John R. Higgins

Nitric oxide in the uteroplacental, fetoplacental, and peripheral circulations in preeclampsia

OBJECTIVE Altered production of nitric oxide by the vascular endothelium may influence the pathogenesis of preeclampsia. The aim of this study was to measure circulating levels of nitric oxide metabolites (nitrites) in the uteroplacental, fetoplacental, and peripheral circulation of preeclamptic pregnancies compared with normotensive controls. METHODS Fifteen women with preeclampsia were compared with 16 women with normotensive pregnancies. At cesarean, blood samples were taken from the uterine vein draining the placental site, the umbilical vein, and the antecubital vein after delivery of the baby but before delivery of the placenta. Plasma nitrites were measured using the Greiss reaction after conversion of plasma nitrates to nitrites using nitrate reductase. RESULTS Nitric oxide metabolites were higher in the uteroplacental (P < .01), fetoplacental (P < .001), and peripheral (P < .02) circulations in samples from preeclamptic pregnancies compared with control pregnancies. In samples from the fetoplacental circulation only, nitric oxide metabolite levels were negatively correlated with gestational age (r = -.489, P < .01) and birth weight (r = -.544, P < .004). Nitric oxide metabolite levels were not significantly correlated with blood pressure, placental weight, or maternal age. CONCLUSION In established preeclampsia, production of nitric oxide was higher in the uteroplacental, fetoplacental, and peripheral circulation than in normotensive pregnancies. This increase may be part of a compensatory mechanism to offset the pathologic effects of preeclampsia.

Can 24-hour ambulatory blood pressure measurement predict the development of hypertension in primigravidae?

Objective To assess the role of 24‐hour ambulatory blood pressure measurement in the mid‐second trimester as a predictive test for the development of hypertension in pregnancy.

Haemostasis in normal and abnormal pregnancy

Haemostasis is a complex and dynamic equilibrium involving pro-coagulants, the natural anticoagulation system and fibrinolysis. Normal human pregnancy is associated with profound alterations to the process of haemostasis such that the pro-coagulant effect becomes dominant. There are very few studies which have attempted to elucidate the adaptations that take place in the uteroplacental circulation where the haemostatic system faces the conflicting tasks of maintaining blood fluidity during pregnancy while preparing for the haemostatic challenge of delivery. It is hypothesised that excessive thrombosis within the uteroplacental circulation provides the mechanistic basis for the reported associations between the inherited thrombophilias and major pregnancy complications. The evidence underpinning this widely quoted hypothesis is weak.

Inherited thrombophilia polymorphisms and pregnancy outcomes in Nulliparous women

OBJECTIVE: To estimate the association between five commonly inherited thrombophilia polymorphisms and adverse pregnancy outcomes in women who had no prior history of adverse pregnancy outcomes or personal or family history of venous thromboembolism. METHODS: Healthy nulliparous women (n=2,034) were recruited to this prospective cohort study before 22 weeks of gestation. Genotyping for factor V Leiden, prothrombin gene mutation, methylenetetrahydrofolate reductase enzyme (MTHFR) C677T, MTHFR A1298C, and thrombomodulin polymorphism was performed. Clinicians caring for women were blinded to the results of thrombophilia tests. The primary composite outcome was the development of severe preeclampsia, fetal growth restriction, placental abruption, stillbirth, or neonatal death. RESULTS: Complete molecular results and pregnancy outcome data were available in 1,707 women. These complications were experienced by 136 women (8.0%). Multivariable logistic regression demonstrated two statistically significant findings. Women who carried the prothrombin gene mutation had an odds ratio of 3.58 (95% confidence interval [CI] 1.20–10.61, P=.02) for the development of the composite primary outcome. Homozygous carriers of the MTHFR 1298 polymorphism had an odds ratio of 0.26 (95% CI 0.08–0.86, P=.03). None of the other polymorphisms studied showed a significant association with the development of the primary outcome in this cohort of women. CONCLUSION: Prothrombin gene mutation confers an increased risk for the development of adverse pregnancy outcomes in otherwise asymptomatic, nulliparous women, whereas homozygosity for MTHFR 1298 may protect against these complications. The majority of asymptomatic women who carry an inherited thrombophilia polymorphism have a successful pregnancy outcome. LEVEL OF EVIDENCE: II

