Nigel Simpson

Diagnostic Accuracy of Placental Growth Factor in Women With Suspected Preeclampsia A Prospective Multicenter Study

Background— Hypertensive disorders of pregnancy are a major contributor to death and disability for pregnant women and their infants. The diagnosis of preeclampsia by using blood pressure and proteinuria is of limited use because they are tertiary, downstream features of the disease. Placental growth factor (PlGF) is an angiogenic factor, a secondary marker of associated placental dysfunction in preeclampsia, with known low plasma concentrations in the disease. Methods and Results— In a prospective multicenter study, we studied the diagnostic accuracy of low plasma PlGF concentration (<5th centile for gestation, Alere Triage assay) in women presenting with suspected preeclampsia between 20 and 35 weeks’ gestation (and up to 41 weeks’ gestation as a secondary analysis). The outcome was delivery for confirmed preeclampsia within 14 days. Of 625 women, 346 (55%) developed confirmed preeclampsia. In 287 women enrolled before 35 weeks’ gestation, PlGF <5th centile had high sensitivity (0.96; 95% confidence interval, 0.89–0.99) and negative predictive value (0.98; 0.93–0.995) for preeclampsia within 14 days; specificity was lower (0.55; 0.48–0.61). Area under the receiver operating characteristic curve for low PlGF (0.87, standard error 0.03) for predicting preeclampsia within 14 days was greater than all other commonly used tests, singly or in combination (range, 0.58–0.76), in women presenting with suspected preeclampsia (P<0.001 for all comparisons). Conclusions— In women presenting before 35 weeks’ gestation with suspected preeclampsia, low PlGF has high sensitivity and negative predictive value for preeclampsia within 14 days, is better than other currently used tests, and presents an innovative adjunct to management of such women.

Maternal caffeine intake during pregnancy and risk of fetal growth restriction: a large prospective observational study

Correction to Maternal caffeine intake during pregnancy and risk of fetal growth restriction: a large prospective observational study, dx.doi.org/10.1136/bmj.a2332 available on the LRA at http://hdl.handle.net/2381/16058

An investigation into the association among preterm birth, cytokine gene polymorphisms and periodontal disease

Objective  To investigate a putative relationship between preterm delivery and the carriage of polymorphic genes that code for the cytokines interleukin‐1β (IL‐1β) at codon +3953 and tumour necrosis factor‐α (TNF‐α) at codon −308 in a group of postpartum women and to elucidate if the concurrent presence of periodontal disease increased the risk of preterm delivery in this group.

Early pregnancy prediction of preeclampsia in nulliparous women, combining clinical risk and biomarkers: the Screening for Pregnancy Endpoints (SCOPE) international cohort study

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. # Novelty and Significance {#article-title-41}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.

The management of pregnancy in paroxysmal nocturnal haemoglobinuria on long term eculizumab

In Paroxysmal nocturnal haemoglobinuria (PNH), pregnancy is associated with increased maternal and foetal complications to such an extent that the condition has been considered relatively contra‐indicated in PNH. Eculizumab has revolutionized the treatment of PNH. We evaluate its use in pregnancy to date. We report on seven patients exposed to eculizumab at different stages of pregnancy including the first two patients to receive the drug from conception to delivery. There was no evidence of complement blockade from cord blood samples taken at delivery. Eculizumab appears safe to use in this setting and is likely to prevent many of the complications usually observed.

Maternal alcohol intake prior to and during pregnancy and risk of adverse birth outcomes: evidence from a British cohort

Background Evidence is conflicting regarding the relationship between low maternal alcohol consumption and birth outcomes. This paper aimed to investigate the association between alcohol intake before and during pregnancy with birth weight and gestational age and to examine the effect of timing of exposure. Methods A prospective cohort in Leeds, UK, of 1303 pregnant women aged 18–45 years. Questionnaires assessed alcohol consumption before pregnancy and for the three trimesters separately. Categories of alcohol consumption were divided into ≤2 units/week and >2 units/week with a non-drinking category as referent. This was related to size at birth and preterm delivery, adjusting for confounders including salivary cotinine as a biomarker of smoking status. Results Nearly two-thirds of women before pregnancy and over half in the first trimester reported alcohol intakes above the Department of Health (UK) guidelines of ≤2 units/week. Associations with birth outcomes were strongest for intakes >2 units/week before pregnancy and in trimesters 1 and 2 compared to non-drinkers. Even women adhering to the guidelines in the first trimester were at significantly higher risk of having babies with lower birth weight, lower birth centile and preterm birth compared to non-drinkers, after adjusting for confounders (p<0.05). Conclusions We found the first trimester to be the period most sensitive to the effect of alcohol on the developing fetus. Women adhering to guidelines in this period were still at increased risk of adverse birth outcomes. Our findings suggest that women should be advised to abstain from alcohol when planning to conceive and throughout pregnancy.

Thromboelastography Identifies Sex-Related Differences in Coagulation

Thromboelastography is an in vitro, point-of-care monitor of whole blood coagulation. Thromboelastography studies have demonstrated a hypercoagulable state during pregnancy. Perhaps the hypercoagulability is attributable to female sex hormones. The aim of the study was to determine if sex, in addition to pregnancy, affected thromboelastography variables by studying male and female (pregnant and nonpregnant) volunteers. Thromboelastography showed significant (P <0.01) differences in sex, with a significant (P < 0.0001) trend of increasing whole blood coagulability from men through nonpregnant to pregnant women. The thromboelastograph, used as a diagnostic tool, shows that women have more whole blood coagulability than men. Implications The thromboelastograph, used as a diagnostic tool, shows that women have more whole blood coagulability than men.

