Metabolic syndrome and time to pregnancy: a retrospective study of nulliparous women.

OBJECTIVE: To determine: (1) the association between metabolic syndrome (MetS), time to pregnancy (TTP), and infertility; (2) associations between individual and an increasing number of MetS components, TTP, and infertility; and (3) whether these relationships differ by body mass index (BMI < 30 kg/m2 versus BMI ≥ 30 kg/m2 ). DESIGN: Retrospective cohort study. SETTING: Multiple centres (in Australia, Ireland, New Zealand, and the UK). POPULATION: Five thousand five hundred and nineteen low-risk nulliparous pregnant women. METHODS: Data on retrospectively reported TTP (number of months to conceive) and a blood sample to assess metabolic health were collected between 14 and 16 weeks of gestation. MetS was defined according to the International Diabetes Federation criteria. Accelerated failure time models with log-normal distribution were conducted to estimate time ratios (TRs) and 95% CIs. Differences in MetS on infertility (TTP > 12 months) were compared using a generalised linear model (Poisson distribution) with robust variance estimates (relative risks, RRs; 95% CIs). All analyses (entire cohort and split by BMI) were controlled for a range of maternal and paternal confounding factors. MAIN OUTCOME MEASURES: Time to pregnancy and infertility. RESULTS: Of the 5519 women included, 12.4% (n = 684) had MetS. Compared with women without MetS, women with MetS had a longer TTP (adjusted TR 1.30; 95% CI 1.15-1.46), which was similar in women who were obese and in women who were not obese. Marginal estimates for median TTP in women with MetS versus without MetS was 3.1 months (3.0-3.3 months) versus 4.1 months (3.6-4.5 months), respectively. Women with MetS were at a 62% greater risk for infertility and were at a greater risk for infertility whether they were obese (adjusted RR 1.62; 95% CI 1.15-2.29) or not (adjusted RR 1.73; 95% CI 1.33-2.23). Reduced high-density lipoprotein cholesterol (HDL-C) and raised triglycerides (TGs) were the main individual components associated with risk for infertility. CONCLUSION: Metabolic syndrome is associated with longer TTP and infertility, independent of obesity. Additional studies, before pregnancy, are required to support our findings and to determine the applicability of which combinations of metabolic abnormalities pose the greatest risk to delayed fertility, or whether individual components are amenable to modification. TWEETABLE ABSTRACT: Metabolic syndrome is associated with longer time to pregnancy and infertility, independent of obesity.

STRIDER NZAus: a multicentre randomised controlled trial of sildenafil therapy in early-onset fetal growth restriction.

OBJECTIVE: To assess the effect of maternal sildenafil therapy on fetal growth in pregnancies with early-onset fetal growth restriction. DESIGN: A randomised placebo-controlled trial. SETTING: Thirteen maternal-fetal medicine units across New Zealand and Australia. POPULATION: Women with singleton pregnancies affected by fetal growth restriction at 22+0 to 29+6 weeks. METHODS: Women were randomised to oral administration of 25 mg sildenafil citrate or visually matching placebo three times daily until 32+0 weeks, birth or fetal death (whichever occurred first). MAIN OUTCOME MEASURES: The primary outcome was the proportion of pregnancies with an increase in fetal growth velocity. Secondary outcomes included live birth, survival to hospital discharge free of major neonatal morbidity and pre-eclampsia. RESULTS: Sildenafil did not affect the proportion of pregnancies with an increase in fetal growth velocity; 32/61 (52.5%) sildenafil-treated, 39/57 (68.4%) placebo-treated [adjusted odds ratio (OR) 0.49, 95% CI 0.23-1.05] and had no effect on abdominal circumference Z-scores (P = 0.61). Sildenafil use was associated with a lower mean uterine artery pulsatility index after 48 hours of treatment (1.56 versus 1.81; P = 0.02). The live birth rate was 56/63 (88.9%) for sildenafil-treated and 47/59 (79.7%) for placebo-treated (adjusted OR 2.50, 95% CI 0.80-7.79); survival to hospital discharge free of major neonatal morbidity was 42/63 (66.7%) for sildenafil-treated and 33/59 (55.9%) for placebo-treated (adjusted OR 1.93, 95% CI 0.84-4.45); and new-onset pre-eclampsia was 9/51 (17.7%) for sildenafil-treated and 14/55 (25.5%) for placebo-treated (OR 0.67, 95% CI 0.26-1.75). CONCLUSIONS: Maternal sildenafil use had no effect on fetal growth velocity. Prospectively planned meta-analyses will determine whether sildenafil exerts other effects on maternal and fetal/neonatal wellbeing. TWEETABLE ABSTRACT: Maternal sildenafil use has no beneficial effect on growth in early-onset FGR, but also no evidence of harm.

