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Electronic Letters to:
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Electronic letters published:
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Unexpected Relationship between Plasma Homocysteine and Intrauterine Growth Restriction.
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Majid Y Moridani, Clinical Chemist Texas Tech University Health Sciences Center
Send letter to journal:
m.moridani{at}utoronto.ca Majid Y Moridani
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To the Editor: In their article, Infante-Rivard et al. (1) present evidence that the homocysteine values were largely <15 micromol/L in the subjects of their case control study. The cases were born at their institution over a 2 year period whose birthweight was below the 10th percentiles for gestational age and sex. The control group included babies born at or above 10th percentiles. The mothers were also included in the study. These investigators initiated their research based on an assumption that higher maternal and newborn homocystiene concentrations in plasma would increase the risk of intrauterine growth restriction through placental thrombosis. In contrast to their proposed hypothesis, they have concluded that mothers with small babies have lower homocysteine concentrations than those giving birth to larger infants. There are several issues with the conclusion that the authors made in their article which should be addressed. First the maternal total homocysteine (t-Hcy) was measured within 48 h postpartum. This measurement does not reflect the actual t-Hcy during pregnancy, which may have been fallen or elevated during 48 hours after labor. The proper investigation should include specimen collection at various points during pregnancy (first trimester, second and third trimesters), immediately after labor and at least one week postpartum and ideally even before pregnancy to see if there is a meaningful and statistically significant difference between the obtained t-Hcy values. Without these data such conclusion or argument made in the article does not hold valid. These investigators previously published a reference range study (2) for t-Hcy for maternal blood however the study suffers from the same problem of inappropriate sampling time. The authors indicated that contrary to their hypothesis the probability of a mother giving birth to a baby with growth restriction decreased with increasing total homocysteine; i.e birthweight increased with t-Hcy concentrations. There was no conclusive statistical data included in their communication showing that the values for t-Hcy were significantly different between control infants and cases and between their mothers. Although the mean t-Hcy 5.11 micomol/L (CI, 4.95-5.26; range, 1.76-14.03) from Table 2 (1) for case mothers seems different from the mean t-Hcy 5.59 micromol/L (CI, 5.41- 5.76; range 1.92-15.98) for control mothers it does not say much about individuals at risk. It would have been more interesting to see the distribution of the results and their quartiles using boxplot so the reader could see if there is a significant overlap between the data in two groups or not. The confidence interval for the mean is calculated based on “mean +/- 2 SEM” and what this conveys is that the two populations are different but it does not provide us with additional information on individuals at risk. In the first paragraph of their discussion authors claimed that the results for Hcy in the newborn were in the same direction as mothers, but it is hard to believe that the mean 4.99 micromol/L (CI, 4.84-5.15; range 1.03-17.94) from Table 2 (1) for newborn cases is statistically different from the mean 5.06 micromol/L (CI, 4.92-5.21; range, 0.73-15.62) for the newborn controls especially when the analytical CV was 10%. Again a boxplot presentation of the data will be a great help to see the trends. The authors raised the question that what factors could be invoked to explain their unexpected findings. They indicated that since the range of t-Hcy values fall below the cut off for mild hyperhomocysteinemia therefore the postulated atherothrombotic effects (3) in that range (<15 micromol/L) may be either altered or nonexistent. They provided an alternative theory by referencing Zappacosta et al report (4) that in vitro homocyesteine at low concentrations does not act as a prooxidant but shows an antioxidant effect. One should note that there may be a third mechanism that worth mentioning. Since all the t-Hcy values were bellow the cutoff for mild hyperhomocysteinemia it should be considered within normal range. However those who had a t-Hcy value closer to upper reference limit may have had a better diet during pregnancy. Hcy is derived from methionine, an essential amino acid (5), and this could qualify it as a novel nutritional biomarker for risk assessment of intrauterine growth restriction during