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Preconception Folate and Vitamin B₆ Status and Clinical Spontaneous Abortion in Chinese Women

From the Department of Environmental Health, Program for Population Genetics, Department of Maternal and Child Health, and Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts; Department of Environmental Health and Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; Vitamin Bioavailability Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts; New England Research Institutes, Watertown, Massachusetts; Beijing Medical University Center for Ecogenetics and Reproductive Health, Beijing, China; and Anhui Medical University, Anqing Biomedical Institute, Anhui, China.

Address reprint requests to: Alayne G. Ronnenberg, ScD, Harvard School of Public Health, Department of Environmental Health, FXB101, 665 Huntington Avenue, Boston, MA 02115; E-mail: ronnenberg{at}attbi.com.

	ABSTRACT

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OBJECTIVE: To assess the association between preconception homocysteine and B vitamin status and risk of clinical spontaneous abortion in women from Anqing, China.

METHODS: All women were aged 21–34 years, had never smoked, and were primigravid. Patients (n = 49) were women with a clinically recognized pregnancy who experienced a fetal death before 100 days’ gestation. Controls (n = 409) were women who maintained a pregnancy that ended in a live birth. Homocysteine, folate, and vitamins B₆ and B₁₂ concentrations were measured in plasma obtained before conception.

RESULTS: Mean vitamin B₆ concentration was lower in patients than in controls (34.0 versus 37.9 nmol/L, P = .04). In addition, the risk of spontaneous abortion tended to increase with decreasing plasma vitamin B₆ and folate concentration (P for trend = .06 and .07, respectively), although the significance of these trends was further reduced in logistic models that included age, body mass index, and both vitamins. The risk of spontaneous abortion was four-fold higher among women with suboptimal plasma concentrations of both folate and vitamin B₆ (folate less than or equal to 8.4 nmol/L and vitamin B₆ less than or equal to 49 nmol/L) than in those with higher plasma concentrations of both vitamins (odds ratio 4.1, 95% confidence interval 1.2, 14.4). Homocysteine and vitamin B₁₂ status were not associated with spontaneous abortion risk.

CONCLUSION: Suboptimal preconception folate and vitamin B₆ status, especially when they occur together, may increase the risk of clinical spontaneous abortion. Additional prospective studies are needed to confirm these findings and to determine whether antenatal B vitamin supplementation reduces spontaneous abortion risk.

Spontaneous abortion is the most common adverse pregnancy outcome,¹ affecting between 12% and 15% of clinically recognized pregnancies.² Although as many as half of clinical spontaneous abortions may be caused by chromosomal abnormalities, maternal factors, including nutritional status, also contribute to their occurrence. Poor folate status during pregnancy has been associated with a number of adverse pregnancy outcomes, including spontaneous abortion,^3,4 placental abruption,⁵ pre-term delivery, and infant low birth weight.⁶ Although less information is available on the pregnancy risks associated with poor vitamin B₆ status, lower plasma levels of pyridoxal-5'-phosphate, the active form of vitamin B₆, have been observed in women with recurrent early pregnancy losses⁷ and those experiencing placental abruption or infarction⁸ compared with women with normal pregnancy outcomes. Elevated plasma concentrations of total homocysteine, caused by either genetic abnormalities or suboptimal folate, vitamin B₁₂, and/or vitamin B₆ status, also have been associated with increased risk of recurrent spontaneous abortion^4,7–9 and other adverse pregnancy events.^10,11

Despite evidence from observational studies that maternal B vitamin and homocysteine status influence the risk of spontaneous abortion,¹² no studies to date have prospectively examined these relationships. The nutritional status of women who are attempting to become pregnant is likely to provide a better picture of the early gestational environment than are measures taken during pregnancy because it is unaffected by the pregnancy-induced expansion of plasma volume, which dilutes most biochemical analytes.¹³ Assessment of homocysteine and B vitamin status just before pregnancy would also help to clarify the temporal relationship between early pregnancy complications, such as spontaneous abortion, and maternal nutritional status.

We recently reported a high prevalence of folate and vitamin B₆ deficiencies in a group of Chinese women who were attempting to become pregnant.¹⁴ Because we also found that prenatal vitamin supplementation was uncommon in this area of China, we suspected that the high prevalence of vitamin deficiencies, coupled with the additional nutrient demands of pregnancy, could increase the risk of spontaneous abortion in these women. The purpose of this case-control study was to assess the association between prepregnancy B vitamin status and homocysteine concentrations and the risk of clinical spontaneous abortion in young Chinese women.

