Fiona Broughton Pipkin

Prediction of adverse maternal outcomes in pre-eclampsia: development and validation of the fullPIERS model

BACKGROUND Pre-eclampsia is a leading cause of maternal deaths. These deaths mainly result from eclampsia, uncontrolled hypertension, or systemic inflammation. We developed and validated the fullPIERS model with the aim of identifying the risk of fatal or life-threatening complications in women with pre-eclampsia within 48 h of hospital admission for the disorder. METHODS We developed and internally validated the fullPIERS model in a prospective, multicentre study in women who were admitted to tertiary obstetric centres with pre-eclampsia or who developed pre-eclampsia after admission. The outcome of interest was maternal mortality or other serious complications of pre-eclampsia. Routinely reported and informative variables were included in a stepwise backward elimination regression model to predict the adverse maternal outcome. We assessed performance using the area under the curve (AUC) of the receiver operating characteristic (ROC). Standard bootstrapping techniques were used to assess potential overfitting. FINDINGS 261 of 2023 women with pre-eclampsia had adverse outcomes at any time after hospital admission (106 [5%] within 48 h of admission). Predictors of adverse maternal outcome included gestational age, chest pain or dyspnoea, oxygen saturation, platelet count, and creatinine and aspartate transaminase concentrations. The fullPIERS model predicted adverse maternal outcomes within 48 h of study eligibility (AUC ROC 0·88, 95% CI 0·84-0·92). There was no significant overfitting. fullPIERS performed well (AUC ROC >0·7) up to 7 days after eligibility. INTERPRETATION The fullPIERS model identifies women at increased risk of adverse outcomes up to 7 days before complications arise and can thereby modify direct patient care (eg, timing of delivery, place of care), improve the design of clinical trials, and inform biomedical investigations related to pre-eclampsia. FUNDING Canadian Institutes of Health Research; UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development, and Research Training in Human Reproduction; Preeclampsia Foundation; International Federation of Obstetricians and Gynecologists; Michael Smith Foundation for Health Research; and Child and Family Research Institute.

A Redox Switch in Angiotensinogen Modulates Angiotensin Release.

Blood pressure is critically controlled by angiotensins, which are vasopressor peptides specifically released by the enzyme renin from the tail of angiotensinogen—a non-inhibitory member of the serpin family of protease inhibitors. Although angiotensinogen has long been regarded as a passive substrate, the crystal structures solved here to 2.1 Å resolution show that the angiotensin cleavage site is inaccessibly buried in its amino-terminal tail. The conformational rearrangement that makes this site accessible for proteolysis is revealed in our 4.4 Å structure of the complex of human angiotensinogen with renin. The co-ordinated changes involved are seen to be critically linked by a conserved but labile disulphide bridge. Here we show that the reduced unbridged form of angiotensinogen is present in the circulation in a near 40:60 ratio with the oxidized sulphydryl-bridged form, which preferentially interacts with receptor-bound renin. We propose that this redox-responsive transition of angiotensinogen to a form that will more effectively release angiotensin at a cellular level contributes to the modulation of blood pressure. Specifically, we demonstrate the oxidative switch of angiotensinogen to its more active sulphydryl-bridged form in the maternal circulation in pre-eclampsia—the hypertensive crisis of pregnancy that threatens the health and survival of both mother and child.

Selenium in reproductive health.

Selenium is an essential trace element of importance to human biology and health. Increasing evidence suggests that this mineral plays an important role in normal growth and reproduction in animals and humans, and selenium supplementation is now recommended as part of public health policy in geographical areas with severe selenium deficiency in soil. This review addresses the biological functions of selenium followed by a detailed review of associations between selenium status and reproductive health. In many countries, selenium dietary intake falls below the recommended nutrient intakes and is inadequate to support maximal expression of the selenoenzymes. Numerous reports implicate selenium deficiency in several reproductive and obstetric complications including male and female infertility, miscarriage, preeclampsia, fetal growth restriction, preterm labor, gestational diabetes, and obstetric cholestasis. Currently, there is inadequate information from the available small intervention studies to inform public health strategies. Larger intervention trials are required to reinforce or refute a beneficial role of selenium supplementation in disorders of reproductive health.

