Unexpected relationship between plasma homocysteine and intrauterine growth restriction.
Mild hyperhomocysteinemia has been associated with pregnancy outcomes such as abruptio placentae, preeclampsia, and fetal loss (3, 4). However, results on the association between plasma total homocysteine (tHcy) and atherothrombotic conditions in general are not consistent (5), and some authors have even suggested that the association is an effect rather than a cause, e.g., the increase in plasma homocysteine could be caused by the decrease in renal function that is common in atherosclerosis (6).
One small study measured maternal tHcy immediately after delivery and compared it between 37 IUGR cases and 35 controls; these results did not show a difference (7). Recently, Murakami et al. (8) measured tHcy as well as the MTHFR C677T genotype in pregnant Japanese women at 6-12 weeks of gestation; 27 eventually had a newborn with IUGR, and the tHcy concentration was determined to be within the reference interval in 26 of these mothers.
We reported maternal reference intervals for tHcy for the period immediately after an uncomplicated pregnancy, as well as values for healthy newborns (9). In this group, smoking during pregnancy as well as consumption of coffee and colas significantly increased the newborn tHcy, whereas maternal vitamin intake and consumption of foods rich in folic acid reduced it. On the other hand, MTHFR C677T and A1298C did not significantly influence the tHcy concentration, although maternal concentrations increased slightly with the number of C677T variant copies.
We now report results on the relationship between maternal and newborn tHcy and IUGR in the patient population used for our study of MTHFR and IUGR (2).
Materials and Methods
SELECTION OF CASES AND CONTROLS (2)
Cases were newborns whose birthweight was below the 10th percentiles for gestational age and sex, based on Canadian standards (10). All cases seen at our university center between May 1998 and June 2000, born alive after the 24th week of gestation and without severe congenital anomalies, were eligible for the study. During that period, 505 cases were seen and 493 participated in the study (97.6%). The same criteria applied to the selection of controls whose birthweights were at or above the 10th percentile. They were matched to cases for gestational week, sex, and race (white, black, Hispanic, or Amerindian and Asian). The mothers of 480 controls were invited to participate, and 472 accepted (98.3%). Slightly more cases than controls were accrued because cases entered the study first; at the preset time for study termination, 21 cases were without a matched control. The project was approved by the Institutional Review Board of the hospital. Informed consent was signed by the mother to collect cord and maternal blood.
A face-to-face interview with all mothers of cases and controls was carried out at the hospital after delivery. The interview was based on a similar interview used previously in the same environment (11) and included the measure of potential confounding factors such as demographic factors, anthropometric measures before and after pregnancy, pregnancy diseases, maternal chronic diseases, obstetric history, smoking, and use of multivitamin supplements.
Blood samples were collected and analyzed as described previously (9,12). Briefly, venous maternal blood was obtained within 48 h of delivery (median, 25 h). Placental blood from the umbilical vein was taken from the newborn. Citrate-buffered blood samples were kept at 4[degrees]C until centrifugation, which took place within 6 h (median, 0.58 h) for maternal samples and within 24 h for newborns (median, 6.06 h). This difference reflects the fact that the maternal specimen was obtained by the research nurse on duty, whereas that from the newborn was taken by the delivery room personnel at all hours. Under these collection and storage conditions, tHcy concentrations were stable for at least 24 h (12). After centrifugation, samples were stored at -70[degrees]C.
MEASUREMENT OF PLASMA tHcy
Briefly, N-acetyl-L-cysteine (internal standard) subjected to reduction with tri-n-butylphosphine in dimethylformamide was added to plasma samples. After incubation, the plasma proteins were precipitated with perchloric acid, and thiols of interest were derivatized with 7-fluorobenzofurazane-4-sulfonic acid. Isocratic elution of Hcy was carried out on a Kromasil [C.sub.18] column (Phenomenex) with a mobile phase containing 980 mL/L sodium acetate (0.2 mol/L; pH 4) and 20 mL/L methanol. The fluorescence detection was performed on a Shimadzu RF551 fluorescence spectrometer (Shimadzu Corporation). Data were collected and analyzed with the Gold software (Ver. 6.0) from Beckman-Coulter. More than 100 standardization assays were carried out over the course of determining tHcy in our specimens. Calibration curves constructed with calibrators prepared in water were linear over tHcy concentrations of 0.78-50 [micro]mol/L. We analyzed 44 samples by both HPLC and an immunologic method (fluorescence polarization immunoassay run on an IMx analyzer; Abbott): the CV was <10%. The limit of quantification was below the lowest point on the calibration curves. The mean intra- and interassay CVs were 4.9% and 4.4%, respectively.
