20. Klingler M., Demmelmair H., Larque E., Koletzko B. Analysis of FA contents in individual lipid fractions from human placental tissue. Lipids. 2003;38:561-566.[Medline]

21. Percy P., Vilbergsson G., Percy A., Mansson J.-E., Wennergren M., Svennerholm L. The fatty acid composition of placenta in intrauterine growth retardation. Biochim. Biophys. Acta. 1991;1084:173-177.[Medline]

22. Lakin V., Haggarty P., Abramovich D. R., Ashton A. J., Moffat C. F., McNeill G., Danielian P. J., Grubb D. Dietary intake and tissue concentration of fatty acids in omnivore, vegetarian and diabetic pregnancy. Prostaglandins Leukot. Essent. Fatty Acids. 1998;59:209-220.[Medline]

23. Matorras R., Lopez De Larrucea A., Sanjurjo P., Ruiz J. I., Echevarria Y., Nieto A., Perteagudo L., Aldamiz-Echevarria J. L. Increased tissue concentrations of arachidonic acid in umbilical artery and placenta in fetal growth retardation. Acta Obstet. Gynecol. Scand. 2001;80:807-812.[Medline]

24. Powell T. L., Jansson T., Illsley N. P., Wennergren M., Korotkova M., Strandvik B. Composition and permeability of syncytiotrophoblast plasma membranes in pregnancies complicated by intrauterine growth restriction. Biochim. Biophys. Acta. 1999;1420:86-94.[Medline]

25. Wijnberger L. D., de Kleine M., Voorbij H. A., Arabin B., van de Leur J. J., Bruinse H. W., Visser G. H., Bossuyt P. M., Mol B. W. The effect of clinical characteristics on the lecithin/sphingomyelin ratio and lamellar body count: a cross-sectional study. J. Matern. Fetal Neonatal Med. 2003;14:373-382.[Medline]

26. Poggi S. H., Spong C. Y., Pezzullo J. C., Bannon P. Z., Goodwin K. M., Vink J., Ghidini A. Lecithin/sphingomyelin ratio and lamellar body count. What values predict the presence of phosphatidylglycerol?. J. Reprod. Med. 2003;48:330-334.[Medline]

27. Bohles H., Arndt S., Ohlenschlager U., Beeg T., Gebhardt B., Sewell A. C. Maternal plasma homocysteine, placenta status and docosahexaenoic acid concentration in erythrocyte phospholipids of the newborn. Eur. J. Pediatr. 1999;158:243-246.[Medline]

28. Min Y., Ghebremeskel K., Lowy C., Thomas B., Crawford M. A. Adverse effect of obesity on red cell membrane arachidonic and docosahexaenoic acids in gestational diabetes. Diabetologia. 2004;47:75-81.[Medline]

29. Min Y., Lowy C., Ghebremeskel K., Thomas B., Bitsanis D., Crawford M. A. Fetal erythrocyte membrane lipids modification: preliminary observation of an early stage sign of compromised insulin sensitivity in offspring of gestational diabetics. Diabet. Med. 2005;22:914-920.[Medline]

30. Crawford M. A., Costeloe K., Doyle W., Leighfield M. J., Lennon E. A., Meadows N. Potential diagnostic value of the umbilical artery as a definition of neural fatty acid status of the fetus during its growth: the umbilical artery as a diagnostic tool. Biochem. Soc. Trans. 1990;18:761-766.[Medline]

31. Crawford M. A., Golfetto I., Ghebremeskel K., Min Y., Moodley T., Poston L., Phylactos A., Cunnane S., Schmidt W. The potential role for arachidonic and docosahexaenoic acids in protection against some central nervous system injuries in preterm infants. Lipids. 2003;38:303-315.[Medline]

32. Das U. N. Essential fatty acids in health and disease-review article. J. Assoc. Physicians India. 1999;47:906-911.[Medline]

33. Hindenes J. O., Nerdal W., Guo W., Di L., Small D. M., Holmsen H. Physical properties of the transmembrane signal molecule, sn-1-stearoyl 2-arachidonoylglycerol. Acyl chain segregation and its biochemical implications. J. Biol. Chem. 2000;275:6857-6867.[Abstract/Free Full Text]

34. Min Y., Crawford M. A. Essential fatty acids. Curtis-Prior P. eds. Essential fatty acids. The Eicosanoids. :257-265 John Wiley & Sons London, UK.

35. Benirschke K., Kaufmann P. Essential fatty acids. Pathology of the Human Placenta. 3rd ed. Springer-Verlag New York, NY.

36. Burrows T. D., King A., Loke Y. W. Trophoblast migration during human placental implantation. Hum. Reprod. Update. 1996;2:307-321.

37. Pijnenborg R. The origin and future of placental bed research. Eur. J. Obstet. Gynecol. Reprod. Biol. 1998;81:185-190.[Medline]

38. Kliman H. J. Uteroplacental blood flow: the story of decidualization, menstruation, and trophoblast invasion—commentary. Am. J. Pathol. 2000;157:1759-1768.[Free Full Text]

39. Matsumoto K., Yoshitomi H., Rossant J., Zaret K. S. Liver organogenesis promoted by endothelial cells prior to vascular function. Science. 2001;294:559-563.[Abstract/Free Full Text]

40. Bahary N., Zon L. I. Endothelium—chicken soup for the endoderm. Science (Washington, DC). 2001;294:530-531.[Free Full Text]

41. Lammert E., Cleaver O., Melton D. Induction of pancreatic differentiation by signals from blood vessels. Science (Washington, DC). 2001;294:564-567.[Abstract/Free Full Text]

42. Burton G. J., Jauniaux E., Watson A. L. Maternal arterial connections to the placental intervillous space during the first trimester of human pregnancy: the Boyd collection revisited. Am. J. Obstet. Gynecol. 1999;181:718-724.[Medline]

43. Tessier-Prigent A., Willems R., Lagarde M., Garrone R., Cohen H. Arachidonic acid induces differentiation of uterine stromal to decidual cells. Eur. J. Cell Biol. 1999;78:398-406.[Medline]

44. Delton-Vandenbroucke I., Lemaire P., Lagarde M., Laugier C. Hydrolysis of nuclear phospholipids in relation with proliferative state in uterine stromal cells. Biochimie. 2004;86:269-274.[Medline]

45. Okita J. R., Johnston J. M., MacDonald P. C. Source of prostaglandin precursor in human fetal membranes: arachidonic acid content of amnion and chorion laeve in diamnionic-dichorionic twin placentas. Am. J. Obstet. Gynecol. 1983;147:477-482.[Medline]

46. Schafer W. R., Zahradnik H. P., Arbogast E., Wetzka B., Werner K., Breckwoldt M. Arachidonate metabolism in human placenta, fetal membranes, decidua and myometrium: lipoxygenase and cytochrome P450 metabolites as main products in HPLC profiles. Placenta. 1996;17:231-238.[Medline]

47. Meadows J. W., Eis A.L.W., Brockman D. E., Myatt L. Expression and localization of prostaglandin E synthase isoforms in human fetal membranes in term and preterm labor. J. Clin. Endocrinol. Metab. 2003;88:433-439.[Abstract/Free Full Text]

48. Kuhn D. C., Crawford M. A., Stuart M. J., Botti J. J., Demers L. M. Alterations in transfer and lipid distribution of arachidonic acid in placentas of diabetic pregnancies. Diabetes. 1990;39:914-918.[Abstract]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bitsanis, D. Articles by Djahanbakhch, O. Search for Related Content PubMed PubMed Citation Articles by Bitsanis, D. Articles by Djahanbakhch, O.