Gustaaf A. Dekker

Etiology and pathogenesis of preeclampsia: current concepts.

Abstract The etiology of preeclampsia is unknown. At present, 4 hypotheses are the subject of extensive investigation, as follows: (1) Placental ischemia—Increased trophoblast deportation, as a consequence of ischemia, may inflict endothelial cell dysfunction. (2) Very low-density lipoprotein versus toxicity-preventing activity—In compensation for increased energy demand during pregnancy, nonesterified fatty acids are mobilized. In women with low albumin concentrations, transporting extra nonesterified fatty acids from adipose tissues to the liver is likely to reduce albumin’s antitoxic activity to a point at which very-low density lipoprotein toxicity is expressed. (3) Immune maladaptation—Interaction between decidual leukocytes and invading cytotrophoblast cells is essential for normal trophoblast invasion and development. Immune maladaptation may cause shallow invasion of spiral arteries by endovascular cytotrophoblast cells and endothelial cell dysfunction mediated by an increased decidual release of cytokines, proteolytic enzymes, and free radical species. (4) Genetic imprinting—Development of preeclampsia-eclampsia may be based on a single recessive gene or a dominant gene with incomplete penetrance. Penetrance may be dependent on fetal genotype. The possibility of genetic imprinting should be considered in future genetic investigations of preeclampsia. (Am J Obstet Gynecol 1998;179:1359-75.)

Psychosocial factors and pregnancy outcome: A review with emphasis on methodological issues

This review focuses on the research concerning the relation between psychosocial factors and pregnancy outcome. The following four outcome measures are dealt with: (1) birth weight, (2) preeclampsia, (3) preterm labour, and (4) intrapartum complications. The most consistent finding concerns the association between maternal exposure to taxing situations and preterm delivery. Three possible pathways are hypothesized: (1) an indirect influence via unhealthy coping and life style behaviour, (2) a direct influence via stress-dependent hormones, and (3) an additional direct influence via psycho-immunological factors. Intervention studies aimed at improving pregnancy outcome show fairly mixed results. It is recommended that studies on the relationship between psychosocial factors and pregnancy outcome should employ a prospective design with due attention to chronic stressors, should include appropriate biochemical assessments, and multivariate techniques are applied.

