Antihypertensive treatment during pregnancy and functional development at primary school age in a historical cohort study.

OBJECTIVE: To determine the functional development of children born after treatment of mild-to-moderate gestational hypertension with labetalol versus methyldopa, and no antihypertensive treatment. DESIGN: Historical cohort study. SETTING: Twelve Dutch hospital departments of obstetrics. POPULATION: Live-born children born in these hospitals and prenatally exposed to labetalol, methyldopa, or bed rest because of mild-to-moderate gestational hypertension. METHODS: Central nervous system development was measured with standard tests at 4-10 years of age. Linear regression techniques and Pearson's chi-square tests were used to compare the groups with regard to the outcome measures. MAIN OUTCOME MEASURES: Intelligence quotient (IQ), concentration, motor development, and behaviour at primary school age. RESULTS: A total of 202 children were included in the analyses. More children exposed to labetalol had attention deficit hyperactivity disorder (ADHD) than those exposed to methyldopa (OR 2.3; 95% CI 0.7-7.3), or those born to women who had been admitted for bed rest (OR 4.1; 95% CI 1.2-13.9). Sleeping problems seemed to be reported more frequently after prenatal methyldopa exposure than after exposure to labetalol (OR 3.2; 95% CI 0.6-16.7) or bed rest (OR 4.5; 95% CI 0.9-23.2), although the differences were not statistically significant. Test scores on other aspects of functional development did not differ between the three groups. CONCLUSIONS: In this hypothesis-generating study, labetalol exposure in utero seemed to increase the risk of ADHD among children of primary school age, whereas prenatal methyldopa exposure might influence sleep. Further studies with appropriate sample sizes are warranted to determine the long-term effects of antihypertensive medications.

The scientific output of a Catholic university department of obstetrics and gynecology.

The introduction of in-vitro fertilization (IVF) and prenatal diagnostics (PND) raised moral and ethical problems for Catholic universities. As expected, reproductive medicine research output was very low in departments that did not provide these facilities. It can be demonstrated that, by initiating IVF and PND under strong restrictions, a low scientific output in IVF and PND can be compensated for by increasing scientific output in new areas such as maternofetal physiology, primary prevention of birth defects and preconception care (folic acid and neural tube defects). This increase was mainly due to multidisciplinary efforts.

Abnormal folate metabolism in mothers with Down syndrome offspring: review of the literature.

Altered maternal folate status and homozygous mutation in the methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) genes can promote chromosomal instability and non-dysjunction resulting in fetal trisomy 21. Folate supplementation around conception therefore has the potential to reduce the frequency of Down syndrome. This finding, in addition to the prevention of neural tube defects, strengthens the recommendation to use folic acid around conception.

Decreased methylene tetrahydrofolate reductase activity due to the 677C-->T mutation in families with spina bifida offspring.

Periconceptional folate intake reduces both the occurrence and recurrence risk of neural tube defects. Plasma homocysteine levels can be elevated in mothers of a child with a neural tube defect, suggesting a dysfunctional folate metabolism. Very recently we showed that a common 677C-->T mutation in the 5,10-methylene tetrahydrofolate reductase gene, causing thermolability of the enzyme, is a risk factor for spina bifida offspring. Restriction enzyme analysis of the genomic 5,10-methylene tetrahydrofolate reductase polymerase chain reaction fragment revealed a significantly higher prevalence of a +/+ genotype among spina bifida patients and their mothers. The risk for spina bifida offspring is the strongest if both the mother and her child have the mutation in the homozygous state. Enzymatic analysis showed that homozygosity for the 677C-->T mutation causes a decreased 5,10-methylene tetrahydrofolate reductase activity, resulting in elevated plasma homocysteine and red blood cell folate levels and lowered plasma folate and cysteine values. This extended study demonstrates that a nucleotide substitution in the coding region of 5,10-methylene tetrahydrofolate reductase, resulting in reduced activity and an impaired homocysteine and folate metabolism, is a genetic risk factor for spina bifida.

Dietary sodium restriction in the prophylaxis of hypertensive disorders of pregnancy: effects on the intake of other nutrients.