MTHFR C677T and A1298C gene polymorphisms were determined for newborns and their mothers. An assay incorporating PCR and allele-specific oligonucleotide hybridization was used (2).
PATHOLOGY REPORTS ON THE PLACENTA
All placentas are routinely examined for infarctions by the pathologist on duty, and a report is generally included in the medical record. This information was retrieved by the nurse coordinator.
To include all study cases and controls with tHcy measures and because matching involved only categorical factors (gestational week, sex, and race), we calculated exposure odds ratios (ORs) for IUGR and 95% confidence intervals (95% CIs) using unconditional logistic regression analysis and adjusting for these factors. We also used birthweight as the outcome, estimating regression coefficients and their confidence intervals by multiple linear regression. For both outcomes, the first model included only the matching variables along with the tHcy measure; a second model included the matching factors, the tHcy measure, and the following risk factors: weight gain during pregnancy, body mass index (prepregnancy weight/height in [m.sup.2]), parity, history of preeclampsia (as determined from the medical record), previous history of IUGR, and smoking during the third trimester. In a third model, we included the matching factors, the risk factors listed above, and the MTHFR C677T or A1298C genotype; we also looked at the effect of tHcy on IUGR, stratifying for the genotype categories (homozygous wild, heterozygous, and homozygous variant). A fourth model included the matching factors, the risk factors, and nutritional variables (maternal vitamin intake and consumption of coffee, cola, and lentils in the third trimester) shown to influence the mean tHcy concentrations in newborn controls (9). We report results for the mothers and for the newborns separately.
Homocysteine results were log transformed, but results were not different in their interpretation from those obtained with the original units. We therefore retained the latter for ease of interpretation. As mentioned previously, venous maternal blood was obtained within 48 h of delivery, with a median time of collection at 25 h. However, even within this range of time, the maternal tHcy concentration increased slightly with the number of hours between delivery and blood collection, whereas time between sample taking and centrifugation (for the mother and for the baby) did not statistically change results (9). We conservatively adjusted all maternal analyses (including the first model) for time between delivery and blood collection and time between blood collection and centrifugation; analyses for newborn tHcy were adjusted for the latter. (There was no material delay between birth and blood collection for the newborn.)
Maternal tHcy was measured in 483 cases and 468 controls, which represent 98% and 99%, respectively, of the mothers included in the study; newborn tHcy was measured in 409 cases and 438 controls, equivalent to 83% and 93%, respectively, of the newborns included in the study. The main reason for not obtaining tHcy measurements in newborns was the small quantity of blood. The mean birthweight difference between all cases and controls in the study was 814 g, whereas it was 767 g for newborns included in the present analysis. Table 1 describes the distributions of newborn and maternal characteristics for the cases and controls included in the analysis. The proportion of girls with IUGR was higher (the proportion of control girls was similar because of matching); most cases and controls were born after the 35th week of pregnancy. A substantial proportion of case and control women were black (23%) in each group. Mothers of cases had gained less weight during pregnancy, had a lower body mass index, and slightly fewer took multivitamin supplements; in addition, more of them were 36 years of age or older, had smoked during pregnancy, were primiparas, had preeclampsia, and reported a previous pregnancy with IUGR.
As shown in Table 2, the mean maternal tHcy concentration differed between cases and controls (as evidenced by confidence intervals for the mean values that do not overlap), whereas the tHcy concentrations in newborns did not differ. Newborn concentrations were somewhat lower than maternal values.