The relationship between maternal 25-hydroxyvitamin D status in pregnancy and childhood adiposity and allergy: an observational study.

BACKGROUND: Vitamin D insufficiency (defined as <75 nmol l-1) is widespread among pregnant women around the world and has been proposed to influence offspring outcomes in childhood and into adult life, including adiposity and allergy. Disorders, including asthma and eczema, are on the rise among children. Our aim was to investigate the relationship between maternal 25-hydroxyvitamin D status in pregnancy and offspring adiposity, asthma and eczema in childhood. SUBJECTS AND METHODS: Maternal 25-hydroxyvitamin D concentrations were analysed in serum samples collected at 15 weeks' gestation from 1710 participants of the prospective Screening for Pregnancy Endpoints cohort study. The offspring of 1208 mothers were followed up at age 5-6 years. Data collected included height, weight, percentage body fat (PBF, measured by bioimpedance) and history of asthma and eczema. Multivariable analysis controlled for maternal body mass index (BMI), age and sex of the child and season of serum sampling. RESULTS: Complete data were available for 922 mother-child pairs. Each 10 nmol l-1 increase in maternal 25-hydroxyvitamin D concentration at 15 weeks' gestation was associated with a decrease in offspring PBF of 0.2% (95% confidence interval 0.04-0.36%, P=0.01) after adjustment for confounders but was not related to child BMI z-score. Maternal mean (±s.d.) 25-hydroxyvitamin D concentration was similar in children who did and did not have asthma (71.7±26.1 vs 73.3±27.1 nmol l-1, P=0.5), severe asthma (68.6±28.6 vs 73.3±26.8 nmol l-1, P=0.2) and eczema (71.9±27.0 vs 73.2±27.0 nmol l-1, P=0.5). CONCLUSIONS: The finding of a relationship between maternal vitamin D status and adiposity in childhood is important, particularly because vitamin D insufficiency in pregnancy is highly prevalent. The association between maternal vitamin D supplementation in pregnancy and adiposity in the offspring merits examination in randomised controlled trials.

Enoxaparin for the prevention of preeclampsia and intrauterine growth restriction in women with a prior history - an open-label randomised trial (the EPPI trial): study protocol.

BACKGROUND: Preeclampsia and intrauterine fetal growth restriction (IUGR) are two of the most common causes of maternal and perinatal morbidity and mortality. Current methods of predicting those at most risk of these conditions remain relatively poor, and in clinical practice past obstetric history remains the most commonly used tool. Aspirin and, in women at risk of preeclampsia only, calcium have been demonstrated to have a modest effect on risk reduction. Several observational studies and randomised trials suggest that low molecular weight heparin (LMWH) therapy may confer some benefit. METHODS/DESIGN: This is a multicentre open label randomised controlled trial to determine the effect of the LMWH, enoxaparin, on the prevention of recurrence of preeclampsia and/or IUGR in women at high risk due to their past obstetric history in addition to standard high risk care for all participants. INCLUSION CRITERIA: A singleton pregnancy >6+0 and <16+0 weeks gestation with most recent prior pregnancy with duration >12 weeks having; (1) preeclampsia delivered <36+0 weeks, (2) Small for gestational age (SGA) infant <10th customised birthweight centile delivered <36+0 weeks or, (3) SGA infant ≤3rd customised birthweight centile delivered at any gestation. Randomisation is stratified for maternal thrombophilia status and women are randomly assigned to 'standard high risk care' or 'standard high risk care' plus enoxaparin 40 mg from recruitment until 36+0 weeks or delivery, whichever occurs sooner. Standard high risk care includes the use of aspirin 100 mg daily and calcium 1000-1500 mg daily (unless only had previous SGA with no preeclampsia). The primary outcome is preeclampsia and/or SGA <5th customised birthweight centile. Analysis will be by intention to treat. DISCUSSION: The EPPI trial has more focussed and clinically relevant inclusion criteria than other randomised trials with a more restricted composite primary outcome. The inclusion of standard use of aspirin (and calcium) for all participants will help to ensure that any differences observed in outcome are likely to be related to enoxaparin use. These data will make a significant contribution to future meta-analyses and systematic reviews on the use of LMWH for the prevention of placental mediated conditions. TRIAL REGISTRATION: ACTRN12609000699268 Australian New Zealand Clinical Trials Registry. Date registered 13/Aug/2009 (prospective registration).

