Biomedical subjects
Publications and source records attributed to E A Steegers.
Chronic hypertension occurs in 5% of pregnancies and can threaten the life of the mother and the fetus. Chronic hypertension should be evaluated before pregnancy; special attention should be paid to the existence of organ damage and the presence of an acceptable incentive for treatment. The risk of complications of chronic hypertension in pregnancy should be discussed with the couple before pregnancy.
Deep vein thrombosis is one of the main causes of maternal death in the Western world, pulmonary embolism, as a complication, being the immediate cause of death in most cases. Deep vein thrombosis is the end result of several, partly interrelated, inherited and acquired risk factors. Thrombophilia is the overall name for a number of specific abnormalities resulting in an increased tendency towards haemocoagulation. In order to reduce the morbidity and mortality caused by thromboembolic complications in pregnant women, all women who want to become pregnant should be screened for risk factors in order to assess the a priori risk of venous thrombosis. Based on the individual thrombosis history and the presence of thrombophilia, a prophylactic policy can be determined for every pregnant woman. Currently, there are no data available from prospective and randomised trials assessing the effects of anticoagulants in pregnant women with thrombophilia.
Endothelium-derived nitric oxide (NO) plays a key role in the regulation of vascular tone in health and disease. The present study addresses the contribution of NO to the baseline vascular tone in the fetal placental circulation of type 1 diabetic women. To this end, we performed ex-vivo dual perfusions of isolated cotyledons from seven women with type 1 diabetes mellitus and 24 healthy women. The fetal arterial pressure was considered to be a measure of fetal vascular resistance. The contribution of NO to the baseline vascular tone of the fetal placental circulation was quantified by addition of the NO-synthase inhibitor N(G)-nitro-arginine-methylester (L-NAME). Apart from the diabetic state, we studied the influence of exogenous insulin on the response to L-NAME. Mean (+/-SEM) baseline fetal arterial pressure was higher in diabetes (25.7+/-3.4 mm Hg vs 18.0+/-1.7 mm Hg, P<0.05). Maximum perfusion pressure after L-NAME was 87.9+/-7.1 mm Hg in diabetes vs 58.9+/-4.5 mm Hg in controls (P<0.01). The net L-NAME-induced increase in fetal arterial pressure was higher in diabetes (62.2+/-9.1 mm Hg vs 40.9+/-3.5 mm Hg, P<0.05). Although insulin induced a shift to the left of the L-NAME-curve, the net L-NAME-induced increase in fetal arterial pressure was not affected. We conclude that diabetes is associated with an increased baseline vascular tone of the fetal placental vascular bed. This can not be explained by attenuated NO-mediated effects. In contrast, the activity of the NO-pathway seems to be increased in diabetes. The latter observation seems not to be caused by high insulin levels.
A 30-year-old woman in her first, twin, pregnancy presented with progressive erythematous edematous papulae and pruritus at 31 weeks amenorrhoea. She was diagnosed with polymorphic eruption of pregnancy. The symptoms disappeared after elective cesarean section at 36 weeks.
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OBJECTIVE: To determine whether severe pre-eclampsia complicated by hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome alters neutrophil oxygen radical production. MATERIALS AND METHODS: Neutrophils were obtained from 10 healthy non-pregnant, 9 normal pregnant and 9 women with severe pre-eclampsia with concurrently HELLP syndrome. Oxygen radical production was evaluated using luminol-enhanced chemiluminescence and measured by cytochrome C reduction. Furthermore we incubated sera from cases and controls with isolated healthy neutrophils and measured their capacity to generate oxygen radicals. RESULTS: Unstimulated neutrophil oxygen radical production was significantly lower in severe pre-eclamptics compared with healthy non-pregnant and pregnant subjects, whereas phorbol ester-induced oxygen radical production did not differ among categories. Cytochrome C reduction of unstimulated neutrophils showed similar results. Healthy neutrophils incubated with sera from pre-eclamptics enhanced the oxygen radical production significantly more than neutrophils incubated with sera from the healthy subjects. CONCLUSIONS: Severe pre-eclampsia is characterised by decreased unstimulated neutrophil oxygen radical production. This may be the result of an exhausted cellular response due to stimulation by a factor present in the serum of these patients.