Results for the relationship between maternal and newborn tHcy, using the case/control status or birth-weight as the outcome, are shown in Table 3. Plasma homocysteine was used as a continuous variable, and as is customary, to better illustrate results with continuous variables (13), they are reported for an increase in a number of units in the predictor variable: we chose 5 units of tHcy. (For example, we can ask: What is the IUGR OR for women with a tHcy of 8 [micro]mol/L relative to one with a value of 3 [micro]mol/L?) If the OR for tHcy in the logistic regression is 0.89, Table 3 will show that the estimated OR for a difference of 5 units in tHcy is 0.55 (i.e., [0.89.sup.5]), which means a 45% reduction in risk of IUGR. Conversely, to determine the OR for 1 unit based on the data in Table 3, one takes the natural logarithm of the OR [e.g., ln(0.55) = -0.59], divides it by 5 (= -0.11), and exponentiates this value ([e.sup.-0.11] = 0.89). With birthweight as the outcome, if the regression coefficient for tHcy is, e.g., 35.6, then a 5-unit increase in tHcy will produce an estimated increase of 178 g in birthweight (36.5 g x 5). Higher maternal tHcy was associated with a statistically significant reduction in risk for IUGR in all models. Results for the model using the genotype MTHFR A1298C were only slightly different from those obtained for the model including only MTHFR C677T (results not shown). The fourth model, which included nutritional variables and vitamin supplement intake, suggested that a 5-unit difference in tHcy would be associated with an estimated OR of 0.37 (95% CI, 0.24-0.58) or a reduction in risk of IUGR of 63%.
The reduction in risk with higher newborn tHcy concentrations was not as marked; in the fourth model, the estimated OR for a 5-unit difference in tHcy was 0.54 (95% CI, 0.31-0.92). Another way to look at the data is to use birthweight as the outcome; in the fourth model, we observed that birthweight increased by a mean of 35.6 g for every unit of increase in maternal tHcy (or an estimated 178.1 g for a 5-unit increase in tHcy). That value was 30.3 g for newborn tHcy. A maternal or newborn model including both MTHFR variants did not materially change the results compared with those obtained with the model including only MTHFR C677T (results not shown).
We also determined that there was no indication of statistically significant interaction between the MTHFR C677T or A1298C genotype and plasma homocysteine in the maternal or the newborn data (data not shown).
The mean maternal tHcy concentrations according to the MTHFR C677T genotype groups were 5.30 [micro]mol/L (95% CI, 5.13-5.47 [micro]mol/L) for the homozygous wild type, 5.36 (5.17-5.55) [micro]mol/L for the heterozygous group, and 5.42 (5.09-5.75) [micro]mol/L for the homozygous variant. The results for newborn tHcy for the same genotypes were 4.96 (4.81-5.11) [micro]mol/L, 5.12 (4.76-5.07) [micro]mol/L, and 5.06 (4.72-5.40) [micro]mol/L, respectively. Known risk factors for IUGR, such as primiparity, weight gain during pregnancy, body mass index, previous IUGR, history of preeclampsia, cigarette smoking, and intake of multivitamin supplements during pregnancy, were all strongly associated in the expected direction with IUGR (case/ control status) as well as with birthweight (data not shown).
As reported previously (2), at the time of data extraction from the medical records, routine pathologic reports on the presence or absence of placental infarction were available for 77% of cases (n = 379) and for 84% of controls (n = 395). Placental infarction was noted in 46 specimens. Plasma homocysteine values were available for 45 of the specimens with evidence of infarction (39 cases and 6 controls) and for 718 of the specimens with no such evidence (2). The mean tHcy concentration was 5.65 [micro]mol/L (95% CI, 5.09-6.21 [micro]mol/L) in the cases and 6.15 (4.39-7.91) [micro]mol/L in the controls. In the cases and controls without placental infarctions, mean tHcy was 5.13 (4.92-5.33) and 5.56 (5.38-5.70) [micro]mol/L, respectively. The mean tHcy concentration in the 45 mothers with evidence of placental infarction [5.72 (5.20-6.23) [micro]mol/L] was not statistically different from that in the 718 with no such evidence [5.56 (5.23-5.49) [micro]mol/L].