Dietary sodium restriction is used in the Netherlands in the prophylaxis of preeclampsia. To study the effects of long-term sodium restriction on the intake of other nutrients and the outcome of pregnancy, 68 healthy nulliparous pregnant women were randomly assigned to either a low-sodium diet (20 mmol/24 h) or an unrestricted diet. The diet was consumed between week 14 of gestation and delivery. The dietary intakes of energy, fat, protein, carbohydrate, sodium, potassium, and calcium were estimated with the dietary-history technique. A low-sodium diet reduced the intake of protein (by approximately 15 g/24 h), fat (by 20 g/24 h), and calcium (by 350 mg/24 h) and tended to decrease the energy intake (by approximately 0.7 MJ/24 h). The intakes of carbohydrate and potassium did not differ between the groups. The maternal weight gain was less in the low-sodium group (6.0 +/- 3.7 compared with 11.7 +/- 4.7 kg). Mean birth weight was not significantly different (3.2 +/- 0.5 compared with 3.4 +/- 0.5 kg).

Low-dose folic acid supplementation decreases plasma homocysteine concentrations: a randomized trial.

BACKGROUND: An elevated plasma total homocysteine concentration is a risk factor for cardiovascular disease and neural tube defects. A high daily intake of supplemental folic acid is known to decrease total homocysteine concentrations. OBJECTIVE: We studied the effect of low-dose folic acid administration (250 or 500 (microgram/d) for 4 wk on plasma total homocysteine concentrations and folate status. We also investigated whether total homocysteine concentrations and blood folate concentrations returned to baseline after an 8-wk washout period. DESIGN: In this placebo-controlled study, 144 healthy women aged 18-40 y received 500 microgram folic acid/d, 500 microgram folic acid every second day (250 microgram/d), or a placebo tablet with their habitual diet (mean dietary folate intake: 280 microgram/d). RESULTS: Administration of 250 and 500 microgram folic acid/d for 4 wk significantly increased folate concentrations in plasma (P < 0.001) and red blood cells (P < 0.01). Total homocysteine concentrations decreased significantly (P < 0.001) in women (n = 50) who took 250 microgram folic acid/d [mean (+/-SEM) deviation from baseline: - 11.4 +/- 198%] and in women (n = 45) who took 500 microgram folic acid/d (-21.8 + 1.49%). Eight weeks after the end of the intervention period (week 12), plasma total homocysteine concentrations in the folic acid-supplemented groups had not returned to baseline (week 0). CONCLUSIONS: Doses of folic acid as low as 250 microgram/d, on average, in addition to usual dietary intakes of folate significantly decreased plasma total homocysteine concentrations in healthy, young women. An 8-wk washout period was not sufficient for blood folate and plasma total homocysteine concentrations to return to baseline concentrations.

Bioavailability of lutein from vegetables is 5 times higher than that of beta-carotene.

BACKGROUND: To gain more insight into the relation between vegetable consumption and the risk of chronic diseases, it is important to determine the bioavailability of carotenoids from vegetables and the effect of vegetable consumption on selected biomarkers of chronic diseases. OBJECTIVE: To assess the bioavailability of beta-carotene and lutein from vegetables and the effect of increased vegetable consumption on the ex vivo oxidizability of LDL. DESIGN: Over 4 wk, 22 healthy adult subjects consumed a high-vegetable diet (490 g/d), 22 consumed a low-vegetable diet (130 g/d), and 10 consumed a low-vegetable diet supplemented with pure beta-carotene (6 mg/d) and lutein (9 mg/d). RESULTS: Plasma concentrations of vitamin C and carotenoids (ie, alpha-carotene, beta-carotene, lutein, zeaxanthin, and beta-cryptoxanthin) were significantly higher after the high-vegetable diet than after the low-vegetable diet. In addition to an increase in plasma beta-carotene and lutein, the pure carotenoid-supplemented diet induced a significant decrease in plasma lycopene concentration of -0.11 micromol/L (95% CI: -0.21, -0.0061). The responses of plasma beta-carotene and lutein to the high-vegetable diet were 14% and 67%, respectively, of those to the pure carotenoid- supplemented diet. Conversion of beta-carotene to retinol may have attenuated its plasma response compared with that of lutein. There was no significant effect on the resistance of LDL to oxidation ex vivo. CONCLUSIONS: Increased vegetable consumption enhances plasma vitamin C and carotenoid concentrations, but not resistance of LDL to oxidation. The relative bioavailability of lutein from vegetables is higher than that of beta-carotene.

