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Original Research

Hyperhomocysteinemia, Pregnancy Complications, and the Timing of Investigation

Steegers-Theunissen, Régine P. PhD; Van Iersel, Carola A. MSc; Peer, Petronella G. PhD; Nelen, Willianne L. PhD; Steegers, Eric A. PhD

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doi: 10.1097/01.AOG.0000129955.47943.2a
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Vascular-related pregnancy complications are a major cause of maternal and fetal morbidity and mortality. Along with inadequate endovascular trophoblastic invasion resulting in oxidative stress, a derangement in placental vascularization due to preexisting endothelial dysfunction or injury is considered to contribute to the occurrence of pregnancy-induced hypertension; preeclampsia; hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome; recurrent early pregnancy loss; abruptio placentae; intrauterine growth restriction; and intrauterine fetal death.1,2

Several biochemical characteristics are associated with vascular-related pregnancy complications and oxidative stress. Homocysteine is an intermediate product in the metabolism of the essential amino acid methionine. The vitamins folate and cobalamin are involved in the remethylation of homocysteine into methionine, and vitamin B6 as pyridoxal 5-phosphate is a cofactor in the transsulfuration of homocysteine by way of cystathionine to cysteine. A shortage of these vitamins, increased age, gender, and polymorphisms in related enzymes lead to elevated homocysteine plasma concentrations.3,4 In vitro studies suggest that the pathogenesis of vascular disease associated with homocysteine is related to endothelial dysfunction, smooth muscle cell proliferation, and abnormalities of coagulation.5 In addition, homocysteine generates reactive oxygen species such as H2O2 that may induce oxidative stress and thereby endothelial dysfunction.5 This is in line with research of the last 2 decades pointing to the association between hyperhomocysteinemia and both cardiovascular diseases6 and vascular-related pregnancy complications in the mother, such as recurrent early pregnancy loss, placental abruption, and preeclampsia.7–9 Abnormal fetal outcomes as intrauterine fetal death have been associated with hyperhomocysteinemia as well.7

The objective of our study was to investigate vitamin-dependent homocysteine metabolism by performing a standardized methionine loading test and a fasting vitamin profile. In our analysis interval between delivery and testing, maternal age, and renal function were considered.

MATERIALS AND METHODS

The subjects of our study were postpartum patients who had a history of vascular-related pregnancy complications. The controls were postpartum patients who were comparable with the patient groups with regard to social class, geographic area, and age. They were friends or acquaintances of the patients and had uncomplicated pregnancies.

From January 1991 to October 2000, 1,241 patients who had experienced at least 1 vascular-related pregnancy complication were referred to the University Medical Center Nijmegen in the Netherlands after their last pregnancy. They were categorized into 1 of 7 groups: pregnancy-induced hypertension (n = 37), preeclampsia (n = 145), HELLP syndrome (n = 105), recurrent early pregnancy loss (n = 569), abruptio placentae (n = 135), intrauterine growth restriction (n = 145), and intrauterine fetal death (n = 105).

Pregnancy-induced hypertension was defined as having had a diastolic blood pressure of more than 90 mm Hg on 2 or more consecutive occasions with an interval of more than 4 hours after 20 weeks of gestation. Patients with preeclampsia had had pregnancy-induced hypertension and concordant proteinuria (urinary protein more than 0.3 g/24 hours). The HELLP syndrome was defined as a lactic dehydrogenase level greater than 600 IU/L, both aspartate aminotransferase and alanine aminotransferase more than 70 IU/L, and thrombocyte concentrations less than 100 × 109/L. Patients having had recurrent early pregnancy loss had had at least 2 consecutive spontaneous early pregnancy losses before 16 weeks of amenorrhea with the same partner. The diagnosis of abruptio placentae had been made clinically as the presence of a hypertonic uterus together with the histologic observation of a retroplacental hematoma. An infant was diagnosed with growth restriction if birth weight was below the 10th percentile according to the Kloosterman classification.10 Intrauterine fetal death was defined when the fetus died after 16 weeks of amenorrhea.

Controls were friends, but not family, of the patients and were tested during the same time period as the patients. After exclusion of users of B vitamins, contraceptives, pharmacologic agents, and restricted diets and women who showed gastrointestinal or endocrine disorders, the control group comprised 176 healthy females with uncomplicated obstetric histories. Data on the controls have been published before.7,8,11,12 Some controls and patients experienced recurrent spontaneous abortions.