	MATERIALS AND METHODS

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The current study was conducted in conjunction with an ongoing prospective study of the effects of rotating shift work on reproductive outcomes among female textile workers in Anqing, China. Eligible subjects were selected from among the 563 married women enrolled in the shift-work study between August 1996 and December 1998 for whom prepregnancy nutritional status data were available. All women were aged between 21 and 34 years, had never smoked, and had obtained governmental permission to have a child. All women employees of the textile mills receive prenatal, delivery, and postnatal care in the nearby hospital. Women were excluded if they were pregnant at the initial interview, had tried unsuccessfully to become pregnant for at least 1 year, had previously been pregnant or experienced a clinically recognized spontaneous abortion, or planned to quit, change jobs, or move out of the city in the coming year. After enrollment in the study, women were monitored during any ensuing pregnancy or up to 1 year after beginning to attempt pregnancy, and all pregnancy outcomes were recorded. All suspected pregnancies were confirmed by a positive urinary human chorionic gonadotropin test. Clinical spontaneous abortion patients (n = 49) were defined as women who experienced a fetal death of a clinically recognized pregnancy by 100 days’ gestation. Controls (n = 409) were women who maintained a pregnancy that ended in a live birth. Gestation length (in days) was estimated from the first day of the woman’s last menstrual period.

At enrollment, height and body weight in light clothing were measured to the nearest 0.1 cm and 0.1 kg, respectively, with a beam weighing scale and measuring system. At that time, interviewers administered a previously validated questionnaire to the women and their husbands to collect baseline information on sociodemographic, environmental, and personal attributes that might be related to reproductive outcomes. Included among these variables were education level, type of shift worked (rotating or nonrotating), exposure to passive smoking at home, use of vitamin and/or mineral supplements, use of tea, and alcohol intake.

Nonfasting blood samples were obtained from women before the initial interview via venipuncture and were collected into 10-mL, metal-free, ethylenediaminetetraacetic acid-treated tubes. Blood was centrifuged, and plasma was obtained and stored at -20C until shipped on dry ice to the Harvard School of Public Health, where it was stored at -70C before nutritional analyses. Frozen samples were transported to the United States Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA, where plasma concentrations of homocysteine, folate, and vitamins B₆ and B₁₂ were measured. The Human Subjects Committees at the Harvard School of Public Health and Beijing Medical University approved all study procedures, and informed consent was obtained from each participant.

Total homocysteine concentration in plasma was determined using a method based on the principles described by Araki and Sako.¹⁵ Although analyses were performed on plasma samples obtained from nonfasting subjects at a single point in time, fasting status has been shown to have no appreciable effect on homocysteine concentrations,¹⁶ and nonfasting vitamin concentrations are frequently used to assess vitamin status.17,18 Plasma folate and vitamin B₁₂ were determined by a radioimmunoassay method using a commercially available kit from BioRad Diagnostics Group (Hercules, CA). Plasma vitamin B₆ (as pyridoxal-5'-phosphate) was measured by the tyrosine decarboxylase apoenzyme method.¹⁹ Homocysteine and vitamin measurements were completed in four batches over an 11-month period, with between 63 and 282 samples in each batch. Typical coefficients of variation for in-house control plasma samples were less than 8% for homocysteine, folate, and vitamin B₁₂, and less than 6% for vitamin B₆.

Statistical analyses were performed using SAS for Windows 8.0 (Cary, NC). Because of their skewed distributions, nutrition variables and covariates are presented as medians with the range or as geometric means with their 95% confidence intervals (CI). Differences between patients and controls were assessed using the Wilcoxon rank sum test (medians) or a t test on logarithmically transformed variables. Plasma vitamin concentrations were compared with published reference values to determine the proportion of patients and controls with biochemical evidence of vitamin deficiencies. Vitamin deficiency was defined as plasma concentrations less than 6.8 nmol/L (3 ng/mL) for folate,²⁰ less than 30 nmol/L of pyridoxal-5'-phosphate for vitamin B₆,²¹ and less than 221 pmol/L (300 pg/mL) for vitamin ²² B₁₂. There is no standard definition of elevated homocysteine. We defined it for these analyses as a value greater than or equal to 15.5 µmol/L, which was greater than or equal to the 95th percentile for the combined cohort of patients and controls.