Plasma tHcy concentrations in mothers who had just delivered and in their newborns were below the concentration often used to define mild hyperhomocysteinemia (15 [micro]mol/L) (6). Within the observed range of values, we nevertheless show a clear reduction in risk for IUGR or alternatively an increase in birthweight with increasing maternal plasma tHcy. Results for homocysteine in the newborn were in the same direction, but the effect is not as large. These observations are contrary to our hypothesis that the atherothrombotic effect of homocysteine would increase the risk having smaller babies.
One study from the UK, published in 1992, reported tHcy in 37 women who delivered babies with weights below the 10th percentile and 35 women delivering babies with weights above the 10th percentile; blood was taken 48-72 h after delivery. The mean (SD) tHcy value was 7.7 (2.3) [micro]mol/L in the cases and 7.9 (2.3) in controls (7). These concentrations are high compared with the results in our study, but we previously observed that adult concentrations in European countries are higher than in North America (9). On the other hand, the concentrations seen in our study are almost identical to those measured at delivery or late in pregnancy in studies from North America (14-16) and among newborns in a large study, contemporary to ours, from Italy (17).
Vollset et al. (18) measured plasma tHcy in 1992-1993 in a large group of women 40-42 years of age and related these measures with pregnancy outcomes occurring in these same women from 1967 to 1996. tHcy concentrations varied between 3.6 and 78 [micro]mol/L, with ~27% of women with previous growth-retarded babies in the range >8.9 [micro]mol/L (compared with 3.8% in our data). Risk was increased only in the highest tHcy quartile (10.7-78 [micro]mol/L), where it was estimated at 1.21 (95% CI, 1.02-1.43). These results are difficult to interpret because homocysteine at age 40 could be different from that up to 25 years previously; in addition, the range of results is not compatible with ours because pregnancy and peripregnancy homocysteine concentrations are lower than outside the pregnancy period (16) and possibly again because adult concentrations in Europe seem higher than those in North America (9). Nevertheless, within the range of results similar to ours, no increase in IUGR risk was observed in the study by Vollset et al. (18).
In the study by Murakami et al. (8), tHcy was measured in 749 pregnant Japanese women very early in pregnancy; hyperhomocysteinemia was defined as a concentration above the mean + 1.96 SD for the group (but this mean value was not given). Mothers in this category were compared for pregnancy outcomes with those classified as having no hyperhomocysteinemia. From the study's published data, we calculated a relative risk of 0.78 for IUGR associated with hyperhomocysteinemia, a value that is compatible with our data. Unfortunately, IUGR was not defined in that report, and there were only 26 such cases. Finally, Hogg et al. (15) measured tHcy at 26 and 37 weeks of pregnancy in a subgroup of African-American women participating in a clinical trial on zinc supplementation. No difference was found in the tHcy concentrations between 22 cases of IUGR (defined as we did) and 402 controls.
From these studies, it is difficult to reach firm conclusions because in most, the numbers of IUGR cases were very small, selection of study participants was often not clear, and adjustment, if any, for confounders was very limited.
In our study, selection bias is unlikely given the very high participation rates in the study and the almost complete availability of tHcy measures for maternal participants. Availability of tHcy measures for the newborns was also very high although slightly less for the cases; however, the unavailability of tHcy measures for smaller babies (among cases and controls) produced a somewhat reduced birthweight difference between newborn cases and controls included in the analysis, in comparison with all newborns in the study. This could have led to more conservative estimates for risk factors in the study. Confounding bias is also unlikely because we adjusted in the analyses for known risk factors for IUGR.
The potential for measurement errors in plasma homocysteine needs to be addressed. The analyses were carried out blindly with respect to the case/control status and in a completely random fashion with respect to order of entry, eliminating the potential for a differential bias. Measurement errors independent of the case/control status could have occurred, but stringent quality-control measures reduced that possibility. Such nondifferential errors would tend to bias our results toward the null. Large field studies, such as ours, that collect blood for determination of plasma tHcy face the challenge of rapid increases in the tHcy as a result of cellular export observed when EDTA-containing samples are not stored on ice and processed shortly thereafter. This is challenging in a perinatal research setting with deliveries occurring at all hours. We have shown that the use of citric acid rather than EDTA for keeping whole blood in the refrigerator will prevent a material increase in tHcy for at least 24 h (12). Nevertheless, we meticulously measured the delay between delivery and blood collection, as well as that between blood collection and centrifugation in the laboratory for both maternal and newborn samples. We conservatively adjusted for these delays in the analysis, although the delay between blood collection and centrifugation did not affect results (9).
