[Show abstract][Hide abstract] ABSTRACT: More than half of all cases of preeclampsia occur in healthy first-time pregnant women. Our aim was to develop a method to predict those at risk by combining clinical factors and measurements of biomarkers in women recruited to the Screening for Pregnancy Endpoints (SCOPE) study of low-risk nulliparous women. Forty-seven biomarkers identified on the basis of (1) association with preeclampsia, (2) a biological role in placentation, or (3) a role in cellular mechanisms involved in the pathogenesis of preeclampsia were measured in plasma sampled at 14 to 16 weeks' gestation from 5623 women. The cohort was randomly divided into training (n=3747) and validation (n=1876) cohorts. Preeclampsia developed in 278 (4.9%) women, of whom 28 (0.5%) developed early-onset preeclampsia. The final model for the prediction of preeclampsia included placental growth factor, mean arterial pressure, and body mass index at 14 to 16 weeks' gestation, the consumption of ≥3 pieces of fruit per day, and mean uterine artery resistance index. The area under the receiver operator curve (95% confidence interval) for this model in training and validation cohorts was 0.73 (0.70-0.77) and 0.68 (0.63-0.74), respectively. A predictive model of early-onset preeclampsia included angiogenin/placental growth factor as a ratio, mean arterial pressure, any pregnancy loss <10 weeks, and mean uterine artery resistance index (area under the receiver operator curve [95% confidence interval] in training and validation cohorts, 0.89 [0.78-1.0] and 0.78 [0.58-0.99], respectively). Neither model included pregnancy-associated plasma protein A, previously reported to predict preeclampsia in populations of mixed parity and risk. In nulliparous women, combining multiple biomarkers and clinical data provided modest prediction of preeclampsia.
[Show abstract][Hide abstract] ABSTRACT: An overrepresentation of adverse pregnancy outcomes has been observed in pregnancies associated with a male fetus. We investigated the association between fetal gender and candidate biomarkers for preeclampsia. Proteins were quantified in samples taken at 20 weeks from women recruited to the SCreening fOr Pregnancy Endpoints (SCOPE) study (preeclampsia n = 150; no preeclampsia n = 450). In contrast to placental growth factor, soluble endoglin, and insulin-like growth factor acid labile subunit, levels of metallopeptidase domain 12 (ADAM12) at 20 weeks were dependent on fetal gender in pregnancies complicated by preeclampsia, for male (n = 73) fetuses the multiples of the median (MoM; interquartile range [IQR] 1.1-1.5) was 1.3, whereas for female fetuses (n = 75) MoM was 1.1 (1.0-1.3); P < .01. Prediction of preeclampsia using ADAM12 levels was improved for pregnancies associated with a male fetus (area under receiver-operator curve [AUC] 0.73 [95% confidence interval [CI] 0.67-0.80]) than that of a female fetus (AUC 0.62 [0.55-0.70]); P = .03. The data presented here fit a contemporary hypothesis that there is a difference between the genders in response to an adverse maternal environment and suggest that an alteration in ADAM12 may reflect an altered placental response in pregnancies subsequently complicated by preeclampsia.
[Show abstract][Hide abstract] ABSTRACT: Pre-eclampsia (PE) is a serious complication of pregnancy with potentially life threatening consequences for both mother and baby. Presently there is no test with the required performance to predict which healthy first-time mothers will go on to develop PE. The high specificity, sensitivity and multiplexed nature of selected reaction monitoring (SRM) holds great potential as a tool for the verification and validation of putative candidate biomarkersfor disease states. Realisation of this potential involves establishing a high throughput, cost effective, reproducible sample preparation workflow. We have developed a semi-automated HPLC-based sample preparation workflow prior to a label-free SRM approach. This workflow has been applied to the search for novel predictive biomarkers for PE. To discover novel candidate biomarkers for PE, we used isobaric tagging to identify several potential biomarker proteins inplasma obtained at 15 weeks gestation from nulliparous women who later developed PE compared to pregnant women who remained healthy. Such a study generates a number of candidate biomarkers which require further testing in larger patient cohorts. As proof-of-principle, two of these proteins were taken forward for verification in a 100 women (58 PE, 42 controls) using label-free SRM. We obtained reproducible protein quantitation across the 100 samples and demonstrated significant changes in protein levels, even with as little as 20% change in protein concentration. The SRM data correlated with a commercial ELISA, suggesting that this is a robust workflow suitable for rapid, affordable, label-free verification of which candidate biomarkers should be taken forward for thorough investigation.A subset of pregnancy-specific glycoproteins (PSGs) had value as novel predictive markers for PE.
