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Technical Briefs |
Departments of
1
Gastroenterology and
2
Obstetrics and Gynecology, University Hospital St. Radboud, PO Box 9101, 6500 HB Nijmegen, The Netherlands
3
Department of Obstetrics and Gynecology, ‘Nij Smellinghe’ Hospital, PO Box 20200, 9200 DA Drachten, The Netherlands
a author for correspondence: fax 31-24-3540103, e-mail w.peters{at}gastro.azn.nl
Cysteine is the only sulfhydryl-containing amino acid in proteins and is the thiol residue in glutathione (1). In addition to its importance in the storage and transport of cysteine, glutathione plays a pivotal role in detoxification by the action of glutathione S-transferases and in scavenging free (oxygen) radicals by the action of glutathione peroxidases (1).
Thiol metabolism may be altered during pregnancy. In healthy pregnant women, plasma concentrations of cysteine, glutathione, and homocysteine are decreased, whereas increased homocysteine and cysteine concentrations are seen in pathologic conditions, such as preeclampsia, in which oxidative stress may play an important role (2)(3)(4).
Thiols may have important physiological functions in fetal metabolism. Although protein and amino acid turnover in the human placenta has been studied extensively (5)(6)(7), few data concerning fetal concentrations of thiols and placental maternal-fetal thiol interactions are currently available (8). During normal pregnancy, fetal growth depends on the supply of nutrients from the mother, and a clear correlation between maternal and fetal amino acid and homocysteine concentrations has been shown (6)(7)(8). Decreased concentrations of amino acids in the umbilical artery, as compared with the umbilical vein, have been interpreted as an uptake of amino acids into fetal tissues where they may be used in protein biosynthesis or as sources of energy (5). We studied fetal and maternal thiol plasma concentrations in normal pregnancies to determine reference concentrations for cysteine, homocysteine, and cysteinylglycine in arterial and venous umbilical cord plasma to gain insight into maternal-fetal thiol interactions.
Arterial and venous umbilical cord blood samples from 320 consecutive
neonates were drawn in preheparinized tubes immediately after
birth (cat. no. 260545; Kemper Medical) from March 1997 to
January 1998 at the Department of Obstetrics/Gynecology of the ‘Nij
Smellinghe’ Hospital. Approval for this study was granted by the
Institutional Review Board of the hospital. Blood gas values were
assessed on an ABL-330 analyzer (Radiometer Nederland). Samples with a
pH difference between arterial and venous umbilical cord blood <0.02
pH units and samples from neonates with a gestational age <37 weeks,
an umbilical artery pH <7.20, a birth weight below the 10th percentile
according to Kloosterman (9), or who were the offspring of
women with a diastolic blood pressure >90 mmHg during gestation were
excluded. Antecubital maternal venous blood of 35 women was collected
in parallel with the umbilical cord samples after informed consent.
Samples were taken in heparinized tubes (cat. no. 367684; Becton and
Dickinson) <4 h before elective caesarian delivery or <15 min after
vaginal birth. Blood was centrifuged within 10 min at 1200g
for 10 min at room temperature. Plasma samples were stored at
-30 °C for 
2 years until analysis. Plasma concentrations of
total cysteine (tCys), total homocysteine (tHcy), and total
cysteinylglycine (tCysGly) in 195 umbilical cord (102 males and 92
females; no gender was recorded for 1 neonate) and 35 maternal samples
were determined by HPLC as described previously (2).
After log transformation to approach normalization, we analyzed the data by the paired t-test to assess statistical differences between maternal venous blood and arterial umbilical cord blood values. The Spearman rank coefficient of correlation was calculated when appropriate using Astute for Microsoft Excel 5.0. P <0.05 was considered significant.
The median (central 0.95 interval) characteristics for the study group (n = 195) were as follows: maternal age, 29 years (20–41 years); gestational age, 40 weeks, 3 days (37 weeks, 3 days to 42 weeks, 3 days); maternal blood pressure, 80 mmHg, phase IV Korothoff (K4; 60–90 mmHg); birth weight, 3510 g (2800–4570 g); and placental weight, 695 g (500–980 g). These characteristics were representative of the population as admitted for term deliveries in the Drachten Hospital. The maternal characteristics of the subgroup (n = 35) were not different from the total study group.
In arterial umbilical cord plasma, median (central 0.95 interval) values for the following were significantly lower than in venous umbilical cord plasma: PO2, 17 kPa (9–34 kPa) for arterial vs 28 kPa (16–43 kPa) for venous (P <0.0001); HCO3-, 19.2 mmol/L (14.7–24.5 mmol/L) for arterial vs 20.2 mmol/L (16.7–23.0 mmol/L) for venous (P <0.0001); pH 7.27 (7.20–7.37) for arterial vs 7.34 (7.26–7.43) for venous (P < 0.0001); and base deficit -4.4 (-9.1 to 0.5) for arterial vs -4.0 (-8.1 to 0.5) for venous (P = 0.0001). PCO2 was significantly higher in umbilical cord blood: 52 kPa (35–64 kPa) for arterial vs 40 kPa (29–50 kPa) for venous (P <0.0001).