Open or closed? A world of difference: a history of homocysteine research.

This article presents the research of the Nijmegen homocysteine team on birth defects and vascular disease. Hyperhomocysteinemia was found in women who gave birth to offspring with neural tube defects (NTDs) and other birth defects and in women with vascular disease. Elevated homocysteine levels in the blood plasma can be explained by lack of B vitamins (folic acid), mutation of the 5,10-methylenetetrahydrofolate reductase (MTHFR) genes, or both. Genetic mutations were found on the first chromosome (677 C T and 1298 A-C) and can explain up to 50% of the protective effect of folic acid against NTDs. The inborn error of methionine-homocysteine metabolism was also found in cases with recurrent early pregnancy loss, schisis, congenital heart defects, and vascular problems such as placental abruption, infarcts, and fetal growth retardation. One of the most exciting medical findings of recent years is that folic acid can prevent NTDs. This might also hold true for other birth defects and vascular disease.

Maternal hyperhomocysteinemia: a risk factor for neural-tube defects?

The maternal vitamin status, especially of folate, is involved in the pathogenesis of neural-tube defects (NTDs). Maternal folate administration can prevent these malformations. The precise metabolic mechanism of the beneficial effect of folate is unclear. In this study we focus on homocysteine accumulation, which may derive from abnormalities of metabolism of folate, vitamin B12, and vitamin B6. We studied nonpregnant women, 41 of whom had given birth to infants with NTDs and 50 control women who previously had normal offspring. The determinations included the plasma total homocysteine both in the fasting state and 6 hours after the ingestion of a methionine load. In addition, we measured the fasting blood levels of folate, vitamin B12, and vitamin B6. The mean values for both basal homocysteine and homocysteine following a methionine load were significantly increased in the group of women who previously had infants with NTDs. In nine of these subjects and two controls, the values after methionine ingestion exceeded the mean control by more than 2 standard deviations. Cystathionine synthase levels in skin fibroblasts derived from these methionine-intolerant women were within the normal range. Our findings suggest a disorder in the remethylation of homocysteine to methionine due to an acquired (ie, nutritional) or inherited derangement of folate or vitamin B12 metabolism. Increased homocysteine levels can be normalized by administration of vitamin B6 or folate. Therefore, we suggest that the prevention of NTDs by periconceptional folate administration may effectively correct a mild to moderate hyperhomocysteinemia.

Labor pain: a comparison of parturients in a Dutch and an American teaching hospital.

Women giving birth in two university hospitals, one in the Netherlands and the other in the United States, were surveyed postpartum regarding expectations of pain in labor and availability of medication for its relief, perceptions of the painfulness of labor, and use of analgesia and anesthesia. American women expected labor to be more painful, anticipated that they would receive medication for it, and did receive such medication in significantly greater proportions compared with Dutch parturients. These findings point to fundamental, culturally determined differences between these two societies with respect to women's views of the painfulness of childbirth.

Homocysteine and folate levels as risk factors for recurrent early pregnancy loss.