All participants were tested after delivery. Women were excluded when they were tested less than 6 weeks after delivery, lactating, or using a B vitamin supplement within 3 months before testing. Only women whose interval between delivery and postpartum investigation was known were included. Vitamin supplementation was determined by evaluation of the blood vitamin concentrations. The cutoff value for serum folate was based on the study of Brouwer et al13 showing that in women of reproductive age receiving 250 μg folic acid per day for 4 weeks the folate concentrations increased to a mean value of 22.5 nmol/L. Accordingly, subjects with serum folate concentrations more than 22.5 nmol/L were excluded for the evaluation of serum and red blood cell folate and fasting and afterload homocysteine. Based on the preconceptional values described by Steegers et al,14 women having a serum cobalamin concentration more than 554 pmol/L were excluded for the evaluation of cobalamin and fasting and afterload homocysteine. Subjects with whole blood pyridoxine 5-phosphate concentrations more than 76 nmol/L were excluded from the analysis of pyridoxine 5-phosphate and fasting and afterload homocysteine. Therefore, the data of 176 controls and 1,212 patients with a vascular-related pregnancy complication remained for further evaluation, being either pregnancy-induced hypertension (n = 37), preeclampsia (n = 144), HELLP syndrome (n = 104), recurrent early pregnancy loss (n = 544), abruptio placentae (n = 135), intrauterine growth restriction (n = 144), or intrauterine fetal death (n = 104). All women were subjected to a standardized evaluation of vitamin-dependent homocysteine metabolism by performing an oral methionine loading test including the measurement of serum and red blood cell folate, serum cobalamin, and whole blood pyridoxal 5-phosphate. We described the protocol of the oral methionine loading test and vitamin assays before.11 Alanine aminotransferase was routinely measured by the guidelines of the International Federation of Clinical Chemistry at 30°C. Hematocrit in the venous blood samples was determined by the microhematocrit method according to standard laboratory procedures to calculate red blood cell folate concentrations.

Patient data were derived from previously performed studies on recurrent early pregnancy loss and abruptio placentae.7,8,12 A subset of control data was collected in the case-control studies on neural tube defects and recurrent early pregnancy loss.7,8,11,12 These studies have been approved by the Institutional Review board and Medical Ethical committee of the University Medical Centre Nijmegen, the Netherlands. Patients who experienced pregnancy-induced hypertension, preeclampsia, HELLP syndrome, intrauterine growth restriction, intrauterine fetal death, and a subgroup of women who experienced abruptio placentae were routinely tested in a clinical setting of preconceptional counseling. All participants gave their informed consent.

Patient groups were separately compared with the control group. Differences between patients and controls in interval between delivery and testing, in maternal age at testing, and in parity were tested with the Mann-Whitney U test. To adjust for multiple testing, a P value of less than 0.05 divided by 7 was considered statistically significant. In clinical practice only abnormal test results are of interest. Therefore, we dichotomized all blood measures according to the clinical reference values used by the central clinical chemical laboratory from the University Medical Centre Nijmegen in the Netherlands. Cutoff values were fasting homocysteine more than 15 μmol/L, afterload homocysteine more than 51 μmol/L, serum folate less than 7.0 nmol/L, red blood cell folate less than 298 nmol/L and more than 805 nmol, serum cobalamin less than 160 pmol/L, pyridoxine 5-phosphate less than 28 nmol/L, and creatinine more than 90 μmol/L. Logistic regression analysis was used to determine crude and adjusted odds ratios and 95% confidence intervals. Odds ratios were adjusted for interval between delivery and testing, maternal age at testing, and creatinine concentrations.

RESULTS

The characteristics of the patient groups and controls are presented in Table 1. The interval between delivery and testing was significantly longer in controls (median 3.3 years, range 0.3–25 years) compared with patients with pregnancy-induced hypertension (median 0.6 years, range 0.12–4.8 years; P < .001), recurrent early pregnancy loss (median 0.3 years, range 0.12–17.4 years; P < .001), abruptio placentae (median 0.5 years, range 0.12–17.3 years; P < .001), intrauterine growth restriction (median 0.4 years, range 0.12–8.1 year; P < .001), and intrauterine fetal death (median 0.4 years, range 0.12–11.9 years; P < .001).

Table 1
Table 1:
Interval Between Testing and Delivery and Demographics at Testing

Controls were significantly older at the time of testing (median 34.4 years, range 23.3–50.5 years) compared with patients with pregnancy-induced hypertension (median 31.3 years, range 20.3–44.3 years; P < .001), recurrent early pregnancy loss (median 32.9 years, range 19.5–47.0 years; P < .001), abruptio placentae (median 32.0 years, range 22.7–48.8 years; P < .001), intrauterine growth restriction (median 31.1 year, range 19.8–41.7 years; P < .001) and intrauterine fetal death (median 32.1 year, range 21.7–43.2 years; P < .001). Parity was slightly but significantly lower in pregnancy-induced hypertension (P < .001) and higher in intrauterine fetal death compared with controls (P ≤ .01).