pregnancy if their conclusion is valid. Obviously this needs further data to be substantiated and requires an appropriate statistical analysis of the t-Hcy concentration between the cases and controls. To do this, an appropriate reference range study for t -Hcy is needed in pregnant and non pregnant women along with studying the weight gain during pregnancy. This may further support Zappacosta (4) because a better nutritional supply may provide sufficient t-Hcy to work as anti-oxidant. Therefore, a higher t-Hcy means that the mother of the infant with a higher birthweight may have had a better diet and so there were more nutrients available in maternal blood to be transferred to fetus. On the other hand Haulrik (6) showed that a high-protein, high- methionine diet did not raise homocysteine concentrations compared with a low-protein, low-methionine diet in overweight adults. They also showed that homocysteine concentrations after the 3-month intervention were inversely associated with vitamin B12 intake and with weight change. The authors claimed in their response letter that their results were comparable with other North American results (7-9). I did not see any comparability between the authors and the cited references (7-9). Walker et al (7) measured Hcy in non-pregnant control women and in first, second and third semester normal pregnant women. However, Walker et al did not measure Hcy postpartum. Walker et al also found that Hcy level decreased during pregnancy. This is evident from the figure 2 of their publication (7). Therefore Infante-Rivard et al results (1) are not comparable to Walker et al (7) findings especially when the latter group did not measure the Hcy in women after the delivery. Malinow et al (8) hypothesized in their publication that Hcy, an amino acid that is not a constituent of proteins, crosses the maternal/placental/fetal interphases and is taken by the fetus. To test this hypothesis, Malinow et al (8) determined the concentration of plasma Hcy in maternal vein, and neonatal umbilical vessels at the time of delivery. Their findings demonstrated a progressive decrease in the concentration of plasma Hcy going from the maternal vein to the umbilical vein and to the umbilical artery. Their data support the hypothesis that Hcy is sequestered by the fetus. In my view this study had a proper design for the time of specimen collection. They sampled the blood at the time of delivery but not 48 h postpartum. Pagan et al (9) studied the serum Hcy in smoker and non-smoker pregnant women (18-30 weeks of gestation only). They found that the level of Hcy in smokers 5.7 +/- 3.4 micromol/L was not different from that of the non-smokers 4.9 +/- 1.6 micromol/L. Interestingly the difference between the Hcy levels between the two groups was almost the same as the one that Infante-Rivard reported (1) however Pegan et al (9) did not report the difference significant. To conclude, additional data is required to support the unexpected relationship observed between plasma Hcy and intrauterine growth restriction. In addition the role of vitamin B12 and folic acid should also be investigated. Majid Y. Moridani School of Pharmacy Texas Tech University Health Sciences Center Amarillo, TX 79106, USA. 1. Infante-Rivard C, Rivard GE, Gauthier R, Theoret Y. Unexpected relationship between plasma homocysteine and intrauterine growth restriction. Clin Chem. 2003;49(9):1476 1482. 2. Infante-Rivard C, Rivard GE, Yotov WV, Theoret Y. Perinatal reference intervals for plasma homocysteine and factors influencing its concentration. Clin Chem. 2002;48(7):1100-1102. 3. Knekt P, Reunanen A, Alfthan G, Heliovaara M, Rissanen H, Marniemi J, Aromaa A. Hyperhomocystinemia: a risk factor or a consequence of coronary heart disease? Arch Intern Med. 2001;161(13):1589-1594. 4. Zappacosta B, Mordente A, Persichilli S, Minucci A, Carlino P, Martorana GE, Giardina B, De Sole P. Is homocysteine a pro-oxidant? Free Radic Res. 2001;35(5):499-505. 5. Langman LJ. Cole DE. Homocysteine. Crit Rev Clin Lab Sci. 1999;36(4):365-406. 6. Haulrik N. Toubro S. Dyerberg J. Stender S. Skov AR. Astrup A. Effect of protein and methionine intakes on plasma homocysteine concentrations: a 6-mo randomized controlled trial in overweight subjects. Am J Clin Nutr. 2002;76(6):1202-1206. 7. Walker MC, Smith GN, Perkins SL, Keely EJ, Garner PR. Changes in homocysteine levels during normal pregnancy. Am. J. Obstet. Gynecol. 1999;180:660-664. 8. Malinow MR, Rajkovic A, Duell PB, Hess DL, Upson BM. The relationship between maternal and neonatal umbilical cord plasma homocyst(e)ine suggests a potential role for maternal homocyst(e)ine in fetal metabolism. Am. J. Obstet. Gynecol. 1998;178:228-233. 9. Pagan K, Jinrong H, Goldenberg RL, Cliver SP, tamura T. Effect of smoking on serum concentrations of total homocysteine and B vitamins in mid-pregnancy. Clin. Chim. Acta. 2001;306:103-111. |
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