OBJECTIVE: To provide an overview of the outcomes from an outpatients' clinic for preconceptional counselling in the Netherlands and to assess its activities in terms of referrals, referral indications, supplementary investigations, treatment policy and a possible future pregnancy. DESIGN: Retrospective, descriptive. METHOD: Data were collected from the medical records of women who were seen at the outpatients' clinic for preconceptional counselling, University Medical Centre St Radboud, Nijmegen, the Netherlands, during the period 1 January 1996-6 July 2000. RESULTS: Of the 484 women studied, medical records were available for 459 (95%); their median age was 31 years (range: 19-44). Most of the women with one or more risk factors were referred by gynaecologists (65%), followed by general practitioners (17%) and other specialists (14%). The main categories of referral were previous complicated obstetric history, previous fetal abnormality, and chronic maternal disease. Half of the women were subjected to supplementary investigations on the basis of an indication; hyperhomocysteinaemia was diagnosed in 24%, other form of thrombophilia (coagulopathy) in 21% and vitamin deficiency in 18%. The most frequent preconceptional interventions were the correction of hyperhomocysteinaemia by means of administering folic acid or other vitamin supplements and a change of therapy or cessation of therapy for potentially teratogenic medications. CONCLUSION: The outpatients' clinic for preconceptional counselling helped to minimise risk factors for adverse pregnancy outcome amongst high-risk women by providing extensive advice as well as by means of the early detection and treatment of diagnosed abnormalities.
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In 2000, the Health Council of the Netherlands produced new dietary reference values for the intake of several vitamins, including vitamin D. These stated that pregnant and breast-feeding women without usual exposure to sunlight should consume at least 10 micrograms of vitamin D per day, while for women who were exposed to sunlight 7.5 micrograms daily would be sufficient. Because the mean intake through food is about 3 micrograms daily, the Health Council recommendations imply that all these women should take additional vitamin D. However, the recommendations are not evidence-based. Relevant clinical benefits of vitamin D supplementation in pregnant or breast-feeding women, such as increased bone mass and a reduced fracture risk for mother or child, have never been shown and, given the robust capacity of the skin to produce vitamin D under the influence of ultraviolet light, are rather improbable. Therefore, the intake of extra vitamin D by pregnant and breast-feeding women is unnecessary if they are regularly outside with at least their face and hands uncovered.
OBJECTIVE: To measure levels of oxidized and free thiols in whole blood of normotensive pregnant and preeclamptic women and evaluate the role of oxidative stress. METHODS: We measured whole blood oxidized and free levels of cysteine, homocysteine, cysteinylglycine, and glutathione by high performance liquid chromatography in women with normotensive pregnancies (n = 50), preeclampsia (n = 29), and preeclampsia complicated by the hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome (n = 16). RESULTS: Oxidized and free levels (median [range], micromol/L) of cysteine and homocysteine were higher in women with preeclampsia than normotensive pregnancies (45 [27-81] versus 29 [9-91], P <.001, and 98 [57-193] versus 69 [33-215], P <.001; 0.8 [0.2-4.4] versus 0.4 [0.01-1.6], P <.001, and 2.1 [0.7-9.4] versus 1.2 [0.2-21.2], P <.01; respectively). The ratios of free to oxidized cysteine, homocysteine, and cysteinylglycine were lower in preeclampsia than normotensive pregnancy (2.2 [1.3-3.0] versus 2.4 [1.7-4.3], P <.001; 2.3 [0.5-5.4] versus 2.9 [1.1-24], P <.001; 4.1 [2.3-11.6] versus 5.4 [2.6-24.3], P <.02, respectively), indicating a shift in favor of the oxidized form of those thiols. In HELLP syndrome, levels of oxidized and free cysteine and levels of oxidized homocysteine were higher than normal (44 [33-63] versus 29 [9-91], P <.001, and 102 [82-133] versus 69 [33-215], P <.001; 1.0 [0.3-2.9] versus 0.4 [0.01-1.6], P <.001, respectively). No significant differences were found in oxidized glutathione levels in women with preeclampsia (22 [5-49] versus 17 [2- 60], P =.06) or free levels in preeclamptic women with HELLP syndrome (757 [624-993] versus 842 [539-1516], P =.09) as compared with normotensive pregnant women. The ratios of free to oxidized cysteinylglycine and glutathione were higher in women with HELLP syndrome than in those with preeclampsia (5.4 [3.3-12.7] versus 4.1 [2.3-11.6], P =.02, and 56 [28-124] versus 45 [16-166], P =.02, respectively). CONCLUSION: Significantly lower ratios of free to oxidized cysteine, homocysteine, and cysteinylglycine in preeclampsia might indicate oxidative stress.