In Tables 2, 3, and 4 associations are presented between the biochemical measures and pregnancy complications as crude odds ratios and odds ratios adjusted for time interval and maternal age at testing. Table 2 reveals a crude association between fasting hyperhomocysteinemia and pregnancy-induced hypertension (odds ratio [OR] 2.9). Fasting and afterload hyperhomocysteinemia are estimated as risk factors for abruptio placentae and intrauterine growth restriction. However, these associations diminished after adjustment for time interval and maternal age at testing. An increased fasting or afterload homocysteine concentration was not detected as a risk factor for any of the other vascular-related pregnancy complications.

Table 2
Table 2:
Crude and Adjusted Odds Ratios for Time Interval and Maternal Age for Fasting, Afterloading, and Fasting and/or Afterload Total Homocysteine Concentrations
Table 3
Table 3:
Crude and Adjusted Odds Ratios for Time Interval and Maternal Age for Serum Folate and Low and High Red Blood Cell Folate
Table 4
Table 4:
Crude and Adjusted Odds Ratios for Time Interval and Maternal Age for Cobalamin, Pyridoxal 5-phosphate, and Creatinine

The crude and adjusted ORs for serum and red cell folate as shown in Table 3 do not demonstrate significant associations between low folate levels and vascular-related pregnancy complications. Red blood cell folate concentration more than 805 nmol/L was associated with a significantly reduced risk for abruptio placentae of 80% and intrauterine growth restriction of 60%. Table 4 shows that cobalamin deficiency is associated with HELLP syndrome, abruptio placentae, and intrauterine growth restriction. Pyridoxal 5-phosphate deficiency is significantly associated with pregnancy-induced hypertension. After adjustment for time interval and maternal age, these associations diminished. Furthermore, a serum creatinine concentration more than 90 μmol/L seemed a risk factor also after adjustment for pregnancy-induced hypertension, preeclampsia, HELLP syndrome, and abruptio placentae. The crude OR for creatinine was significant for intrauterine growth restriction.

DISCUSSION

We demonstrate that when the interval between postpartum investigation and delivery and maternal age are considered, hyperhomocysteinemia is not associated with pregnancy-induced hypertension, preeclampsia, HELLP syndrome, recurrent pregnancy loss, abruptio placentae, intrauterine growth restriction, and intrauterine fetal death. Thus, in most cases hyperhomocysteinemia may be a consequence rather than a cause of these vascular-related pregnancy complications.

This is in contrast to our previous studies7,8,12,15 and that of others16–18 in which this time interval and maternal age never were considered. Thus, no associations exist in most cases between hyperhomocysteinemia and vascular-related pregnancy complications or the median time interval is too short. These data do not allow us to calculate a minimal time period after delivery after which a methionine loading test as a screening tool is informative.

This study was not designed to investigate whether hyperhomocysteinemia during pregnancy is associated with vascular-related pregnancy complications. Vascular-related pregnancy complications are suggested to develop in the first weeks of pregnancy.2 In the pathogenesis of preeclampsia, endothelial cell activation or dysfunction is a central theme. Therefore, hyperhomocysteinemia during pregnancy may contribute to this process. This has been shown by studies performed in early pregnancy,19 in the second trimester,20 and in the third trimester of pregnancy.21 However, Hogg et al22 support our negative finding by showing that second trimester plasma homocysteine concentrations are also not predictive of the subsequent development of pregnancy-induced hypertension, preeclampsia, and intrauterine growth restriction.

Fasting hyperhomocysteinemia is a marker of functional folate or cobalamin depletion, and afterload hyperhomocysteinemia is inversely correlated with pyridoxal 5-phosphate concentrations. During normal pregnancy blood concentrations of folate, cobalamin, and pyridoxal 5-phosphate decrease.14 Whether primary vitamin deficiencies or secondary hyperhomocysteinemia is a cause or consequence of vascular-related pregnancy complications is unknown. Our study was performed in nonpregnant women. It is not clear how long it takes after pregnancy to restore these vitamin depots. Neither low serum nor red cell folate seemed a risk factor in our study populations. This is in contrast to previous studies in which an abnormal formiminoglutamic acid test as a functional test for folate deficiency or low red cell folate was associated with abruptio placentae23 or recurrent spontaneous abortion.8 Sutterlin et al24 confirm our finding that maternal folate or cobalamin concentrations are in general not significantly lower in recurrent spontaneous abortion, abruptio placentae, and intrauterine growth restriction. Of interest is the significantly protective effect of a high level of red blood cell folate for abruptio placentae and intrauterine growth restriction.