The Carriage of Pro‐Inflammatory Cytokine Gene Polymorphisms in Recurrent Pregnancy Loss

PROBLEM: Recurrent pregnancy loss (RPL) affects 2–4% of couples, and remains largely unexplained. Recent studies have examined the role of cytokines in the maintenance of normal pregnancy, which is linked with an increased expression of Th2 cytokines. Overexpression of Th1 cytokines is associated with RPL. Knowing that functional polymorphisms exist for certain cytokines, it has therefore been suggested that women with RPL may have a genetic predisposition to overexpress Th1 cytokines.
 METHOD OF STUDY: The genes for interleukin‐1 beta (IL‐1β) and tumor necrosis factor alpha (TNF‐α) carry functional gene polymorphisms. In both cases these are biallelic polymorphisms that can be detected by polymerase chain reaction followed by restriction fragment length polymorphism. The aim of this pilot study was to assess whether carriage of the rarer alleles (TNF*2 and IL‐1B*2) could act as independent risk factors in recurrent miscarriage.
 RESULTS: We found an increased incidence in the carriage of TNF*2, more pronounced in those women with two or more miscarriages. Carriage of the IL‐1B*2 either alone or in association with TNF*2 was not associated with recurrent miscarriage.
 CONCLUSION: There may be a role for these cytokine gene polymorphisms in RPL.

Dietary iron intake during early pregnancy and birth outcomes in a cohort of British women

BACKGROUND Iron deficiency during pregnancy is associated with adverse birth outcomes, particularly, if present during early gestation. Iron supplements are widely recommended during pregnancy, but evidence of their benefit in relation to infant outcomes is not established. This study was performed in the UK, where iron supplements are not routinely recommended during pregnancy, to investigate the association between iron intake in pregnancy and size at birth. METHODS From a prospective cohort of 1274 pregnant women aged 18–45 years, dietary intake was reported in a 24-h recall administered by a research midwife at 12-week gestation. Dietary supplement intake was ascertained using dietary recall and three questionnaires in the first, second and third trimesters. RESULTS Of the cohort of pregnant women, 80% reported dietary iron intake below the UK Reference Nutrient Intake of 14.8 mg/day. Those reported taking iron-containing supplements in the first, second and third trimesters were 24, 15 and 8%, respectively. Women with dietary iron intake >14.8 mg/day were more likely to be older, have a higher socioeconomic profile and take supplements during the first trimester. Vegetarians were less likely to have low dietary iron intake [odds ratio = 0.5, 95% confidence interval (CI): 0.4, 0.8] and more likely to take supplements during the first and second trimesters. Total iron intake, but not iron intake from food only, was associated with birthweight centile (adjusted change = 2.5 centiles/10 mg increase in iron, 95% CI: 0.4, 4.6). This association was stronger in the high vitamin C intake group, but effect modification was not significant. CONCLUSION There was a positive relationship between total iron intake, from food and supplements, in early pregnancy and birthweight. Iron intake, both from diet and supplements, during the first trimester of pregnancy was higher in vegetarians and women with a better socioeconomic profile.

Risk Factors for Preterm Birth in an International Prospective Cohort of Nulliparous Women

Objectives To identify risk factors for spontaneous preterm birth (birth <37 weeks gestation) with intact membranes (SPTB-IM) and SPTB after prelabour rupture of the membranes (SPTB-PPROM) for nulliparous pregnant women. Design Prospective international multicentre cohort. Participants 3234 healthy nulliparous women with a singleton pregnancy, follow up was complete in 3184 of participants (98.5%). Results Of the 3184 women, 156 (4.9%) had their pregnancy complicated by SPTB; 96 (3.0%) and 60 (1.9%) in the SPTB-IM and SPTB-PPROM categories, respectively. Independent risk factors for SPTB-IM were shorter cervical length, abnormal uterine Doppler flow, use of marijuana pre-pregnancy, lack of overall feeling of well being, being of Caucasian ethnicity, having a mother with diabetes and/or a history of preeclampsia, and a family history of low birth weight babies. Independent risk factors for SPTB-PPROM were shorter cervical length, short stature, participant’s not being the first born in the family, longer time to conceive, not waking up at night, hormonal fertility treatment (excluding clomiphene), mild hypertension, family history of recurrent gestational diabetes, and maternal family history of any miscarriage (risk reduction). Low BMI (<20) nearly doubled the risk for SPTB-PPROM (odds ratio 2.64; 95% CI 1.07–6.51). The area under the receiver operating characteristics curve (AUC), after internal validation, was 0.69 for SPTB-IM and 0.79 for SPTB-PPROM. Conclusion The ability to predict PTB in healthy nulliparous women using clinical characteristics is modest. The dissimilarity of risk factors for SPTB-IM compared with SPTB-PPROM indicates different pathophysiological pathways underlie these distinct phenotypes. Trial Registration ACTR.org.au ACTRN12607000551493