OBJECTIVE: To estimate the relative risk of recurrent early pregnancy loss for different total plasma homocysteine and serum folate concentrations. METHODS: In a case-control study, we measured homocysteine (fasting and afterload), folate (serum and red cells), pyridoxal 5'-phosphate, and cobalamin concentrations in 123 women who had at least two consecutive spontaneous early pregnancy losses each and compared concentrations with those of 104 healthy controls. RESULTS: Women with recurrent early pregnancy losses had significantly lower serum folate concentrations than controls, whereas the other measurements were similar to those of controls. Elevated homocysteine, fasting greater than 18.3 micromol/L and afterload greater than 61.5 micromol/L, was a risk factor for recurrent early pregnancy loss, with odds ratios (ORs) and 95% confidence intervals (95% CIs) of 3.6 (1.2, 12.7) and 2.7 (0.9, 8.8) in the group with recurrent miscarriages: 6.4 (1.9, 24.3) and 4.3 (1. 2, 17.3) in primary aborters, and 4.2 (1.3, 15.4) and 3.4 (1.0, 12. 8) in those with three or more miscarriages. The ORs (95% CIs) in the same study populations for serum folate concentrations less than 8.4 nmol/L were 2.1 (0.9, 4.8), 2.7 (1.0, 7.8), and 3.2 (1.3, 8.1), respectively. A significant dose-response relationship between serum folate concentrations and risk of recurrent early pregnancy loss suggested a protective effect by high serum folate concentrations. CONCLUSION: Elevated homocysteine and reduced serum folate concentrations were risk factors for recurrent spontaneous early pregnancy losses. Folic acid supplementation might be beneficial in women with histories of early pregnancy loss.

Is the common 677C-->T mutation in the methylenetetrahydrofolate reductase gene a risk factor for neural tube defects? A meta-analysis.

The common 677C-->T mutation (+) in the 5,10-methylenetetrahydrofolate reductase gene, resulting in decreased activity of the enzyme, has been associated with spina bifida neural tube defects (NTD). We combined all known Dutch control groups, a total of 1273 individuals, and found a prevalence of the 677C-->T mutation of 8.4%. When compared with the frequencies in 55 SB patients and to mothers with a child with SB their parents, this gave an OR of 1.9 [95% CI 1.1-3.3] for mothers and an OR of 1.5 [95% CI 0.74-3.1] for patients. The frequency of this mutation and its associated risk for NTD may be population-dependent. However, the frequencies of the 677C-->T mutation in different national and international control groups are almost all in the same range. We therefore combined the observed frequencies of the 677C-->T mutation in all reported studies. The mutation was present in 9.2% of controls, resulting in ORs for all reported NTD patients and their parents of: 1.7 [95% CI: 1.1-2.6]; 1.8 [95% CI: 1.1-3.1] and 1.9 [95% CI: 1.3-2.8] for mothers (combined prevalence 14.5%), fathers (combined prevalence 15.5%) and NTD patients (combined prevalence 16.4%), respectively, vs. all international controls. This meta-analysis confirms that the 677C-->T mutation is a genetic risk factor for NTD.

Altered folate and vitamin B12 metabolism in families with spina bifida offspring.

Folic acid intake reduces the risk of neural tube defects (NTDs). Although the 677C-->T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene is a risk factor for NTDs, it only partly explains the elevated homocysteine levels in mothers of children with NTDs. We measured vitamin B12, folate and homocysteine in patients with spina bifida (SB), their parents, and in controls, to investigate which other enzymes of homocysteine metabolism might be defective. Because homozygosity for the 677C-->T mutation causes decreased plasma folate and increased red-cell folate (RCF) and plasma homocysteine levels, we excluded individuals homozygous for that mutation. The remaining SB patients and their parents still had lowered plasma folate and elevated total homocysteine levels, and a small subset had decreased vitamin B12 levels. Red-cell folate was the same in all groups, suggesting that dietary folate intake and its uptake was normal. Risk of SB was increased at the 25th percentile of plasma folate and at the 75th percentile of homocysteine values in SB patients and their parents, and at the 5th and 25th percentiles of vitamin B12 in mothers with SB-affected offspring. This underlines the functional importance of homocysteine remethylation to methionine. There was no correlation between vitamin B12 and homocysteine or RCF. In combination with the lowered plasma folate (80-90% 5-methyltetrahydrofolate), our data do not support a major involvement of methionine synthase in the aetiology of SB. Our data rather favour the involvement of genetic variation at loci coding for the formation of 5-methyltetrahydrofolate, such as MTHFR, methylenetetrahydrofolate dehydrogenase or serine hydroxymethyltransferase.

Sequence analysis of the coding region of human methionine synthase: relevance to hyperhomocysteinaemia in neural-tube defects and vascular disease.