Influence of Sex Hormones on Plasma Endothelin Levels

Atherosclerosis and hypertension are more common in men than in women, a difference that may be due, in part, to the actions of their respective sex hormones. Men have more atherogenic lipid profiles than women, and sex hormones play an important role in the development of this difference [1-3]. In addition, some evidence has emerged that androgens can induce insulin resistance [3, 4]; several case reports describe cardiovascular events in young persons after the use of anabolic steroids [5, 6]. Sex hormone-associated differences in lipid profiles and insulin sensitivity may partly explain why premenopausal women are relatively protected against cardiovascular disease. It remains to be determined, however, whether the difference between men and age-matched women in the incidence of atherosclerosis can be explained by differences in lipid profiles and insulin sensitivity alone or whether other mechanisms might be involved. Endothelial cells synthesize many active substances that regulate local blood pressure and maintain the fluidity of blood and the patency of blood vessels [7]. These include vasodilators such as endothelium-derived relaxing factor and prostacyclin (which also inhibit platelet adhesion and aggregation), vasoconstrictors such as endothelin, and larger molecules such as fibronectin. Endothelin may also have mitogenic properties [7, 8]. The release of these substances affects the local environment in the blood vessel; endothelin may also have a systemic function [7]. Some evidence has emerged that endothelin may be involved in the pathogenesis of hypertension [7, 9] and atherosclerosis [10]. Elevated plasma levels of endothelin have been observed in patients with myocardial infarction and diabetes. Whether sex hormones have direct effects on the endothelium is not known. We found that plasma endothelin levels tended to be higher in men than in women and lower in pregnant women than in nonpregnant controls. These considerations prompted us to compare endothelin levels in healthy young men and women and to assess the effects of long-term sex hormone therapy in male-to-female and female-to-male transsexuals on plasma endothelin levels. Methods We measured endothelin levels in 29 healthy young women (18 to 31 years of age; mean age, 24.1 years), 20 pregnant women (20 to 32 years of age; mean age, 26.3 years), and 23 healthy men (23 to 33 years of age; mean age, 24.7 years). To assess the effects of sex hormone therapy on plasma levels of endothelin, we measured endothelin levels before and during sex hormone therapy in 12 male-to-female transsexual patients (17 to 33 years of age; mean age, 28.4 years) and 13 female-to-male transsexual patients (17 to 26 years of age; mean age, 24.4 years). Informed consent was obtained from all participants, and the study was approved by the hospital ethics committee. All patients were within 10% of their ideal body weight (Metropolitan Life Insurance Tables, 1959). None had a personal or family history of diabetes or hypertension or had evidence of cardiovascular disease on routine examination (medical history, physical examination, and electrocardiogram). No hormone preparations (such as oral contraceptives) had been used by any of the participants in the 6 months before the study. All women had a regular menstrual cycle (28 to 31 days) before hormone treatment; blood samples were drawn during the follicular phase of the menstrual cycle (days 3 to 5). Female-to-male transsexuals received intramuscular injections of testosterone esters (Sustanon, Organon, Oss, the Netherlands), 250 mg every 2 weeks. Male-to-female transsexuals received oral ethynylestradiol (Lynoral, Organon), 0.1 mg/d, and cyproterone acetate (Androcur, Schering, Weesp, the Netherlands), 100 mg/d, to counteract the effects of testosterone. Plasma endothelin levels were measured before therapy and after 4 months of hormone use. Blood samples were drawn between 0900 hours and 0930 hours after an overnight fast, patients having rested in the supine position for at least 30 minutes. Samples were immediately placed in ice. Testosterone levels were determined 10 to 14 days after injection, and blood samples were drawn simultaneously with those in which plasma endothelin levels were determined. Plasma was separated within 1 hour and then stored at 20C until assayed. Plasma endothelin was measured by radioimmunoassay (Nichols Institute [formerly ITS], Wijchen, the Netherlands) after extraction on Sep-Pak C18 cartridges (Waters, Milford, Massachusetts), as described previously [17]. Recovery rate for this assay is 92.4%. Intra-assay and interassay coefficients of variation according to the manufacturer are 2.4% and 4.2%, respectively. (We found these values to be slightly higher: 3.6% and 5.1%, respectively.) Sensitivity of the assay is 1 pg/mL; cross-reactivity with endothelin-2 is 52%; with endothelin-3, 96%; and with big endothelin, 7%. Intra-assay variation ranged from 2% to 