The validity of our tHcy results is supported by the following observations: (a) The mean tHcy concentrations observed are almost identical to those reported in a few studies in pregnant women from North America (14-16); in addition, as observed previously by Malinow et al. (14), newborn tHcy concentrations were lower than maternal values. (b) We have also previously shown (9), as others have (19), that plasma tHcy is influenced by smoking, caffeine and cola consumption, folate intake, and consumption of folate-rich foods. (c) Finally, we observed that the maternal homocysteine concentrations, although not statistically different across categories of the MTHFR C677T genotype, were in the expected direction. Of note also is that the frequency distribution of the MTHFR C677T genotype among Caucasians in our study was similar to that reported in similar groups in the Quebec population (20).
In summary, in a large and carefully controlled study, we show expected results for tHcy values and for the factors influencing these values. Contrary to our hypothesis, however, the probability of a mother giving birth to a baby with growth restriction decreased with increasing tHcy; indeed, birthweight increased with tHcy concentration. These observations were consistent in all racial groups and in all models of analysis. What factors can be invoked to explain this? One factor is that, as mentioned previously, we are dealing with a range of tHcy values that falls below the usual criterion for mild hyperhomocysteinemia (>15 [micro]mol/L); postulated atherothrombotic effects in this range may be altered or nonexistent. Several authors have proposed that moderately increased plasma homocysteine is a marker of an effect such as tissue damage or repair rather than the cause of incident cardiovascular problems (6, 21, 22). This could not explain our results because even this alternative view on tHcy implies that it will be increased in those who are affected (albeit as a consequence of disease rather than as a cause). Increased homocysteine concentrations could lead to enhanced oxidative stress, endothelial dysfunction, and hemostatic activation (23). However, in patients with chronic renal failure, Mezzano et al. (24) showed that inflammatory proteins were correlated with plasma markers of these processes but that homocysteine was not. In addition, Zappacosta et al. (25) recently reported unique and provoking data showing that, in vitro, homocysteine at low concentrations does not act as a prooxidant but, on the contrary, shows an antioxidant effect on both cellular and chemical systems. This observation could support ours of an apparent beneficial effect of increased plasma homocysteine on fetal growth; however, even if the data from Zappacosta et al. (25) and ours were confirmed, the underlying mechanism for IUGR remains puzzling.
This project was supported by a grant from the Canadian Institutes of Health (Research No. MA-14705). C.I.R. holds a Canada Research Chair from McGill University (James McGill Professorship).
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CLAIRE INFANTE-RIVARD, [1,2] * GEORGES-ETIENNE RIVARD, [2,3] ROBERT GAUTHIER,  and YVES THEORET [2,3]
 Department of Epidemiology, Biostatistics, and Occupational Health, Faculty of Medicine, McGill University, Montreal, Province of Quebec, H3A 1A3 Canada.
 Research Centre,  Division of Hematology and Oncology, Department of Pediatrics, and  Department of Obstetrics, Centre Hospitalier Universitaire Mere-Enfant (CHUME), Hopital Sainte-Justine, Universite de Montreal, Montreal, H3T 1C5 Canada.
 Nonstandard abbreviations: IUGR, intrauterine growth restriction; MTHFR, 5,10-methylenetetrahydrofolate reductase; tHcy, total homocysteine; OR, odds ratio; and 95% CI, 95% confidence interval.
* Address correspondence to this author at: Department of Epidemiology, Biostatistics, and Occupational Health, Faculty of Medicine, McGill University, 1130 Pine Ave. West, Montreal, Province of Quebec, H3A 1A3 Canada. Fax 514-398-7435; e-mail firstname.lastname@example.org.
