BackgroundRecent decades have witnessed an increase in mean maternal age at childbirth in most high-resourced countries. Advanced maternal age has been associated with several adverse maternal and perinatal outcomes. Although there are many studies on this topic, data from large contemporary population-based cohorts that controls for demographic variables known to influence perinatal outcomes is limited.MethodsWe performed a population-based cohort study using data on all singleton births in 2004–2008 from the North Western Perinatal Survey based at The University of Manchester, UK. We compared pregnancy outcomes in women aged 30–34, 35–39 and ≥40 years with women aged 20–29 years using log-linear binomial regression. Models were adjusted for parity, ethnicity, social deprivation score and body mass index.ResultsThe final study cohort consisted of 215,344 births; 122,307 mothers (54.19%) were aged 20–29 years, 62,371(27.63%) were aged 30–34 years, 33,966(15.05%) were aged 35–39 years and 7,066(3.13%) were aged ≥40 years. Women aged 40+ at delivery were at increased risk of stillbirth (RR = 1.83, [95% CI 1.37–2.43]), pre-term (RR = 1.25, [95% CI: 1.14–1.36]) and very pre-term birth (RR = 1.29, [95% CI:1.08–1.55]), Macrosomia (RR = 1.31, [95% CI: 1.12–1.54]), extremely large for gestational age (RR = 1.40, [95% CI: 1.25–1.58]) and Caesarean delivery (RR = 1.83, [95% CI: 1.77–1.90]).ConclusionsAdvanced maternal age is associated with a range of adverse pregnancy outcomes. These risks are independent of parity and remain after adjusting for the ameliorating effects of higher socioeconomic status. The data from this large contemporary cohort will be of interest to healthcare providers and women and will facilitate evidence based counselling of older expectant mothers.

Relaxation of the smooth muscle cells in the cavernosal arterioles and sinuses results in increased blood flow into the penis, raising corpus cavernosum pressure to culminate in penile erection. Nitric oxide, released from non-adrenergic/non-cholinergic nerves, is considered the principle stimulator of cavernosal smooth muscle relaxation, however, the inhibition of vasoconstrictors (that is, norepinephrine and endothelin-1, refs. 5-9) cannot be ignored as a potential regulator of penile erection. The calcium-sensitizing rho-A/Rho-kinase pathway may play a synergistic role in cavernosal vasoconstriction to maintain penile flaccidity. Rho-kinase is known to inhibit myosin light chain phosphatase, and to directly phosphorylate myosin light-chain (in solution), altogether resulting in a net increase in activated myosin and the promotion of cellular contraction. Although Rho-kinase protein and mRNA have been detected in cavernosal tissue, the role of Rho-kinase in the regulation of cavernosal tone is unknown. Using pharmacologic antagonism (Y-27632, ref. 13, 18), we examined the role of Rho-kinase in cavernosal tone, based on the hypothesis that antagonism of Rho-kinase results in increased corpus cavernosum pressure, initiating the erectile response independently of nitric oxide. Our finding, that Rho-kinase antagonism stimulates rat penile erection independently of nitric oxide, introduces a potential alternate avenue for the treatment of erectile dysfunction.

Significant impairment in endothelial-derived nitric oxide is present in the diabetic corpus cavernosum. RhoA͞Rho-kinase may suppress endothelial nitric oxide synthase (eNOS). Here, we tested the hypothesis that RhoA͞Rho-kinase contributes to diabetesrelated erectile dysfunction and down-regulation of eNOS in the streptozotocin (STZ)-diabetic rat penis. Colocalization of Rhokinase and eNOS protein was present in the endothelium of the corpus cavernosum. RhoA͞Rho-kinase protein abundance and MYPT-1 phosphorylation at Thr-696 were elevated in the STZdiabetic rat penis. In addition, eNOS protein expression, cavernosal constitutive NOS activity, and cGMP levels were reduced in the STZ-diabetic penis. To assess the functional role of RhoA͞Rho-kinase in the penis, we evaluated the effects of an adenoassociated virus encoding the dominant-negative RhoA mutant (AAVTCMV19NRhoA) on RhoA͞Rho-kinase and eNOS and erectile function in vivo in the STZ-diabetic rat. STZ-diabetic rats transfected with AAVCMVT19NRhoA had a reduction in RhoA͞Rho-kinase and MYPT-1 phosphorylation at a time when cavernosal eNOS protein, constitutive NOS activity, and cGMP levels were restored to levels found in the control rats. There was a significant decrease in erectile response to cavernosal nerve stimulation in the STZ-diabetic rat. AAVT19NRhoA gene transfer improved erectile responses in the STZ-diabetic rat to values similar to control. These data demonstrate a previously undescribed mechanism for the down-regulation of penile eNOS in diabetes mediated by activation of the RhoA͞Rho-kinase pathway. Importantly, these data imply that inhibition of RhoA͞Rho-kinase improves eNOS protein content and activity thus restoring erectile function in diabetes.gene therapy ͉ neuronal NO synthase ͉ endothelium R elaxation of corporal smooth muscle is essential for normal erectile function, and evidence exists to implicate neuronaland endothelial-derived nitric oxide (NO) as the principal mediator of corporal smooth muscle relaxation (1-3). Impairments in neurogenic and endothelium-dependent corporal smooth muscle relaxation is observed in diabetes mellitus and is responsible for erectile impairment in diabetic patients (4, 5).Contraction of smooth muscle is primarily mediated by phosphorylation of the regulatory myosin light chain (MLC) by the Ca 2ϩ ͞calmodulin-dependent activation of MLC kinase and actin͞myosin cross-bridge formation (6). Relaxation is mediated by the dephosphorylation of MLC by smooth muscle myosin phosphatase. Recent evidence has established the importance of Ca 2ϩ -sensitization through the Ca 2ϩ -independent stimulation of MLC kinase or the attenuation of MLC phosphatase activity (7). A principle regulator of MLC phosphatase is the serine͞ threonine kinase, Rho-kinase. Data from peripheral arteries suggest that RhoA, a GTP-binding protein, mediates agonistinduced activation of Rho-kinase (8). The exchange of GDP for GTP on RhoA and translocation of RhoA from the cytosol to the membrane are markers of activation, and enable the downstr...