Effects of pre-eclampsia and fetal growth restriction on C-type natriuretic peptide.

OBJECTIVE: To determine changes in plasma C-type natriuretic peptide (CNP), a paracrine product of the vascular endothelium, in pregnancies with vascular disorders, and relate these to time of presentation and severity. DESIGN: Retrospective nested cases and controls. SETTING: Community study, Auckland New Zealand. POPULATION: Screening for Pregnancy Endpoints (SCOPE) data and bio-bank of maternal plasma. METHODS: Maternal plasma amino terminal proCNP (NTproCNP) was measured by radioimmunoassay in early (14-16 weeks of gestation, and again at 19-21 weeks of gestation) and late (34-36 weeks of gestation) pregnancy in three groups of women (20 per group): pre-eclampsia (pre-eclampsia); gestational hypertension (GHT) with small for gestational age (SGA); and uncomplicated pregnancy. MAIN OUTCOME MEASURES: Change in NTproCNP and associations with concurrent blood pressure, time of case presentation, severity, and infant birthweight. RESULTS: Plasma NTproCNP in early pregnancy in women with vascular disorders did not differ from those found in controls. In late pregnancy, levels in pre-eclampsia (28.8 ± 2.3 pM) and in GHT with SGA (28.6 ± 4.8 pM) were significantly increased (P = 0.01 and 0.027, respectively) compared with controls (21.3 ± 1 pM). In pre-eclampsia, levels were significantly higher (P < 0.03) at 14-16 weeks of gestation in women diagnosed prior to 34 weeks of gestation. Combining all three groups, associations of NTproCNP with concurrent diastolic and mean arterial pressure were found at 34-36 weeks of gestation (r = 0.46). No significant associations were identified with birthweight. CONCLUSIONS: CNP secretion during gestation is responsive to vascular stress. Plasma NTproCNP measurements may have clinical application in late pregnancy in defining the different phenotypes associated with pre-eclampsia.

Second-trimester maternal distress increases the risk of small for gestational age.

BACKGROUND: The effect of prenatal distress on the risk of a small for gestational age (SGA) infant is uncertain. We have addressed the influences of prenatal stress, anxiety and depression on the risk of SGA. We also examined the effects of infant sex and timing of distress during pregnancy on any observed associations. METHOD: The study population comprised 5606 healthy nulliparous pregnant women who participated in the international prospective Screening for Obstetric and Pregnancy Endpoints (SCOPE) study. Women completed the Perceived Stress Scale (PSS), the short form of the Spielberger State-Trait Anxiety Inventory (STAI) and the Edinburgh Postnatal Depression Scale (EPDS) at 15 ± 1 and 20 ± 1 weeks' gestation. SGA was defined as birthweight below the 10th customized percentile. Logistic regression was used for data analysis, adjusting for several potential confounders such as maternal age, body mass index (BMI), smoking, socio-economic status and physical exercise. RESULTS: The risk of SGA was increased in relation to mild [adjusted odds ratio (aOR) 1.35, 95% confidence interval (CI) 1.07-1.71], moderate (aOR 1.26, 95% CI 1.06-1.49), high (aOR 1.45, 95% CI 1.08-1.95) and very high stress scores (aOR 1.56, 95% CI 1.03-2.37); very high anxiety score (aOR 1.45, 95% CI 1.13-1.86); and very high depression score (aOR 1.14, 95% CI 1.05-1.24) at 20 ± 1 weeks' gestation. Sensitivity analyses showed that very high anxiety and very high depression increases the risk of SGA in males but not in females whereas stress increases the risk of SGA in both males and females. CONCLUSIONS: These findings suggest that prenatal stress, anxiety and depression measured at 20 weeks' gestation increase the risk of SGA. The effects of maternal anxiety and depression on SGA were strongest in male infants.

Angiogenic factors combined with clinical risk factors to predict preterm pre-eclampsia in nulliparous women: a predictive test accuracy study.