Received March 4, 2003; accepted May 15, 2003.
Table 1. Characteristics of newborns and mothers with available plasma homocysteine values. Controls Cases Newborn characteristics n 438 409 Female, n (%) 232 (52.9) 226 (55.2) Male, n (%) 206 (47.0) 183 (44.7) Gestational age, n (%) 25-30 weeks 14 (3.2) 8 (20) 31-35 weeks 54 (12.3) 43 (10.5) 36-40 weeks 370 (84.4) 358 (87.5) Mean (SD) birthweight, g 3239.7 (700.1) 2472.7 (520.8) Maternal characteristics n 468 483 Race, n (%) White 331 (70.7) 323 (66.8) Black 108 (23.1) 114 (23.6) Asian 13 (2.8) 24 (4.9) Hispanic/Amerindian 16 (3.4) 22 (4.5) Age [greater than or equal to] 36 54 (14.3) 79 (17.4) years, n (%) Education <12 years, n (%) 94 (20.1) 105 (21.8) Mean (SD) prepregnancy body 23.1 (5.2) 22.8 (4.4) mass index, kg/[m.sup.2] Mean (SD) weight gain during 14.4 (5.7) 12.7 (5.5) pregnancy, kg Primiparous, n (%) 233 (49.8) 314 (65.1) Preeclampsia, n (%) 12 (2.5) 66 (13.7) Previous IUGR among 23 (9.7) 66 (39.3) parous, n (%) Third-trimester multivitamin 370 (80.6) 367 (76.9) use, n (%) Cigarette smoking (third 73 (15.7) 107 (22.2) trimester), n (%) Table 2. Maternal and newborn plasma tHcy concentrations according to case and control status. Plasma tHcy, mol/L Mothers Newborns Cases Controls Cases Controls No. of 483 468 409 438 individuals Mean value 5.11 5.59 4.99 5.06 95% CI 4.95-5.26 5.41-5.76 4.84-5.15 4.92-5.21 Range 1.76-14.03 1.92-15.98 1.03-17.94 0.73-15.62 Table 3. Maternal and newborn plasma tHcy ORs for IUGR and regression coefficients for birthweight. OR (95% CI) for 5 units of tHcy, using logistic regression and case/control status as outcome Model Maternal Newborn Basic (a) 0.55 (0.39-0.81) 0.80 (0.51-1.21) Adjusted (b) 0.42 (0.27-0.64) 0.62 (0.37-1.03) Adjusted (b) and with genotype MTHFR C677T 0.42 (0.27-0.65) 0.63 (0.38-1.05) Adjusted (b) and with nutritional variables (c) 0.37 (0.24-0.58) 0.54 (0.31-0.92) Regression coefficient (95% CI) for 5 units of tHcy, using linear regression and birthweight as outcome Model Maternal Newborn Basic (a) 127.5 (39.8-215.5) 70.9 (-36.8 to 178.7) Adjusted (b) 158.8 (76.8-240.9) 119.0 (18.5-219.5) Adjusted (b) and with genotype MTHFR C677T 155.3 (72.9-237.6) 114.9 (13.9-215.8) Adjusted (b) and with nutritional variables (c) 178.1 (92.5-263.7) 151.5 (45.0-258.0) (a) Adjusted for gestational age, sex, and race as well as time between delivery and blood collection and time between blood collection and centrifugation for the maternal model and time between blood collection and centrifugation for the newborn model. (b) Adjusted for gestational age, sex, race, time between delivery and blood collection, and time between blood collection and centrifugation for the maternal model, time between blood collection and centrifugation for the newborn model, and for mother's weight gain during pregnancy, body mass index, smoking during the third trimester, primiparity, preeclampsia in the current pregnancy, and previous IUGR. (c) Maternal multivitamin supplement intake and consumption of coffee, colas, and lentils in the third trimester.
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|Title Annotation:||Hemostasis and Thrombosis|
|Author:||Infante-Rivard, Claire; Rivard, Georges-Etienne; Gauthier, Robert; Theoret, Yves|
|Article Type:||Clinical report|
|Date:||Sep 1, 2003|
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