[Show abstract][Hide abstract] ABSTRACT: Preeclampsia, a hypertensive pregnancy complication, is largely unpredictable in healthy nulliparous pregnant women. Accurate preeclampsia prediction in this population would transform antenatal care. To identify novel protein markers relevant to the prediction of preeclampsia, a 3-step mass spectrometric work flow was applied. On selection of candidate biomarkers, mostly from an unbiased discovery experiment (19 women), targeted quantitation was used to verify and validate candidate biomarkers in 2 independent cohorts from the SCOPE (SCreening fOr Pregnancy Endpoints) study. Candidate proteins were measured in plasma specimens collected at 19 to 21 weeks' gestation from 100 women who later developed preeclampsia and 200 women without preeclampsia recruited from Australia and New Zealand. Protein levels (n=25), age, and blood pressure were then analyzed using logistic regression to identify multimarker models (maximum 6 markers) that met predefined criteria: sensitivity ≥50% at 20% positive predictive value. These 44 algorithms were then tested in an independent European cohort (n=300) yielding 8 validated models. These 8 models detected 50% to 56% of preeclampsia cases in the training and validation sets; the detection rate for preterm preeclampsia cases was 80%. Validated models combine insulin-like growth factor acid labile subunit and soluble endoglin, supplemented with maximally 4 markers of placental growth factor, serine peptidase inhibitor Kunitz type 1, melanoma cell adhesion molecule, selenoprotein P, and blood pressure. Predictive performances were maintained when exchanging mass spectrometry measurements with ELISA measurements for insulin-like growth factor acid labile subunit. In conclusion, we demonstrated that biomarker combinations centered on insulin-like growth factor acid labile subunit have the potential to predict preeclampsia in healthy nulliparous women.
[Show abstract][Hide abstract] ABSTRACT: Antepartum haemorrhage of unknown origin (APHUO) is associated with preterm birth and perinatal mortality.
To determine whether smoking beyond the first trimester of pregnancy was an independent risk factor for APHUO.
Rates of APHUO were compared between non-smokers and smokers, and non-smokers and ceased smokers. Participants were healthy nulliparous women recruited to the Screening for Pregnancy Endpoints (SCOPE) prospective cohort study in New Zealand, Australia, Ireland and United Kingdom. Logistic regression was used to compare adjusted odds ratio, 95% confidence intervals (OR, 95% CI) of APHUO between continued smokers and non-smokers, adjusting for possible confounders.
Of the 3513 participants, 77.9% (n = 2737) were non-smokers, 10.6% (n = 371) ceased in the first trimester and 11.5% (n = 405) continued smoking beyond the first trimester. APHUO rates were higher in smokers than nonsmokers (7.4%, n = 30 vs 4.5%, n = 122; P = 0.01), but there was no difference between ceased smokers and nonsmokers (4.3%, n = 16 vs 4.5%, n = 122; P = 0.90). Smoking was no longer significantly associated with APHUO after adjustment for confounders (adjusted OR = 1.28, 95% CI 0.76–2.14), but vaginal bleeding in early pregnancy (adjusted OR = 2.98, 95% CI 2.12–4.18) and overweight/obesity (adjusted OR = 1.43, 95% CI 1.02–1.99) were independent risk factors. First trimester folic acid use was associated with a reduced risk (adjusted OR = 0.44, 95% CI 0.25–0.77).
Smoking is not an independent risk factor for APHUO after adjustment for confounders, but other risk and protective factors have been identified.