Concentrations of tCys and tHcy were significantly lower in arterial
compared with venous umbilical cord plasma (P = 0.0002
and P = 0.009, respectively; see Table 1
), whereas concentrations of tCysGly were significantly higher
in arterial compared with venous umbilical cord plasma
(P = 0.005).
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Maternal and venous and arterial umbilical cord plasma in the
subgroup of 35 cases are presented in Fig. 1
. Maternal tCys concentrations were lower than venous umbilical cord
plasma (P = 0.04), whereas there was a tendency for
higher tCys concentrations in venous vs arterial umbilical cord plasma
(P = 0.06). Arterial umbilical cord tCys concentrations
tended to be higher than maternal concentrations (P =
0.1). Associations were found between tCys concentrations in maternal
and venous umbilical cord plasma (r = 0.84;
P <0.0001), venous and arterial umbilical cord plasma
(r = 0.82; P <0.0001), and arterial
umbilical cord and maternal plasma (r = 0.81;
P <0.0001).
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tHcy showed a decreasing concentration gradient from maternal to venous and arterial umbilical cord plasma (P = 0.001 and P = 0.04, respectively). Significantly lower tHcy concentrations were found in arterial umbilical cord vs maternal plasma (P <0.0001). Maternal and venous umbilical cord, venous and arterial umbilical cord, and arterial umbilical cord and maternal plasma concentrations of tHcy were correlated (r = 0.83, P <0.0001; r = 0.82, P <0.0001; and r = 0.79, P <0.0001, respectively). No associations were found between maternal, arterial, and venous umbilical cord tHcy concentrations and neonatal weight (r = 0.07, P = 0.9; r = 0.12, P = 0.1; and r = 0.0076, P = 0.9, respectively).
No differences were found between maternal and umbilical venous or arterial tCysGly concentrations, whereas an association was found between arterial and venous cord tCysGly concentrations (r = 0.59; P <0.001).
The samples analyzed in this study were from uncomplicated pregnancies, and consequently the neonatal thiol values can be used as reference values.
Concentrations of tCys and tHcy are lower in arterial vs venous umbilical cord plasma, indicating uptake of both thiols into the fetal circulation, where they may be used in the biosynthesis of glutathione and proteins. tHcy may pass the maternal-fetal barrier driven by a concentration gradient. In contrast, tCys is transported from mother to fetus against a gradient, probably by active transport. tCys must be taken up by the fetus in this way because tHcy cannot be converted to tCys by the fetus because of an absence in the fetus of cystathionine-ß-synthase, which is the enzyme that catalyzes this conversion in adults (10).
Maternal thiol concentrations are comparable to those we reported previously in a study group on increased nonpregnant vs normal pregnant plasma thiol values, most probably because of an increased plasma volume in normal pregnancy (2). Although the median maternal tHcy concentrations seemed higher compared with our previous findings (2), no statistical difference was found (P = 0.45). Our tHcy values are higher than those found previously in a Northern American population (8)(11), which may be explained by a higher intake of folate and B vitamins in the American population, as discussed by den Heyer et al. (12).
In conclusion, tCys, which is an essential amino acid in the human fetus, may be actively transported in the placenta from the maternal to the fetal circulation where it is used in biosynthesis. Similarly, the fetus may extract tHcy from the maternal circulation.
Acknowledgments
This study was supported by Grant 28-2801.1 from the "Praeventiefonds", The Hague, The Netherlands. We thank Claudia van Alphen for patient data management.
References
The following articles in journals at HighWire Press have cited this article:
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  E. M Guerra-Shinohara, O. E Morita, S. Peres, R. A Pagliusi, L. F Sampaio Neto, V. D'Almeida, S. P Irazusta, R. H Allen, and S. P Stabler Low ratio of S-adenosylmethionine to S-adenosylhomocysteine is associated with vitamin deficiency in Brazilian pregnant women and newborns Am. J. Clinical Nutrition, November 1, 2004; 80(5): 1312 - 1321. [Abstract] [Full Text] [PDF]
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 C. Infante-Rivard, G.-E. Rivard, W. V. Yotov, and Y. Theoret Perinatal Reference Intervals for Plasma Homocysteine and Factors Influencing Its Concentration Clin. Chem., July 1, 2002; 48(7): 1100 - 1102. [Full Text] [PDF]
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