Elevated homocysteine (Hcy) levels are observed in two apparently unrelated diseases: neural-tube defects (NTD) and premature vascular disease. Defective human methionine synthase (MS) could result in elevated Hcy levels. We sequenced the coding region of MS in 8 hyperhomocysteinaemic patients (4 NTD patients and 4 patients with pregnancies complicated by spiral arterial disease, SAD). We identified only one mutation resulting in an amino acid substitution: an A-->G transition at bp 2756, converting an aspartic acid (D919) into a glycine (G). We screened genomic DNA for the presence of this mutation in 56 NTD patients, 69 mothers of children with NTD, 108 SAD patients and 364 controls. There was no increased prevalence of the GG and AG genotypes in NTD patients, their mothers or SAD patients. The D919G mutation does not seem to be a risk factor for NTD or vascular disease. We then examined the mean Hcy levels for each MS genotype. There was no correlation between GG- or AG-genotype and Hcy levels. The D919G mutation is thus a fairly prevalent, and probably benign polymorphism. This study, though limited, provides no evidence for a major involvement of MS in the aetiology of homocysteine-related diseases such as NTD or vascular disease.

Hyperhomocysteinemia and recurrent early pregnancy loss: a meta-analysis.

OBJECTIVE: To quantify the risk of recurrent early pregnancy loss in the presence of elevated fasting or afterload homocysteine concentrations or homozygosity for the 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene (T/T genotype). DESIGN: Case-control studies published between January 1992 and November 1999 were identified with a MEDLINE-search. These studies were combined with a recent case-control study performed by our own research group. SETTING: Academic research environment. PATIENT(S): Studies published in the English language, concerning two or more pregnancy losses before 16 weeks' menstrual age were included. INTERVENTION(S): Meta-analysis of all of the studies included. MAIN OUTCOME MEASURE(S): The number of subjects with and without hyperhomocysteinemia or with the T/T genotype were derived, if necessary the study was supplemented by personal communication with the original authors. RESULT(S): Pooled risk estimates of 2.7 (1.4 to 5.2) and 4.2 (2.0 to 8.8) were calculated for fasting and afterload plasma homocysteine concentrations, respectively. For the MTHFR T/T genotype a pooled risk estimate of 1.4 (1.0 to 2.0) was found. CONCLUSION(S): These data support hyperhomocysteinemia as a risk factor for recurrent early pregnancy loss. Further research should be focused on the pathophysiology of this relationship and on the clinical efficacy of B vitamin supplementation.

CA-125 levels in cervical mucus during the menstrual cycle.

OBJECTIVE: To determine CA-125 levels in cervical mucus (CM) during the menstrual cycle and their relationship to gonadal steroids and ovulation. DESIGN: Prospective study. SETTING: Two academic tertiary referral centers. PARTICIPANTS: Thirteen women with a normal fertility work-up. INTERVENTIONS: CA-125 and protein concentrations were measured in CM aspirated from the endocervical canal on alternate days in the early follicular and luteal phases and on a daily basis during the periovulatory period. Results were correlated with hormonal determinations, serum CA-125 levels, and ultrasound examination. RESULTS: Twenty ovulatory nonconceptional cycles were analyzed. Although the mean (+/- SD) concentration of CA-125 in CM (173,900 +/- 128,900 arbitrary U/mL) appeared relatively constant along the cycle, a large variation among the different samples was observed, ranging from 9,000 to 830,000 arbitrary U/mL. No clear trend could be detected as related to hormonal changes and ovulation. However, when the mucus CA-125 concentration was multiplied by the total volume of the correspondent sample, a clear periovulatory increase of total CA-125 levels was found. This was further supported by a similar trend showed by the calculated CA-125:protein concentration ratio. CONCLUSIONS: CA-125 is present in CM in high concentrations that vary widely along the cycle. Although no cyclical variation in CA-125 concentration could be determined, there was an apparent increase of total CA-125 levels parallel to the augmented mucus production during the periovulatory period. This further suggests a possible involvement of this glycoprotein in the secretory process of endocervical glands.

Study on the presence of homocysteine in ovarian follicular fluid.