8%, and interassay variation ranged from 4% to 9%. In all patients, blood pressure was determined during a 2-hour period using an automatic sphygmomanometer; patients remained at rest during this period. Blood pressure measurements were done every 5 minutes, and the results were averaged. Results are expressed as mean SD. The Student two-tailed t-test for paired data was used to compare measurements within the same group before and during hormone therapy. The Student two-tailed unpaired t-test was used for between-group comparisons. A P value of less than 0.05 was considered statistically significant. Results Plasma endothelin levels were significantly higher in men than in women (5.9 1.2 compared with 4.17 0.67 pg/mL; P < 0.01). Endothelin levels were lower in pregnant women than in nonpregnant controls (2.19 0.73 compared with 4.17 0.67 pg/mL; P < 0.01), suggesting that high levels of estradiol and progesterone found during pregnancy are associated with low endothelin levels (Figure 1). Figure 1. Plasma endothelin levels in 23 men, 29 women, and 20 pregnant women. P P In biological women treated with intramuscular injections of testosterone esters, basal testosterone levels increased from 1.25 0.66 nmol/L to 24.8 13.0 nmol/L (P < 0.01). No significant change was seen in levels of estradiol-17 (247 207 compared with 185 94 pmol/L). Biological men were treated with oral ethynylestradiol, 0.1 mg/d, and cyproterone acetate, 100 mg/d. Testosterone levels decreased from 18.4 8.6 to 1.1 0.4 nmol/L in this group (P < 0.01). Levels of estradiol-17 and ethynylestradiol were not assessed. The biological effects of sex hormone therapy were manifest in both groups. Effects of sex hormone therapy on endothelin levels in both groups are shown in Figure 2. Endothelin levels before treatment tended to be higher in men than in women (8.1 3.1 compared with 6.2 1.1 pg/mL; P = 0.06), confirming our earlier observations. In biological women treated with testosterone, average endothelin levels increased from 6.2 1.1 to 7.8 1.2 pg/mL (P < 0.01) after 4 months of therapy. In men treated with estradiol and cyproterone acetate, endothelin levels decreased from 8.1 3.0 to 5.1 2.0 pg/mL (P < 0.01). Thus, the decrease in endothelin levels in men was greater than the increase in women treated with testosterone (37% and 26%, respectively); antiandrogenic actions of cyproterone acetate may have contributed to the decrease in endothelin levels in men. Figure 2. Effects of cross-gender sex hormone treatment on plasma endothelin levels in transsexual patients. Left panel. P Right panel. Blood pressure was measured in all participants (at rest) during a 2-hour period before and during hormone therapy. No significant alterations were seen; mean systolic and diastolic pressures were unchanged. To investigate the variability of endothelin plasma levels, we measured endothelin levels twice within a period of 2 months in 10 normal men. Endothelin levels were 5.90 0.85 pg/mL at the first measurement and 5.85 1.05 pg/mL at the second measurement (P 0.05), the coefficient of variation being 16.2%. These data suggest that endothelin levels are relatively stable over a period of several months. Discussion To our knowledge, this is the first study to compare plasma endothelin levels in healthy men and women. Our observations suggest that endothelin levels are higher in men than in women and that this difference is mediated by sex hormones. Atherosclerosis is characterized by endothelial injury and the proliferation of intimal smooth-muscle cells, which may be a result of the release of growth factors from the vessel wall [11]. The evidence suggests that endothelin, which is a strong vasoconstrictor, also has mitogenic properties [7, 8]. A correlation between endothelin levels and atherosclerosis has been described [10], suggesting that endothelin might participate in atherogenesis. Thus, if sex hormones affect levels of endothelin, this might be one of the mechanisms by which sex hormones influence the risk for cardiovascular disease. We speculate that a sex-associated difference in levels of endothelin may be one of the mechanisms underlying the difference in the incidence of cardiovascular disease between men and women. In our patients, blood pressure did not change during hormonal treatment. Asscheman and colleagues [12] assessed blood pressure in 425 transsexual patients (303 biological men and 122 biological women) receiving long-term sex hormone therapy. High blood pressure developed in 10 biological men treated with estrogens (2.4% of the total group of 425 patients) and in none of the women treated with testosterone. Studies of the effect of estrogen therapy on blood pressure in postmenopausal women [13, 14] and in women using oral contraceptives [15] have produced conflicting results. Thus, the effect of sex hormone therapy on blood pressure remains unclear. In healthy men, the intravenous administration of endothelin induces an increase in blood pressure and serum p