Australian and New Zealand Journal of Obstetrics and Gynaecology 04/2012; 52(2):161-6. · 1.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Anaphylaxis can occur secondary to breastfeeding. The authors present a case of a 30-year-old woman who complained of chest tightness, shortness of breath and a rash on the third day postpartum. She was treated for anaphylaxis and her symptoms resolved. Because she had taken tramadol prior to this event, a drug reaction was initially suspected. However, she experienced further episodes related to breastfeeding, despite stopping tramadol. Effective control of her symptoms was achieved with regular antihistamines, enabling her to continue breastfeeding. Antihistamines were interrupted after 8 weeks at which point lactation (in hospital) was once again associated with anaphylaxis. The diagnosis of breastfeeding induced anaphylaxis was made. There are six previously reported cases of breastfeeding induced anaphylaxis. The authors describe the second case of breastfeeding anaphylaxis extending beyond the neonatal period, controlled with antihistamines.
[Show abstract][Hide abstract] ABSTRACT: There are significant variations in the legalisation, restrictions and legal abortion rates worldwide. This undoubtedly influences the provision and accessibility to abortion services. Although there have been changes to the laws in several countries over the last decade, this has not yet been translated into practice in the provision of safe abortion in these countries. In countries where abortions are permitted without restriction; the majority of abortions are carried out by trained practitioners in approved facilities. In contrast, in countries where restrictions are imposed, the majority of abortions performed are considered to be unsafe and therefore associated with significant morbidity and mortality. This article discusses the most recent data available regarding worldwide legal abortion rates, trends over the last ten years and issues related to specific regions which may influence the provision of safe abortion services in the future.
Best practice & research. Clinical obstetrics & gynaecology 05/2010; 24(4):457-66. · 1.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Characterizing the protein factors released from placentae during pathogenesis remains a key objective toward understanding preeclampsia and related pregnancy disorders. Gel-free proteomics technologies applied to placental explant-conditioned media offers the potential of identifying these factors. Relative quantification mass spectrometry using isobaric tagging for relative and absolute quantification (iTRAQ) labeling was employed to compare the ''secretome'' between healthy term placental tissue cultured under both normoxic and hypoxic oxygen tensions. Of the 499 proteins identified, 45 were differentially expressed (P < .01 level), including interleukin 8 (IL-8) which was significantly upregulated under hypoxia. Global protein level changes are suggestive of decreased extracellular matrix remodeling under the same conditions. A significant enrichment of soluble liberated placental factors is achieved using this model system. Identifying these changes resulting from hypoxic conditioning is hypothesis generating and may provide new mechanistic insights into preeclampsia.
[Show abstract][Hide abstract] ABSTRACT: Pregnant women with the vascular complication of preeclampsia show altered lipid metabolism characterized by elevated circulating triglycerides and nonesterified free fatty acids. We have compared the effect of maternal plasma from women with and without preeclampsia on cultured vascular endothelial cells and determined whether these plasma-induced changes were reproduced with free fatty acid solutions of palmitic, oleic and linoleic acid, representative of circulating levels reported in preeclampsia.
Lipid accumulation was quantified by oil-red O staining, apoptosis by terminal dUTP nick-end labelling (TUNEL) and the measurement of mitochondrial redox capacity, and membrane potential recorded using MTT reduction and JC-1 accumulation for human umbilical vein endothelial cells (HUVECs) exposed to plasma and free fatty acids.
Lipid droplet accumulation was significantly increased in cultured HUVECs conditioned with maternal plasma from pregnancies with preeclampsia compared with normal uncomplicated controls. This increase was replicated following exposure to free fatty acids at the combined concentrations defined in preeclampsia. Plasma from these women also caused a significant decrease in mitochondrial dehydrogenase activity, a marked reduction in mitochondrial membrane potential and an increase in apoptosis compared with normal pregnancy. Again these effects were reproduced using free fatty acids in combination at the levels previously associated with preeclampsia.
These findings support the concept of a circulating pathogenic factor for preeclampsia and highlight the possibility that this factor is not a single compound but perhaps the combined elevation of the free fatty acids palmitic, oleic and linoleic acid in the maternal circulation.
Journal of Hypertension 07/2009; 27(6):1293-302. · 4.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Uterine atony is the most common cause of primary post partum haemorrhage. We report a case where this was complicated by two rare conditions, platelet storage pool disease and placenta diffusa. Platelet storage pool disease is a platelet aggregation disorder associated with mild to moderate bleeding diathesis. There are limited cases reported in pregnancy. Placenta diffusa is a rare anomaly where all or part of the fetal membranes remain covered by chorionic villi, and is associated with post partum haemorrhage.