OBJECTIVE: To study the presence of homocysteine, methionine and the vitamins folate, B12, and B6 in human ovarian follicular fluid (FF). DESIGN: Measurement of homocysteine, methionine, folate, and vitamins B12 and B6 in ovarian FF and blood. SETTING: Academic Department of Obstetrics and Gynecology at St. Radboud Hospital, Nijmegen, The Netherlands. PARTICIPANTS: Fourteen healthy women undergoing an IVF program. RESULTS: Detectable amounts of homocysteine and methionine were found in FF. Homocysteine concentrations were similar to those in serum. Methionine concentrations proved to be slightly but significantly lower than in corresponding serum samples. Concentrations of vitamins B12 and B6 were significantly lower in FF than in serum, whereas folate concentrations were not significantly different. A statistically significant correlation between corresponding serum and FF concentrations of homocysteine, folate, and vitamin B12 could be established. CONCLUSIONS: These data support the hypothesis that the ovum might be exposed to high homocysteine or low methionine concentrations, or both, and a lack of vitamins, which might be important in fertilization and early embryogenesis.

Hyperhomocysteinemia: a risk factor in women with unexplained recurrent early pregnancy loss.

OBJECTIVE: To establish the prevalence of hyperhomocysteinemia in women with unexplained recurrent early pregnancy loss. DESIGN: In a patient-control study, the methionine-homocysteine metabolism was investigated by a standardized oral methionine-loading test. SETTING: Gynecologic outpatient department of university hospital. PATIENTS: One-hundred and two women who had been referred to the hospital because they suffered from at least two consecutive unexplained spontaneous abortions (study group) as well as 41 controls who were recruited by public advertisement were selected. INTERVENTIONS: Blood samples were collected just before and 6 hours after oral methionine administration to determine plasma total homocysteine concentrations. MAIN OUTCOME MEASURE: Plasma total homocysteine concentrations 6 hours after methionine loading. Hyperhomocysteinemia was defined as total homocysteine concentration at 6 hours exceeding the 97.5 percentile level of the controls. RESULTS: Hyperhomocysteinemia was diagnosed in 21 women of the study group (21%). In the parous women of the study group, the prevalence of hyperhomocysteinemia was more than two times greater compared with the nulliparous subjects (33% and 14%, respectively). CONCLUSION: Hyperhomocysteinemia is a risk factor in women with unexplained recurrent early pregnancy loss.

Is there influence of smoking on the mutagenicity of follicular fluid?

The mutagenicity of follicular fluid was examined in 24 patients, 12 smoking and 12 nonsmoking, who were treated in an in vitro fertilization program. The Salmonella microsome assay was used. It was found that the mutagenicity of follicular fluid was not influenced by the number of cigarettes smoked. Urine samples of smoking in vitro fertilization (IVF) patients however showed a dose-dependent elevation of the mutagenicity.

Factors influencing the risk of abnormal pregnancy outcome in epileptic women: a multi-centre prospective study.

We studied pregnancy outcome in preconceptionally recruited epileptic and control women in a multi-centre prospective non-intervention study at two university hospitals and three general hospitals. We evaluated 225 singleton pregnancies: 119 pregnancies of epileptic women who received either antiepileptic drugs (AEDs) (n = 99) or not (n = 20), and 106 pregnancies of controls. The main outcome measures were abnormal pregnancy outcome: major and minor congenital malformations, ectopic pregnancies, abortions; neonatal headcircumference; birth weight and birth length. Epileptic women had a two-fold risk of having an abnormal pregnancy outcome or an infant with minor malformations compared to healthy controls (odds ratio, with 95% confidence interval, respectively 2.1 (1.1, 4.0) and 2.0 (1.0, 4.0)). A significant correlation between the prevalence of abnormal pregnancy outcome and duration of epilepsy and AED treatment was found (risk increased by 9% (6%, 16%) per annum). No significant effect in terms of the type, the number or the serum level of the AEDs could be established. The head circumference of infants of epileptic mothers was significantly smaller (0.7 (1.2, 0.28 cm) compared to controls. An effect on the outcome of pregnancy of maternal folate supplementation or of folate blood concentrations during the periconceptional period and first trimester of pregnancy could not be determined. The severity of maternal epilepsy and/or AED treatment influences pregnancy outcome.