Differences in the proportions of spontaneous abortion patients and controls with vitamin deficiencies or elevated homocysteine were evaluated using ² analyses and Fisher exact test (homocysteine). The association of spontaneous abortion with vitamin deficiencies or elevated homocysteine was estimated using logistic regression. Although the batch in which plasma samples were analyzed was not significantly associated with spontaneous abortion, we included categoric variables for the analytic batch in logistic models to control for variability among batches. To explore the relation between vitamin status and the risk of spontaneous abortion further, subjects were divided into quintiles according to their concentrations of folate and vitamin B₆, and the relative odds of spontaneous abortion were assessed using logistic regression, with the highest vitamin quintile serving as the reference category. Dose-response relations for folate and vitamin B₆ were assessed using the Mantel-Haenszel ² test for trend.²³ Potential confounding by age and body mass index (BMI) (as continuous variables) and the other vitamin (dichotomized) was controlled for using multiple logistic regression. We assessed the presence of effect modification by evaluating the significance of interaction terms created between nutrition variables (low folate, low vitamin B₆) and covariates (age and BMI). Statistical significance refers to P .05.

	RESULTS

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A total of 49 women with clinical spontaneous abortion (patients) and 409 with live births (controls) were included in the analyses (Table 1). The median gestational age at which clinical spontaneous abortions occurred was 59 days; 86% of spontaneous abortions occurred before day 84. There were no significant differences between spontaneous abortion patients and controls in terms of age, BMI, education, work shift, exposure to passive smoking at home, or use of vitamins, tea, or alcohol (Wilcoxon rank sum test, P > 0.05). Both patients and controls tended to be young, with a median age of 24.3 years among patients and 24.8 years among controls. In addition, women in both groups were lean; the median BMI of patients was 19.2 kg/m² compared with 19.5 kg/m² among the controls. Both vitamin supplement use and consumption of alcohol were extremely uncommon among study participants, whereas about half of both patients and controls reported regular consumption of tea. None of the women themselves smoked, but about 70% of both patients and controls were exposed to passive smoking in their homes. Of 458 women included in the study, 28 (two patients and 26 controls) worked nonrotating shifts.

To examine the effects of suboptimal folate and vitamin B₆ status combined, we defined a "nutritionally at-risk" group of 162 women (24 patients and 137 controls) who were below both the 40th percentile for folate (less than or equal to 8.4 pmol/L) and the 80th percentile (less than or equal to 49 nmol/L) for vitamin B₆ and compared their risk of spontaneous abortion to that of 71 women (three patients and 68 controls) with plasma concentrations of both vitamins above these percentile cutoffs. After adjustment for age, BMI, and analytic batch, the risk of spontaneous abortion was four-fold higher (adjusted OR 4.1, 95% CI 1.2, 14.4, P = .03) among women with low plasma concentrations of both vitamins compared with those with higher concentrations of both vitamins.

	DISCUSSION

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We found that vitamin B₆ status was associated with the risk of clinical spontaneous abortion. The mean prepregnancy plasma vitamin B₆ concentration was significantly lower in women whose pregnancies ended in a clinically recognized spontaneous abortion than in those with live births. We also found that vitamin B₆ deficiency (plasma pyridoxal-5'-phosphate less than 30 nmol/L), although common in the entire cohort,¹⁴ tended to be particularly prevalent among women with spontaneous abortion, occurring in nearly 35% of patients. The risk of spontaneous abortion tended to increase with decreasing plasma concentrations of vitamin B₆. Women in the lowest vitamin B₆ quintile were nearly three times more likely to have a spontaneous abortion than those in the highest quintile (P = .04). A tendency for increased risk of spontaneous abortion was evident over a wide range of plasma vitamin B₆ concentrations, including those well above the level typically indicative of deficiency, suggesting that optimal vitamin B₆ status during early pregnancy may differ from that in nonpregnant women.

To our knowledge, ours is the first prospective study to report an association between vitamin B₆ status and spontaneous abortion. Wouters et al⁷ found elevated homocysteine and lower plasma concentrations of vitamin B₆ (46 versus 51 nmol/L, P < .05) in women with histories of recurrent early fetal loss compared with control women, and Goddijn-Wessel et al⁸ reported similar findings of lower plasma vitamin B₆ (42 versus 53 nmol/L, P < .05) among women with placental abruption or infarction. Because vitamin B₆-dependent coenzymes participate in over 100 reactions involved in the metabolism of amino acids, lipids, nucleic acids, and glycogen²⁴ as well as in the synthesis of neurotransmitters and heme,²¹ it seems plausible that maternal vitamin B₆ status could influence early gestational events, including those related to spontaneous abortion. However, a precise mechanism for these possible effects has not been described.