Coeliac disease is a chronic disease caused by a permanent intolerance to ingested gluten resulting in immunologically mediated inflammatory damage of the small-intestinal mucosa. The wide spectrum of clinical symptoms is partly due to the malnourished state caused by the malabsorption of macro- and micronutrients. Fertility problems, sexual dysfunction and obstetrical complications are more frequently observed in patients with coeliac disease. These reproductive disorders may be a consequence of the endocrine derangements caused by selective nutrient deficiencies. Nowadays, the early diagnosis and treatment of coeliac disease is possible and not very costly. Therefore, coeliac disease must be seriously considered in the preconceptional screening and treatment of patients with reproductive disorders.
Preeclampsia represents one of the most frequent complications of pregnancy, however, little is known about its aetiology. Damage of the endothelial layer lining the blood vessel wall is thought to play an important role in the pathophysiology of preeclampsia, accordingly, mild hyperhomocysteinaemia has been reported to be more prevalent among preeclamptic women. Therefore, we investigated the role of hyperhomocysteinaemia in preeclampsia by measuring plasma levels of homocysteine and studying the prevalence of the 677(C-->T) polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, which may lead to reduced MTHFR enzyme activity and subsequently to higher plasma homocysteine levels. Plasma samples of 10 healthy non-pregnant women, 10 normotensive pregnant women, and 20 women with preeclampsia were analysed for total homocysteine levels by high performance liquid chromatography. Furthermore, 167 Dutch non-pregnant women previously hospitalised for preeclampsia and 403 population-based controls were analysed for the 677(C-->T) polymorphism by polymerase chain reaction followed by restriction fragment length polymorphism analysis (PCR/RFLP). In normotensive pregnancy homocysteine levels were lower compared with levels in healthy non-pregnant controls (8.4 versus 13.7micromol/l, P<0.001). Women with preeclampsia showed higher concentrations than women during normotensive pregnancy (13.3 versus 8.4micromol/l, P<0.02). However, levels of homocysteine in preeclampsia were comparable to those found in healthy non-pregnant women. PCR/RFLP showed no significant difference in the incidence of the 677(C-->T) polymorphism in the MTHFR gene between preeclamptic women with or without HELLP syndrome and controls (13 and 9% homozygous for the less common T-allele, respectively; OR 1.5, 95% CI 0.8-2.6, P=0.17). In contrast with previous reports, we cannot confirm that mild hyperhomocysteinaemia is a risk factor for preeclampsia. Pregnancy induced hyperhomocysteinaemia found in preeclampsia might better be explained by fluctuations in plasma volume than by the presence of the 677(C-->T) polymorphism in the MTHFR gene.
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Evidence of the impact of maternal nutritional status on pregnancy outcome is increasing. However, reference values for vitamin and homocysteine concentrations in maternal blood during normal pregnancy are scarce, and are lacking for the preconceptional period and early pregnancy. Thus, in a longitudinal study we evaluated vitamin and homocysteine concentrations in 102 nulliparous women with an uneventful singleton pregnancy and normal outcome not using supplements. The physiological changes in vitamin and homocysteine concentrations in blood were determined from the preconceptional period throughout pregnancy until 6 weeks post-partum. The vitamins evaluated comprised retinol, thiamin, riboflavin, pyridoxal 5'-phosphate, folate in serum and erythrocytes, vitamin B12 and alpha-tocopherol. The plasma homocysteine concentration was also measured, considering the essential roles of folate, vitamin B6 and vitamin B12 in homocysteine metabolism. The concentrations of retinol, thiamin, pyridoxal 5'-phosphate serum folate and vitamin B12 decreased during pregnancy. In contrast, the concentrations of riboflavin, alpha-tocopherol, and folate in erythrocytes increased or showed only minor changes. Homocysteine concentrations also remained approximately constant during pregnancy. These observations emphasize the importance of preconceptional and post-partum concentrations of vitamins in the evaluation of pregnancy-induced changes. These data have provided valuable reference values for vitamins and homocysteine before, during and after pregnancy in order to contribute to better diagnosis of maternal deficiencies and to study further the relationship between maternal vitamin status and adverse course and outcome of pregnancy.