Hemostasis in the uteroplacental and peripheral circulations in normotensive and pre-eclamptic pregnancies

OBJECTIVE Our purpose was to determine the hemostatic changes in the uteroplacental and peripheral circulations in normotensive and pre-eclamptic pregnancies. STUDY DESIGN This prospective, observational study involved 2 patient groups. Group 1 consisted of 30 normotensive women and 22 women with pre-eclampsia who were followed up longitudinally through pregnancy and post partum. Group 2 consisted of 20 women with established pre-eclampsia and 19 normotensive control subjects, all undergoing cesarean section. Plasma levels of thrombin-antithrombin III complex, soluble fibrin, plasmin-alpha2-antiplasmin complex, and fibrin-degradation product (D-dimer) were measured in blood drawn from the antecubital vein (group 1) and from both the antecubital and uterine veins (group 2). Data were analyzed by analysis of variance. RESULTS In group 1 levels of thrombin-antithrombin III complex, soluble fibrin, and fibrin-degradation product were significantly higher during normal pregnancy than at 6 weeks post partum. Plasmin-alpha2-antiplasmin complex levels did not change. No differences between the pre-eclamptic and normotensive pregnancy groups were found for any of the hemostatic markers. In group 2 normotensive women undergoing cesarean section, thrombin-antithrombin III complex and soluble fibrin levels were significantly higher in the uterine vein than in the antecubital vein. In group 2 women with pre-eclampsia, thrombin-antithrombin III complex and fibrin-degradation product levels were significantly higher in the uterine vein than in the antecubital vein. In addition, plasmin-alpha2-antiplasmin complex and fibrin-degradation product levels were higher and soluble fibrin levels were lower in the uterine vein in the pre-eclamptic group than in the normotensive group. CONCLUSION Both the coagulation and fibrinolytic systems are activated during normal pregnancy. Activation of these systems is more marked in the uteroplacental circulation than in the systemic circulation in both normotensive and pre-eclamptic pregnancies. An abnormal pattern of hemostasis occurs in the uteroplacental circulation in pre-eclampsia.

Circulating vascular cell adhesion molecule–1 in pre-eclampsia, gestational hypertension, and normal pregnancy: Evidence of selective dysregulation of vascular cell adhesion molecule–1 homeostasis in pre-eclampsia

OBJECTIVE Our purpose was to investigate circulating levels of vascular cell adhesion molecule-1 in the peripheral and uteroplacental circulations during normotensive and hypertensive pregnancies. STUDY DESIGN This prospective observational study involved 2 patient groups. Group 1 consisted of 22 women with pre-eclampsia and 30 normotensive women followed up longitudinally through pregnancy and post partum. There were an additional 13 women with established gestational hypertension. Group 2 consisted of 20 women with established pre-eclampsia and 19 normotensive control subjects undergoing cesarean delivery. Plasma levels of vascular cell adhesion molecule-1 were measured in blood drawn from the antecubital vein (group 1) and from both the antecubital and uterine veins (group 2). Data were analyzed by analysis of variance. RESULTS In group 1 vascular cell adhesion molecule-1 levels did not change significantly throughout normal pregnancy and post partum. Women with established pre-eclampsia had increased vascular cell adhesion molecule-1 levels compared with the normotensive pregnancy group (P = .01). Vascular cell adhesion molecule-1 levels were not elevated in women with established gestational hypertension. In group 2 significantly higher levels of vascular cell adhesion molecule-1 were detected in the uteroplacental (P < .0001) and peripheral (P < .0001) circulations of pre-eclamptic women by comparison with normotensive women. In the pre-eclamptic group there was a tendency toward higher vascular cell adhesion molecule-1 levels in the peripheral circulation than in the uteroplacental circulation (P = .06). In contrast to vascular cell adhesion molecule-1, circulating levels of E-selectin and intercellular adhesion molecule-1, other major leukocyte adhesion molecules expressed by the endothelium, were not different in pre-eclamptic and normotensive pregnancies. CONCLUSION Established pre-eclampsia is characterized by selective dysregulation of vascular cell adhesion molecule-1 homeostasis. This event is not an early preclinical feature of pre-eclampsia, does not persist post partum, is not a feature of nonproteinuric gestational hypertension, and is not observed with other major leukocyte adhesion molecules. Induction of vascular cell adhesion molecule-1 expression in pre-eclampsia may contribute to leukocyte-mediated tissue injury in this condition or may reflect perturbation of other, previously unrecognized, functions of this molecule in pregnancy.