Possible Roles for Folic Acid in the Regulation of Trophoblast Invasion and Placental Development in Normal Early Human Pregnancy

In addition to its role in the prevention of neural tube defects, folic acid has many other physiological functions, including cell proliferation, DNA replication, and antioxidant protection. The aim of this study was to determine the role that folic acid has in regulating placental trophoblast development. Placental explants from placentae at gestational age 7 wk (n = 3) were cultured in folic acid at concentrations of 10−6 M, 10−8 M, and 10−10 M. Extravillous trophoblast (EVT) invasion was assessed following 6-day culture, and explants were used for immunohistochemical evaluation of proliferation (MKI67) and apoptosis (active caspase 3). In addition, an array was performed on cell culture supernatants to examine a range of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs). Folic acid increased the invasion of EVT cells in this explant model by between 83% and 19% (P = 0.005), and this was associated with increased MKI67 positivity and decreased active caspase 3 positivity; this effect was concentration dependent and showed a biphasic response. In addition, culture in folic acid increased vascular density, as determined by anti-CD31 immunostaining (P = 0.05). The increase in EVT invasion correlated with increased placental explant secretion of MMP2 (P = 0.01), MMP3 (P = 0.01), and MMP9 (P = 0.02). This study demonstrates that folic acid is potentially important in a number of crucial early stages of placental development, including EVT invasion, angiogenesis, and secretion of MMPs, and highlights the need for further studies to address the benefit of longer-term folic acid supplementation throughout pregnancy to prevent pregnancy disorders associated with deficient placental development, including preeclampsia.

Prostaglandin E2 attenuates the pressor response to angiotensin II in pregnant subjects but not in nonpregnant subjects

The effect of prostaglandin E2 (PGE2), 5 microgram/min-1, on the pressor response to exogenous angiotensin II (AII) has been examined in 22 women in second-trimester pregnancy and in 10 nonpregnant control subjects. PGE2 diminished the diastolic pressor response in both groups without altering basal blood pressure. This effect was significant in the pregnant group, and not significant in the nonpregnant patients. The effect was achieved by a significant increase in threshold to AII, rather than an alteration in the slope of the dose-response curve. Five pregnant patients who were given two identical infusion regimes of AII without PGE2 showed no diminution of response. The effect of PGE2 was greatest in the pregnant women who showed greatest initial sensitivity to AII, perhaps suggesting a relative deficiency of E series prostaglandins in some women by midtrimester pregnancy.

Human placental renin–angiotensin system in normotensive and pre-eclamptic pregnancies at high altitude and after acute hypoxia–reoxygenation insult

The development of the human placenta occurs in a low oxygen environment which stimulates angiogenesis and vascularization. Placental expression of the renin angiotensin system (RAS) is highest in early pregnancy. Although both the RAS and oxygen stimulate angiogenesis, it is not known how they interact during placental development. Pre‐eclampsia (PE), a condition characterized by poor placental development and elevated oxidative stress has increased incidence in populations living at high altitude and thus exposed to hypobaric hypoxia. This study aimed to investigate the effects of various forms of oxidative stress on the placental RAS. The results suggest that the placental RAS is activated by oxidative insults but the component type and the degree of activation is dependent on the nature of the insult.

Expression of renin–angiotensin system components in the early bovine embryo

The renin–angiotensin system (RAS), mainly associated with the regulation of blood pressure, has been recently investigated in female reproductive organs and the developing foetus. Angiotensin II (Ang II) influences oviductal gamete movements and foetal development, but there is no information about RAS in the early embryo. The aim of this study was to determine whether RAS components are present in the pre-implantation embryo, to determine how early they are expressed and to investigate their putative role at this stage of development. Bovine embryos produced in vitro were used for analysis of RAS transcripts (RT-PCR) and localisation of the receptors AGTR1 and AGTR2 (immunofluorescent labelling). We also investigated the effects of Ang II, Olmesartan (AGTR1 antagonist) and PD123319 (AGTR2 antagonist) on oocyte cleavage, embryo expansion and hatching. Pre-implanted embryos possessed AGTR1 and AGTR2 but not the other RAS components. Both receptors were present in the trophectoderm and in the inner cell mass of the blastocyst. AGTR1 was mainly localised in granular-like structures in the cytoplasm, suggesting its internalisation into clathrin-coated vesicles, and AGTR2 was found mainly in the nuclear membrane and in the mitotic spindle of dividing trophoblastic cells. Treating embryos with PD123319 increased the proportion of hatched embryos compared with the control. These results, the first on RAS in the early embryo, suggest that the pre-implanted embryo responds to Ang II from the mother rather than from the embryo itself. This may be a route by which the maternal RAS influences blastocyst hatching and early embryonic development.