Clinical risk prediction for pre-eclampsia in nulliparous women: development of model in international prospective cohort

Objectives To develop a predictive model for pre-eclampsia based on clinical risk factors for nulliparous women and to identify a subgroup at increased risk, in whom specialist referral might be indicated. Design Prospective multicentre cohort. Setting Five centres in Auckland, New Zealand; Adelaide, Australia; Manchester and London, United Kingdom; and Cork, Republic of Ireland. Participants 3572 “healthy” nulliparous women with a singleton pregnancy from a large international study; data on pregnancy outcome were available for 3529 (99%). Main outcome measure Pre-eclampsia defined as ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg, or both, on at least two occasions four hours apart after 20 weeks’ gestation but before the onset of labour, or postpartum, with either proteinuria or any multisystem complication. Preterm pre-eclampsia was defined as women with pre-eclampsia delivered before 37+0 weeks’ gestation. In the stepwise logistic regression the comparison group was women without pre-eclampsia. Results Of the 3529 women, 186 (5.3%) developed pre-eclampsia, including 47 (1.3%) with preterm pre-eclampsia. Clinical risk factors at 14-16 weeks’ gestation were age, mean arterial blood pressure, body mass index (BMI), family history of pre-eclampsia, family history of coronary heart disease, maternal birth weight, and vaginal bleeding for at least five days. Factors associated with reduced risk were a previous single miscarriage with the same partner, taking at least 12 months to conceive, high intake of fruit, cigarette smoking, and alcohol use in the first trimester. The area under the receiver operating characteristics curve (AUC), under internal validation, was 0.71. Addition of uterine artery Doppler indices did not improve performance (internal validation AUC 0.71). A framework for specialist referral was developed based on a probability of pre-eclampsia generated by the model of at least 15% or an abnormal uterine artery Doppler waveform in a subset of women with single risk factors. Nine per cent of nulliparous women would be referred for a specialist opinion, of whom 21% would develop pre-eclampsia. The relative risk for developing pre-eclampsia and preterm pre-eclampsia in women referred to a specialist compared with standard care was 5.5 and 12.2, respectively. Conclusions The ability to predict pre-eclampsia in healthy nulliparous women using clinical phenotype is modest and requires external validation in other populations. If validated, it could provide a personalised clinical risk profile for nulliparous women to which biomarkers could be added. Trial registration ACTRN12607000551493.

Spontaneous preterm birth and small for gestational age infants in women who stop smoking early in pregnancy: prospective cohort study

Objectives To compare pregnancy outcomes between women who stopped smoking in early pregnancy and those who either did not smoke in pregnancy or continued to smoke. Design Prospective cohort study. Setting Auckland, New Zealand and Adelaide, Australia. Participants 2504 nulliparous women participating in the Screening for Pregnancy Endpoints (SCOPE) study grouped by maternal smoking status at 15 (±1) week’s gestation. Main outcome measures Spontaneous preterm birth and small for gestational age infants (birth weight <10th customised centile). We compared odds of these outcomes between stopped smokers and non-smokers, and between current smokers and stopped smokers, using logistic regression, adjusting for demographic and clinical risk factors. Results 80% (n=1992) of women were non-smokers, 10% (n=261) had stopped smoking, and 10% (n=251) were current smokers. We noted no differences in rates of spontaneous preterm birth (4%, n=88 v 4%, n=10; adjusted odds ratio 1.03, 95% confidence interval l0.49 to 2.18; P=0.66) or small for gestational age infants (10%, n=195 v 10%, n=27; 1.06, 0.67 to 1.68; P=0.8) between non-smokers and stopped smokers. Current smokers had higher rates of spontaneous preterm birth (10%, n=25 v 4%, n=10; 3.21, 1.42 to 7.23; P=0.006) and small for gestational age infants (17%, n=42 v 10%, n=27; 1.76, 1.03 to 3.02; P=0.03) than stopped smokers. Conclusion In women who stopped smoking before 15 weeks’ gestation, rates of spontaneous preterm birth and small for gestational age infants did not differ from those in non-smokers, indicating that these severe adverse effects of smoking may be reversible if smoking is stopped early in pregnancy.

