Objective To investigate associations between early pregnancy homocysteine, folate and vitamin B12 concentrations and placental weight, birthweight and adverse pregnancy outcomes.Design Population-based birth cohort study.Setting Rotterdam, the Netherlands.Population Cohort of 5805 pregnant women.Methods To analyse homocysteine, folate and vitamin B12 concentrations, blood was drawn in early pregnancy. These concentrations were divided into quintiles. Information on birth outcomes was retrieved from medical records. Multivariate regression analyses were used.Main outcome measures Placental weight, birthweight, small for gestational age at birth (SGA) (<5th centile), prematurity and preeclampsia.Results High homocysteine concentrations (highest quintile) were associated with lower placental weight (difference 30 g; P < 0.001) and birthweight (difference 110 g; P < 0.001), and increased risk of SGA [odds ratio (OR) 1.7; P = 0.006] compared with lowest quintile (reference). Low folate concentrations (lowest quintile) were associated with lower placental weight (difference 26 g; P = 0.001) and birthweight (difference 125 g; P < 0.001), and increased risks of SGA (OR 1.9; P = 0.002), prematurity (OR 2.2; P = 0.002) and pre-eclampsia (OR 2.1; P = 0.04) compared with highest quintile (reference). The risk of developing SGA and preeclampsia was substantially higher in women who had higher homocysteine and lower folate concentrations. No associations were found with vitamin B12.Conclusions Higher homocysteine and lower folate concentrations in early pregnancy are associated with lower placental weight and birthweight, and higher risk of adverse pregnancy outcomes. These findings suggest that high homocysteine and low folate concentrations in early pregnancy may adversely influence placentation and subsequently affect the success of pregnancy and birth outcomes.

Chemotactic stimulation of Dictyostelium cells results in a transient increase in cGMP levels, and transient phosphorylation of myosin II heavy and regulatory light chains. In Dictyostelium, two guanylyl cyclases and four candidate cGMP‐binding proteins (GbpA–GbpD) are implicated in cGMP signalling. GbpA and GbpB are homologous proteins with a Zn2+‐hydrolase domain. A double gbpA/gbpB gene disruption leads to a reduction of cGMP‐phosphodiesterase activity and a 10‐fold increase of basal and stimulated cGMP levels. Chemotaxis in gbpA−B− cells is associated with increased myosin II phosphorylation compared with wild‐type cells; formation of lateral pseudopodia is suppressed resulting in enhanced chemotaxis. GbpC is homologous to GbpD, and contains Ras, MAPKKK and Ras‐GEF domains. Inactivation of the gbp genes indicates that only GbpC harbours high affinity cGMP‐binding activity. Myosin phosphorylation, assembly of myosin in the cytoskeleton as well as chemotaxis are severely impaired in mutants lacking GbpC and GbpD, or mutants lacking both guanylyl cyclases. Thus, a novel cGMP signalling cascade is critical for chemotaxis in Dictyostelium, and plays a major role in myosin II regulation during this process.

Developmental adaptations due to early nutritional exposures may have permanent health consequences. Studies of diet and fetal size have mainly focused on individual nutrients despite evidence that the pattern of food consumption may be of significance. Hence, we evaluated the associations of dietary habits in early pregnancy (gestational age , 18 weeks) with fetal size, uteroplacental vascular resistance, placental weight and birth weight in a prospective observational study of 3207 Caucasian pregnant mothers in Rotterdam, the Netherlands. Participants completed a semiquantitative FFQ during early pregnancy. Logistic regression analysis was used to predict the occurrence of intra-uterine growth retardation at birth as a function of food intake. The derived solution was considered as the dietary pattern. As it was characterised by higher intakes of fruit, vegetables, vegetable oil, fish, pasta and rice, and lower intakes of meat, potatoes and fatty sauces, it was labelled the 'Mediterranean' diet. The degree of adherence to the diet was positively associated with plasma folate and serum vitamin B 12 concentrations and showed an inverse relationship with homocysteine and high-sensitivity C-reactive protein plasma concentrations (P , 0·05). Important fetal size and placental parameters were associated with the degree of adherence to the diet, revealing a 72 g lower birth weight (95 % CI 2 110·8, 233·3) and a 15 g lower placental weight (95 % CI 2 29·8, 2 0·2) for women with low adherence to the diet. To conclude, low adherence to a Mediterranean diet in early pregnancy seems associated with decreased intra-uterine size with a lower placental and a lower birth weight.

The presence of these and other GC sensitivity-modulating polymorphisms may have consequences for the use of GCs in a clinical setting.

P reeclampsia is a pregnancy-related disorder, clinically characterized by the new onset of proteinuria and hypertension in the second half of pregnancy, with a great effect on maternal and fetal morbidity and mortality worldwide. 1A better understanding of the pathogenic mechanisms underlying preeclampsia might help identifying biomarkers that allow early diagnosis and treatment of preeclampsia. Recently, disturbances in angiogenic balance (favoring antiangiogenic over proangiogenic factors), elevated endothelin-1 (ET-1) levels, and a suppressed renin-angiotensin-aldosterone system (RAAS) have been reported. [2][3][4] As a consequence, the ratio of the antiangiogenic soluble Fms-like tyrosine kinase-1 (sFlt-1) and the proangiogenic placental growth factor (PlGF) is now thought to be a reliable biomarker for the diagnosis of preeclampsia. 5 In fact, patients with a ratio ≥85 have a poor pregnancy outcome independent of their clinical diagnosis compared with patients with a ratio <85. 5Of interest, treatment of cancer patients with antiangiogenic drugs (which, like sFlt-1, prevent the actions of vascular endothelial growth factor [VEGF]) resulted in hypertension, proteinuria, renin suppression, and elevated ET-1 levels. 6 Animal studies with antiangiogenic drugs additionally revealed that the renal histological changes observed during such treatment, in particular glomerular endotheliosis, resembled the renal alterations observed in preeclampsia. 7 From the observation that the dual ET A/B receptor antagonist macitentan prevented both the rise in blood pressure and proteinuria during Abstract-Women with preeclampsia display low renin-angiotensin-aldosterone system activity and a high antiangiogenic state, the latter characterized by high levels of soluble Fms-like tyrosine kinase (sFlt)-1 and reduced placental growth factor levels. To investigate whether renin-angiotensin-aldosterone system suppression in preeclampsia is because of this disturbed angiogenic balance, we measured mean arterial pressure, creatinine, endothelin-1 (ET-1), and reninangiotensin-aldosterone system components in pregnant women with a high (≥85; n=38) or low (<85; n=65) soluble Fms-like tyrosine kinase-1/placental growth factor ratio. Plasma ET-1 levels were increased in women with a high ratio, whereas their plasma renin activity and plasma concentrations of renin, angiotensinogen, and aldosterone were decreased. Plasma renin activity-aldosterone relationships were identical in both the groups. Multiple regression analysis revealed that plasma renin concentration correlated independently with mean arterial pressure and plasma ET-1. Plasma ET-1 correlated positively with soluble Fms-like tyrosine kinase-1 and negatively with plasma renin concentration, and urinary protein correlated with plasma ET-1 and mean arterial pressure. Despite the lower plasma levels of renin and angiotensinogen in the high-ratio group, their urinary levels of these components were elevated. Correction for albumin revealed that this was because of increased glomer...