Maternal Dexamethasone Treatment Alters Tissue and Circulating Components of the Renin-Angiotensin System in the Pregnant Ewe and Fetus.

Antenatal synthetic glucocorticoids promote fetal maturation in pregnant women at risk of preterm delivery and their mechanism of action may involve other endocrine systems. This study investigated the effect of maternal dexamethasone treatment, at clinically relevant doses, on components of the renin-angiotensin system (RAS) in the pregnant ewe and fetus. From 125 days of gestation (term, 145 ± 2 d), 10 ewes carrying single fetuses of mixed sex (3 female, 7 male) were injected twice im, at 10–11 pm, with dexamethasone (2 × 12 mg, n = 5) or saline (n = 5) at 24-hour intervals. At 10 hours after the second injection, maternal dexamethasone treatment increased angiotensin-converting enzyme (ACE) mRNA levels in the fetal lungs, kidneys, and heart and ACE concentration in the circulation and lungs, but not kidneys, of the fetuses. Fetal cardiac mRNA abundance of angiotensin II (AII) type 2 receptor decreased after maternal dexamethasone treatment. Between the two groups of fetuses, there were no significant differences in plasma angiotensinogen or renin concentrations; in transcript levels of renal renin, or AII type 1 or 2 receptors in the lungs and kidneys; or in pulmonary, renal or cardiac protein content of the AII receptors. In the pregnant ewes, dexamethasone administration increased pulmonary ACE and plasma angiotensinogen, and decreased plasma renin, concentrations. Some of the effects of dexamethasone treatment on the maternal and fetal RAS were associated with altered insulin and thyroid hormone activity. Changes in the local and circulating RAS induced by dexamethasone exposure in utero may contribute to the maturational and tissue-specific actions of antenatal glucocorticoid treatment.

New‐onset hypertension in pregnancy: a review of the long‐term maternal effects

Women with a history of new‐onset hypertension in pregnancy have an increased risk of future hypertension and cardiovascular disease; women who deliver preterm (before 34 weeks of gestation) are at even higher risk. In this group of women, cardiovascular disease often occurs at a much earlier age. Follow‐up after pregnancy is vital to ensure that ongoing disease is appropriately investigated and managed. Simple lifestyle changes may help reduce these risks.Key content Women with a history of new-onset hypertension in pregnancy have an increased risk of future hypertension and cardiovascular disease; women who deliver preterm (before 34 weeks of gestation) are at even higher risk. In this group of women, cardiovascular disease often occurs at a much earlier age. Follow-up after pregnancy is vital to ensure that ongoing disease is appropriately investigated and managed. Simple lifestyle changes may help reduce these risks. Learning objectives To have increased awareness of the future risks of hypertensive pregnancy. To be able to quantify the risk of future disease from current evidence in the literature. To be able to counsel women and discuss lifestyle changes. Ethical issues Do we counsel women adequately about the long-term risk of disease after hypertensive pregnancy? Are we missing opportunities for disease prevention?

Volume regulatory hormones and plasma volume in pregnant women with sickle cell disorder

Background: Sickle cell disease (haemoglobin SS (HbSS)) mainly affects those of West African origin and is associated with hypervolaemia. Plasma volume rises by up to 50% in normal pregnancy but was previously found to be paradoxically contracted in late sickle cell pregnancy. The renin–angiotensin–aldosterone system is activated very early in human pregnancy to support the plasma volume expansion. We hypothesised that activation of the renin–angiotensin–aldosterone system would be blunted in pregnant women with sickle cell disease. Materials and methods: We measured plasma volume and concentrations of plasma renin, angiotensinogen, aldosterone and other volume-related hormones in a cross-sectional study of pregnant and non-pregnant Nigerian women with HbSS or HbAA. Results: Plasma volume was higher in non-pregnant HbSS than HbAA women, but had not risen by 16 weeks, unlike plasma volume in HbAA women. The concentration of plasma renin also rose significantly less by 16 weeks in HbSS; angiotensinogen and aldosterone concentrations increased. Conclusions: The lower plasma renin concentration at 16 weeks with HbSS could be either primary or secondary to vasoconstriction related to inadequate vasodilator activity. The contracted plasma volume might then stimulate aldosterone synthesis by non-angiotensin II dependent stimulation. Studies of vasodilators such as nitric oxide, vasodilator eicosanoids or the PlGF/VEGF/sFlT-1 axis in pregnant HbSS and HbAA women will test this hypothesis.