A 37-year-old woman was referred to the obstetric haematology clinic for prenatal counselling with a history of three severe post partum haemorrhages, two of which were complicated by placental retention. Platelet aggregation studies confirmed a diagnosis of platelet storage pool disease. She was counselled regarding her risk of a recurrent haemorrhage and a planned delivery was discussed. She subsequently presented at 15 weeks' gestation. Following an uneventful pregnancy, she was covered with prophylactic desmopressin and tranexamic acid before a planned induction of labour. She had a normal delivery but placenta was retained. In theatre, an uncomplicated manual removal was followed by massive haemorrhage secondary to uterine atony. Aggressive medical management and B lynch sutures at laparotomy failed to contract the uterus. Hysterectomy was therefore performed. Placental histology later showed evidence of partial placenta diffusa.
Post partum haemorrhage continues to be a leading cause of maternal morbidity and mortality. In this patient, despite identification and attempts at correction of an identified clotting disorder, major obstetric haemorrhage was not avoided. An additional rare placental abnormality was later found. This case highlights the need for medical staff to be aware and alert to unusual risk factors. However, these factors may be unavoidable and early surgical intervention as per local protocol is recommended to minimise maternal morbidity.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to enrich vasoactive factors that are present in the plasma of women with preeclampsia by the application of sequential fractionation and determination of the activity of each fraction in a bioassay.
Pooled plasma from women with preeclampsia (n = 23) and matched control subjects (n = 23) was subjected to fractionation with ultrafiltration, targeted immunodepletion, or size exclusion chromatography. Myometrial arteries that were isolated from healthy cesarean section biopsy specimens (n = 28) were incubated with plasma fractions (2%, volume/volume), and their endothelial function was assessed by wire myography.
Incubation of arteries with preeclampsia plasma or immunodepleted preeclampsia plasma had a deleterious effect on endothelial-dependent relaxation. Bioactivity of the plasma factors was absent in all fractions after either plasma ultrafiltration or separation with the use of size exclusion chromatography; however, activity was restored after recombination of these fractions.
This study provides the first conclusive evidence that multiple synergistic factors, with a combined vasoactive effect, are present in the plasma of women with preeclampsia.
American journal of obstetrics and gynecology 04/2007; 196(3):266.e1-6. · 3.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In pre-eclampsia (PE), endothelium-dependent function of myometrial small arteries is markedly attenuated. The residual PE response is wholly NO mediated. We have previously demonstrated that PDE5 inhibition can improve endothelial function in myometrial small arteries from women with PE. We aimed to assess whether the effect of PDE5 inhibition in PE was myometrial artery specific.
Small arteries were dissected from omental biopsies obtained at Caesarean section from normal pregnant women (NP, N = 20) and women with PE (N = 11). Chorionic plate small arteries were dissected from NP (N = 13) and PE (N = 11) placentae. Vasoconstriction (arginine vasopressin or thromboxane-mimetic U46619) and endothelial-dependent relaxation were assessed by wire and pressure myography. Constriction/relaxation curves were repeated post 1h incubation with PDE5 inhibitors UK-343664 or sildenafil citrate (0, 10 or 100 nM).
Omental artery constriction was increased in PE. Omental vessel constriction was unaffected by PDE5 inhibition. Sildenafil citrate improved bradykinin-induced but not acetylcholine-induced relaxation of omental small arteries from NP women. PDE5 inhibition did not alter relaxation of omental arteries from women with PE. Placental small arteries were unaffected by PDE5 inhibition.
Use of PDE5 inhibitors does not significantly alter endothelial-dependent relaxation in omental or placental small arteries from PE women.
European Journal of Obstetrics & Gynecology and Reproductive Biology 08/2006; 127(1):41-9. · 1.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fetal growth restriction (FGR) affects up to 8% of all pregnancies and has massive short-term (increased fetal morbidity and mortality) and long-term (increased incidence of cardiovascular disease in adulthood) health implications. Doppler waveform analysis of pregnancies complicated by FGR suggests compromised uteroplacental circulation and placental hypoperfusion. Our aim was to determine whether myometrial small artery function was aberrant in FGR and to assess whether sildenafil citrate could improve vasodilatation in FGR pregnancies.