Guidelines for the management of hypertensive disorders of pregnancy 2008

This is the Executive Summary of updated guidelines developed by the Society of Obstetric Medicine of Australia and New Zealand for the management of hypertensive diseases of pregnancy. They address a number of challenging areas including the definition of severe hypertension, the use of automated blood pressure monitors, the definition of non‐proteinuric pre‐eclampsia and measuring proteinuria. Controversial management issues are addressed such as the treatment of severe hypertension and other significant manifestations of pre‐eclampsia, the role of expectant management in pre‐eclampsia remote from term, thromboprophylaxis, appropriate fluid therapy, the role of prophylactic magnesium sulfate and anaesthetic issues for women with pre‐eclampsia. The guidelines stress the need for experienced team management for women with pre‐eclampsia and mandatory hospital protocols for treatment of hypertension and eclampsia. New areas addressed in the guidelines include recommended protocols for maternal and fetal investigation of women with hypertension, preconception management for women at risk of pre‐eclampsia, auditing outcomes in women with hypertensive diseases of pregnancy and long‐term screening for women with previous pre‐eclampsia.

Cervical incompetence prevention randomized cerclage trial: emergency cerclage with bed rest versus bed rest alone.

OBJECTIVE The purpose of this study was to compare preterm delivery rates and neonatal morbidity/mortality rates for women with cervical incompetence with membranes at or beyond a dilated external cervical os that was treated with emergency cerclage, bed rest plus indomethacin, versus just bed rest. STUDY DESIGN Women with cervical incompetence with membranes at or beyond a dilated external cervical os, before 27 weeks of gestation, were treated with antibiotics and bed rest and randomly assigned for emergency cerclage and indomethacin or bed rest only. RESULTS Twenty-three women were included; 13 women were allocated randomly to the emergency cerclage and indomethacin group, and 10 women were allocated randomly to the bed rest-only group. Gestational age at time of randomization was 22.2 weeks in the emergency cerclage and indomethacin group and 23.0 weeks in the bed rest-only group. Mean interval from randomization until delivery was 54 days in the emergency cerclage and indomethacin group and 20 days in the bed rest-only group (P=.046). Mean gestational age at delivery was 29.9 weeks in the emergency cerclage and indomethacin group and 25.9 weeks in the bed rest-only group. Preterm delivery before 34 weeks of gestation was significantly lower in the emergency cerclage and indomethacin group, with 7 of 13 deliveries versus all 10 deliveries in the bed rest-only group (P=.02). CONCLUSIONS Emergency cerclage, indomethacin, antibiotics, and bed rest reduce preterm delivery before 34 weeks compared with bed rest and antibiotics alone.

Hyperhomocysteinaemia and protein S deficiency in complicated pregnancies

Objective The aim of our study was to investigate whether women with placental abruption, intrauterine fetal death or small for gestational age infants have metabolic and/or haemostatic abnormalities which are known to be risk factors for intravascular thrombosis.

Psychosocial predictors of low birthweight: a prospective study

Objective To examine the role of psychosocial risk factors for low birthweight.

Maternal segregation of the Dutch preeclampsia locus at 10q22 with a new member of the winged helix gene family.

Preeclampsia is a pregnancy-associated disease with maternal symptoms but placental origin. Epigenetic inheritance is involved in some populations. By sequence analysis of 17 genes in the 10q22 region with maternal effects, we narrowed the minimal critical region linked with preeclampsia in the Netherlands to 444 kb. All but one gene in this region, which lies within a female-specific recombination hotspot, encode DNA- or RNA-binding proteins. One gene, STOX1 (also called C10orf24), contained five different missense mutations, identical between affected sisters, cosegregating with the preeclamptic phenotype and following matrilineal inheritance. Four STOX1 transcripts are expressed in early placenta, including invasive extravillus trophoblast, generating three different isoforms. All contain a winged helix domain related to the forkhead (FOX) family. The largest STOX1 isoform has exclusive nuclear or cytoplasmic expression, indicating activation and inactivation, respectively, of the PI3K-Akt-FOX pathway. Because all 38 FOX proteins and all 8 STOX1 homologs have either tyrosine or phenylalanine at position 153, the predominant Y153H variation is highly mutagenic by conservation criteria but subject to incomplete penetrance. STOX1 is a candidate for preeclampsia controlling polyploidization of extravillus trophoblast.