BACKGROUND: Glutathione S-transferases (GSTs) are important in intracellular binding and transport of numerous compounds, and play a central role in human detoxification processes. Human GSTs mainly consist of class Pi (GSTP), Mu (GSTM), Alpha (GSTA) and Theta (GSTT) enzymes, each subdivided into one or more isoenzymes. They catalyse the conjugation of glutathione (GSH) to toxic compounds, resulting in more water-soluble and less biologically active products that may be easily excreted. The reactive -SH group in GSH is provided by cysteine, an important amino acid in GSH synthesis. METHODS: GST expression, enzyme activity and concentrations of cysteine and GSH in cytosolic fractions of organs from an embryo and a fetus at 8 and 13 weeks gestational age respectively were investigated. RESULTS: GSTP1 was predominantly present in all tissues of both the embryo and fetus. GSTA (GSTA1 + GSTA2) concentrations were moderate as compared with GSTP1, whereas GSTM1 was present in only low amounts. GSTT1 was not detected in any tissue. GST activity was highest in organs exposed directly to amniotic fluid. In all embryonic and fetal organs, considerable amounts of GSH and cysteine were detected, with higher GSH concentrations in organs where lower cysteine concentrations were demonstrated. CONCLUSIONS: These results suggest that in embryonic and early fetal development cysteine, GSH and GSTs are present in high amounts, and that GSTP1 is the most important GST isoform at these developmental stages.
The HELLP syndrome has been associated with postpartum unconjugated hyperbilirubinaemia. Several types of disorders cause unconjugated hyperbilirubinaemia, Gilbert's syndrome being the most common. In Caucasians a genetic defect in the TATA box of the promotor region of the gene encoding for bilirubin UDP-glucuronyltransferase is tightly associated with Gilbert's syndrome. This defect was assessed by polymerase chain reaction in 237 women with the HELLP syndrome in their obstetric history and 236 controls. Fifteen percent of the cases and 10% of the controls had a homozygous genetic defect (chi2 = 2.9; P = 0.23). No evidence was found that Gilbert's syndrome is associated with the HELLP syndrome.
OBJECTIVE: Microsomal epoxide hydrolase is an important enzyme involved in the metabolism of endogenous and exogenous toxicants. Polymorphic variants of the human epoxide hydrolase gene vary in enzyme activity. We determined whether genetic variability in the gene encoding for microsomal epoxide hydrolase contributes to individual differences in susceptibility to the development of pre-eclampsia with or without the syndrome of Haemolysis, Elevated Liver enzymes, and Low Platelets (HELLP). METHODS: A total of 183 non-pregnant women with a history of pre-eclampsia, 96 of whom had concurrently developed the HELLP syndrome, and 151 healthy female controls were genotyped for the 113Tyr-->His polymorphism in exon 3 and the 139His-->Arg polymorphism in exon 4 of the epoxide hydrolase gene by a polymerase chain reaction-restriction fragment length polymorphism assay. Chi-square analysis was used for statistical evaluation of differences in polymorphic rates. RESULTS: In pre-eclampsia a higher frequency (29%) of the high activity genotype Tyr113 Tyr113 in exon 3 was found as compared to controls (16%, OR 2.0, 95% CI 1.2-3.7). There was no difference between groups for the 139His-->Arg polymorphism. In women with a history of pre-eclampsia, no difference in epoxide hydrolase genotypes was found between women who either did or did not develop the HELLP syndrome. In addition, a significant association was found between predicted EPHX activity and pre-eclampsia. CONCLUSIONS: Women with the high activity genotype in exon 3, which could reflect differences in metabolic activation of endogenous or exogenous toxic compounds, may have enhanced susceptibility to pre-eclampsia. However, polymorphisms in the epoxide hydrolase gene do not seem to influence the risk for concurrent development of the HELLP syndrome.