Small arteries dissected from myometrial biopsies obtained at cesarean section from normal pregnant women (n = 27) or women whose pregnancies were complicated by FGR (n = 12) were mounted on wire myographs. Vessels were constricted (with arginine vasopressin or U46619) and relaxed (with bradykinin) before and after incubation with a phosphodiesterase-5 inhibitor, sildenafil citrate.
We demonstrated increased myometrial small artery vasoconstriction and decreased endothelium-dependent vasodilatation in vessels from women whose pregnancies were complicated by FGR. Sildenafil citrate significantly reduced vasoconstriction and significantly improved relaxation of FGR small arteries.
We conclude that sildenafil citrate improves endothelial function of myometrial vessels from women whose pregnancies are complicated by intrauterine growth restriction. Sildenafil citrate may offer a potential therapeutic strategy to improve uteroplacental blood flow in FGR pregnancies.
[Show abstract][Hide abstract] ABSTRACT: To determine levels of matrix metalloproteinase (MMP)-2 and MMP-9, and the tissue inhibitors of metalloproteinases (TIMP)-1 and TIMP-2 in the plasma of women destined to develop preeclampsia prior to the onset of clinical disease.
Plasma samples were taken from women whose pregnancies were subsequently complicated by preeclampsia and from normal pregnant women at 22 and 26 weeks and at delivery or diagnosis. Following equal protein loading, MMP-2 and 9 and TIMP-1 and 2 were quantified using zymography and Western blot analysis, respectively.
Plasma MMP-2 levels were significantly elevated at 22 weeks (p = 0.02) and at diagnosis (p = 0.003) in the preeclampsia group, but there was no difference at 26 weeks. TIMP-1 levels were significantly reduced in the preeclampsia group at 26 weeks (p = 0.0002), but TIMP-2 levels were not quantifiable.
At all three gestational time points an imbalance in the MMP-2:TIMP-1 ratio was found in patients who subsequently developed preeclampsia. We speculate that increased net MMP-2 activity may contribute to the endothelial dysfunction that is central to the pathophysiology of preeclampsia.
Hypertension in Pregnancy 02/2005; 24(2):103-15. · 0.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In preeclampsia, endothelium-dependent function is markedly aberrant. Myometrial resistance arteries from women with preeclampsia show a minimal, wholly nitric oxide-mediated, bradykinin-induced relaxation. Our aim was to test that phosphodiesterase 5 (PDE5) inhibition could improve endothelium-dependent function in preeclampsia. Study design Small arteries dissected from myometrial biopsies obtained at cesarean section from normal pregnant women (N=22) or women with preeclampsia (N=24) were mounted on wire or pressure myographs. Vessels were constricted (arginine vasopressin or U46619) and relaxed (bradykinin) before and after incubation with a PDE5 inhibitor, UK-343664.
Endothelium-dependent vasodilatation was decreased in vessels from women with preeclampsia. 100 nmol/L UK-343664 did not affect normal pregnant but significantly improved relaxation of the vessels from women with preeclampsia.
A PDE5 inhibitor enhances endothelial function of myometrial vessels from women with preeclampsia, such that the behavior of these arteries approximates to those from normal women. These agents offer a potential therapeutic strategy for the management of preeclampsia.
American Journal of Obstetrics and Gynecology 06/2004; 190(5):1283-90. · 3.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Worldwide, pre-eclampsia and eclampsia contribute to the death of a pregnant woman every 3 min. In the UK in recent decades, hypertensive disorders of pregnancy have remained one of the leading causes of both maternal and perinatal morbidity and mortality. The management of pregnancies complicated by hypertension has not significantly altered for many years, possibly as a result of little progress being made in our understanding of the condition. New insights, however, have recently been gained into the pathophysiology of pre-eclampsia. These have yet to be translated into new interventions or to make any impact on clinical management of these pregnancies. This review will therefore focus on recent advances relating to research into the aetiology and pathogenesis of pre-eclampsia, but will conclude with a brief update on current therapeutic strategies.
Current Opinion in Obstetrics and Gynecology 05/2002; 14(2):119-25. · 2.64 Impact Factor