Definition of intertwin birth weight discordance.

OBJECTIVE: To establish the level of birth weight discordance at which perinatal morbidity increases in monochorionic and dichorionic twin pregnancy. METHODS: This prospective multicenter cohort study included 1,028 unselected twin pairs recruited over a 2-year period. Participants underwent two weekly ultrasonographic surveillance from 24 weeks of gestation with surveillance of monochorionic twins two-weekly from 16 weeks. Analysis using Cox proportional hazards compared a composite measure of perinatal morbidity (including any of the following: mortality, respiratory distress syndrome, hypoxic–ischemic encephalopathy, periventricular leukomalacia, necrotizing enterocolitis, or sepsis) at different degrees of birth weight discordance with adjustment for chorionicity, gestational age, twin–twin transfusion syndrome, birth order, gender, and growth restriction. RESULTS: Perinatal outcome data were recorded for 977 patients (100%) who continued the study with both fetuses alive beyond 24 weeks, including 14 cases of twin–twin transfusion syndrome. Adjusting for gestation at delivery, twin order, gender, and growth restriction, perinatal mortality, individual morbidity, and composite perinatal morbidity were all seen to increase with birth weight discordance exceeding 18% for dichorionic pairs (hazard ratio 2.2, 95% confidence interval [CI] 1.6–2.9, P<.001) and 18% for monochorionic twins without twin–twin transfusion syndrome (hazard ratio 2.6, 95% CI 1.6–4.3, P<.001). A minimum twofold increase in risk of perinatal morbidity persisted even when both twin birth weights were appropriate for gestational age. CONCLUSION: The threshold for birth weight discordance established by this prospective study is 18% both for dichorionic twin pairs and for monochorionic twins without twin–twin transfusion syndrome. This threshold is considerably lower than that defined by many retrospective series as pathologic. We suggest that an anticipated difference of 18% in birth weight should prompt more intensive fetal monitoring. LEVEL OF EVIDENCE: II

The relationship between increased folate catabolism and the increased requirement for folate in pregnancy

Objectives To estimate the rate of folate catabolism in pregnant and nonpregnant women and to derive the recommended dietary allowance for folate.

PRE-ECLAMPSIA : STILL A DISEASE OF THEORIES?

The pathophysiology of pre-eclampsia remains poorly understood. Moreover, there is no reliable predictive test and no effective prophylactic therapy for this disease. Advances have, however, recently been made in our understanding of the genetics of pre-eclampsia and in the processes which lead to abnormal trophoblastic invasion in pre-eclampsia. Prediction and prevention are intimately linked, and both problems will only be solved by further unravelling of the complex pathophysiology of pre-eclampsia.

Placental cord insertion and birthweight discordance in twin pregnancies: results of the national prospective ESPRiT Study

OBJECTIVE The purpose of this study was to evaluate the impact of noncentral placental cord insertion on birthweight discordance in twins. STUDY DESIGN We performed a multicenter, prospective trial of twin pregnancies. Placental cord insertion was documented as central, marginal, or velamentous according to a defined protocol. Association of the placental cord insertion site with chorionicity, birthweight discordance, and growth restriction were assessed. RESULTS Eight hundred sixteen twin pairs were evaluated; 165 pairs were monochorionic, and 651 pairs were dichorionic. Monochorionic twins had higher rates of marginal (P = .0068) and velamentous (P < .0001) placental cord insertion. Noncentral placental cord insertion was more frequent in smaller twins of discordant pairs than control pairs (29.8% vs 19.1%; P = .004). Velamentous placental cord insertion in monochorionic twins was associated significantly with birthweight discordance (odds ratio, 3.5; 95% confidence interval, 1.3-9.4) and growth restriction (odds ratio, 4; 95% confidence interval, 1.1-14.3). CONCLUSION Noncentral placental cord insertion contributes to birthweight discordance in monochorionic twin pregnancies. Sonographic delineation of placental cord insertion may be of value in antenatal assessment of twin pregnancies.