In the current study, folate deficiency (plasma folate less than 6.8 nmol/L) tended to be more common among women with spontaneous abortion than in those with live births. The adjusted OR for spontaneous abortion (OR 1.7, 95% CI 0.9, 3.1, P = .09) associated with folate concentrations below 8.4 nmol/L (our 40th percentile) observed in this study is remarkably similar to the OR for recurrent spontaneous abortion (OR 1.9, 95% CI 0.8, 4.6) associated with the same serum folate concentration (their 10th percentile) recently reported by Nelen et al,⁴ although the association was not statistically significant in either study. These observations suggest that suboptimal folate status may play a role in both first and recurrent spontaneous abortion, but larger prospective studies are needed to confirm these possible associations.

We found that the risk of spontaneous abortion was particularly high (adjusted OR 4.1, 95% CI 1.2, 14.4) among women with suboptimal plasma concentrations of both folate (less than 40th percentile) and vitamin B₆ (less than 80th percentile) compared with those in the upper ends of both vitamin distributions, which suggests that the detrimental effects of poor vitamin status may be additive. Additional nutritional status measures are needed to determine whether the increased risk of spontaneous abortion is related to these specific nutrients or to generally poor nutritional status before pregnancy. Assessment of dietary intake as well as more thorough documentation of the prepregnancy nutritional status of Chinese women would help to clarify these issues.

In contrast to the reports of others,^4,7,9 we did not find a significant association between elevated homocysteine and spontaneous abortion risk. We did observe a non-significant doubling of the risk of spontaneous abortion among women with plasma homocysteine greater than or equal to 15.5 µmol/L (OR 2.0, 95% CI 0.6, 6.7), although this association appeared to be related to both age and BMI because adjustment for these variables further reduced the OR (data not shown). Our failure to detect a significant effect of elevated homocysteine might be due to the relatively small number of spontaneous abortion patients (n = 49), but it also may be related to the fact that our patients were experiencing their first occurrence of spontaneous abortion. Unlike the previous studies, which focused on women with recurrent pregnancy losses, women who reported a previous clinically recognized spontaneous abortion were excluded from the current study. Most women who experience a spontaneous abortion are able to conceive again and carry a pregnancy successfully to term. This observation suggests that nutritional and other factors that influence the risk of a first spontaneous abortion may be distinct from those associated with recurrent pregnancy loss.

A major strength of the current study is the ability to relate preconception B vitamin status, assessed in women planning to become pregnant, to events that occur in the subsequent pregnancy.²⁵ Limitations of the study include the lack of information on chromosomal studies of the abortus, the small number of patients, and the lack of dietary data. Without detailed information on nutrient intake, we cannot determine whether the observed associations between spontaneous abortion and B vitamin status are due to insufficient dietary intake of these or other nutrients or whether the association is related to nondietary factors, such as altered nutrient absorption or metabolism or genetic polymorphisms that have been linked to recurrent pregnancy losses²⁶ and other adverse pregnancy events.^27,28

In summary, we found modest associations between the first occurrence of clinical spontaneous abortion and suboptimal folate and vitamin B₆ status in young Chinese women. Plasma homocysteine and vitamin B₁₂ concentrations were not related to spontaneous abortion. Additional pregnancy outcome studies among Chinese women of childbearing age are needed to document dietary intake and to determine the prevalence of genetic polymorphisms that may have both nutritional and reproductive implications. It also will be important to determine whether our observations apply to other populations. If they prove consistent, recent efforts to increase periconceptional folate intakes in China²⁹ and the United States³⁰ might reduce the risk of spontaneous abortion as well as neural tube defects.

	Footnotes

 
This study was supported in part by grant 1R01HD/OH32505 from the National Institute of Child Health and Human Development.

PII S0029-7844(02)01978-6

Received July 24, 2001. Received in revised form December 28, 2001. Accepted February 7, 2002.

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This Article Abstract Full Text (PDF) 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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Ronnenberg, A. G. Articles by Xu, X. Search for Related Content PubMed PubMed Citation Articles by Ronnenberg, A. G. Articles by Xu, X.