An explanation for the fasting hyperhomocysteinemia in pregnancy-induced hypertension could be the accompanying pyridoxal 5-phosphate deficiency. This has not been reported in the literature before. Maternal serum or plasma folate9,17,20,21,25,26 and serum cobalamin21 were not associated before with preeclampsia or pregnancy-induced hypertension. Results from a recent meta-analysis of preeclampsia in relation to maternal folate and cobalamin status underscore the need for additional research designed to assess the risk of these determinants.27

Vitamin-dependent homocysteine metabolism is confounded by many known and unknown factors. Renal dysfunction results in increased creatinine concentrations and is often demonstrated in pregnancy-induced hypertension, preeclampsia, and HELLP syndrome and sometimes in abruptio placentae and intrauterine growth restriction. Renal dysfunction increases homocysteine concentrations and has been associated with pyridoxal 5-phosphate and cobalamin depletion and therefore supports our findings.28 An elevated creatinine concentration was associated with most of the vascular-related pregnancy complications investigated. Although we hypothesized that adjustment for time interval and maternal age could be related to the recovery of renal dysfunction, the adjusted ORs for creatinine were comparable with the crude ORs of most biochemical variables (data not shown). An abnormal alanine aminotransferase concentration showed significant adjusted ORs for preeclampsia and HELLP syndrome. Biomarkers of liver damage, including alanine aminotransferase, decrease within 14 days after delivery.29–31 Only 1 patient showed severe liver damage, which however, could not explain the disappearance of the significant ORs after adjustment for time interval and maternal age.

Irgens et al32 showed that women with preeclampsia and preterm delivery had an 8.1-fold higher risk of dying from cardiovascular diseases. Moderately elevated total homocysteine levels are known to be associated with cardiovascular diseases in high-risk subjects.33 Our study suggests that hyperhomocysteinemia is not the link between vascular-related pregnancy complications and the occurrence of cardiovascular diseases.

Primiparity is a well-known although a poorly understood risk factor for preeclampsia. In contrast to the study of Rajkovic et al,26 no association between parity and deranged vitamin-dependent homocysteine metabolism or vascular-related pregnancy complications could be demonstrated.

Several potential limitations of our study merit consideration when interpreting the results. Because of the retrospective design, we cannot determine whether the unadjusted elevations in homocysteine and creatinine concentrations and cobalamin and pyridoxal 5-phosphate deficiencies preceded some of the vascular-related pregnancy complications or whether the differences are attributable to disease-related alterations in vitamin-dependent homocysteine metabolism. Results from one prospective study suggest that elevation in homocysteine during pregnancy precedes the clinical manifestations of preeclampsia by approximately 8–16 weeks.19 Furthermore, we did not have information on such diet and lifestyle factors as smoking and coffee and alcohol consumption, which could affect the biochemical factors.3

It cannot be excluded that some misclassification of folic acid supplement use occurred based on the serum folate cutoff value of 22.5 nmol/L. The serum folate level reflects folate and folic acid intake during a short period of 2–3 days. A low dose of 0.25 mg folic acid per day took 4 weeks to reach this mean value in 50 women of reproductive age.13 This level can also be reached in 1 week after a dose of 0.50 mg folic acid per day.13 Hyperhomocysteinemia, fasting and after loading, can be treated in most cases by low-dose folic acid supplementation. It is not clear, however, for what period hyperhomocysteinemic blood levels will remain normohomocysteinemic after stopping folic acid supplement intake. This will be dependent on dose, duration of intake, needs, and genetic background of the person involved. Theoretically, results in particular patients with a serum folate level less than 22.5 nmol/L and normohomocysteinemic plasma concentrations, due to the recent cessation of folic acid supplements, could have underestimated the risk estimates for fasting or afterload hyperhomocysteinemia. In controls, however, this could have overestimated these risk estimates. Thus, some residual confounding may have occurred. In addition, we can exclude the possibility that preeclampsia-related renal dysfunction explains the homocysteine elevations. Although there was a considerable overlap, the control group was measured in general later compared with most of the patient groups. To verify the validity of the continuous adjustment of time interval and maternal age at testing, we therefore limited the time interval to 10 years and reanalyzed the data, which revealed comparable results (data not shown). The strength of our study is the relatively large sample sizes compared with other studies and the fact that we performed the standardized methionine loading test and a fasting vitamin profile in one clinic.

In conclusion, these findings are inconsistent with some earlier reports suggesting that hyperhomocysteinemia in most nonpregnant women is an important risk factor for vascular-related pregnancy complications. This is mainly due to the fact that previous researchers did not consider interval between delivery and testing and maternal age. Therefore, in future research for identification of risk factors for vascular-related pregnancy complications, the timing of postpartum evaluation needs to be standardized. A preconceptional cohort study before, during, and after pregnancy should be performed to answer the question of whether hyperhomocysteinemia is a risk factor and how long after pregnancy the methionine loading test should be performed to identify hyperhomocysteinemia as a preconceptional risk factor for vascular-related pregnancy complications.

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© 2004 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.