OBJECTIVES: To assess the performance of clinical risk factors, uterine artery Doppler and angiogenic markers to predict preterm pre-eclampsia in nulliparous women. DESIGN: Predictive test accuracy study. SETTING: Prospective multicentre cohort study Screening for Pregnancy Endpoints (SCOPE). METHODS: Low-risk nulliparous women with a singleton pregnancy were recruited. Clinical risk factor data were obtained and plasma placental growth factor (PlGF), soluble endoglin and soluble fms-like tyrosine kinase-1 (sFlt-1) were measured at 14-16 weeks of gestation. Prediction models were developed using multivariable stepwise logistic regression. MAIN OUTCOME MEASURE: Preterm pre-eclampsia (delivered before 37(+0)  weeks of gestation). RESULTS: Of the 3529 women recruited, 187 (5.3%) developed pre-eclampsia of whom 47 (1.3%) delivered preterm. Controls (n = 188) were randomly selected from women without preterm pre-eclampsia and included women who developed other pregnancy complications. An area under a receiver operating characteristic curve (AUC) of 0.76 (95% CI 0.67-0.84) was observed using previously reported clinical risk variables. The AUC improved following the addition of PlGF measured at 14-16 weeks (0.84; 95% CI 0.77-0.91), but no further improvement was observed with the addition of uterine artery Doppler or the other angiogenic markers. A sensitivity of 45% (95% CI 0.31-0.59) (5% false-positive rate) and post-test probability of 11% (95% CI 9-13) were observed using clinical risk variables and PlGF measurement. CONCLUSIONS: Addition of plasma PlGF at 14-16 weeks of gestation to clinical risk assessment improved the identification of nulliparous women at increased risk of developing preterm pre-eclampsia, but the performance is not sufficient to warrant introduction as a clinical screening test. These findings are marker dependent, not assay dependent; additional markers are needed to achieve clinical utility.

Childhood cognitive development after fetal growth restriction.

OBJECTIVE: To examine the relationship between prenatal umbilical artery (UA) and internal carotid artery (ICA) Doppler findings and cognitive development at 3 and 6 years in low-birth-weight children. METHODS: This was a study of 209 low-birth-weight (< 10(th) centile) children born after 28 gestational weeks with UA resistance index (RI) measured within 2 weeks before delivery. Children with normal UA- and ICA-RI were defined as small-for-gestational age (SGA) and those with abnormal UA or ICA Doppler findings as having fetal growth restriction (FGR). Cognitive ability at 3 and 6 years' corrected age was assessed using the fourth edition of the Stanford-Binet Intelligence Scale (SBIS) and compared between SGA and FGR groups. An SBIS score < 85 was considered to indicate delayed development. RESULTS: The median gestational age at diagnosis of abnormal fetal growth was 36.6 (range, 28-41) weeks. There were 87 (41.6%) children classified as having FGR and 122 (58.4%) as SGA. The mean global SBIS score at 3 years was 109.4 (SD, 22.8) and at 6 years it was 110.5 (SD, 13.9). Overall, 22 (10.5%) children had delayed development at 3 years. Total SBIS scores and individual domain scores did not differ between FGR and SGA groups at 3 or 6 years and similar proportions in each group had delayed development. CONCLUSION: Abnormal prenatal UA and ICA Doppler findings are not associated with lower developmental scores in low-birth-weight children delivered in the third trimester of pregnancy.

Maternal and pathological pregnancy characteristics in customised birthweight centiles and identification of at-risk small-for-gestational-age infants: a retrospective cohort study.

OBJECTIVE: To regenerate coefficients for the New Zealand customised birthweight centile calculator using an updated birth cohort, and compare the identification of at-risk small-for-gestational-age (SGA) infants between full customisation (including maternal characteristics) and an ultrasound-based fetal weight and infant gender partial customisation. DESIGN: Retrospective cohort study of prospectively collected maternity data. SETTING: National Women's Health Auckland, New Zealand. POPULATION: Singleton pregnancies in the period 2006-2009; n = 24,176. METHODS: Multiple linear regression analysis was performed for full customisation (adjusted for gestation, infant gender, maternal characteristics and pathological variables) and ultrasound-and-gender customisation (adjusted for gestation and infant gender). MAIN OUTCOME MEASURES: Risks of SGA-related perinatal death were compared between models. RESULTS: Changes occurred in some ethnicity coefficients, including Chinese (-135 g), Tongan (-101 g) and Samoan (-89 g), and ten ethnicities were added. Overall, full customisation identified SGA infants with higher odds of perinatal death (OR 5.6, 95% CI 3.6-8.7) than infants classed as SGA by ultrasound-and-gender customisation (OR 2.1, 95% CI 1.4-3.3) (P = 0.02). In subgroup analyses, infants classed as SGA by full but not ultrasound-and-gender customisation (n = 888, 3.4%) had an increased risk of perinatal death (RR 4.7, 95% CI 2.7-7.9); however, those identified as SGA by ultrasound-and-gender customisation alone were not at an increased risk (n = 676, 2.6%, RR 1.1, 95% CI 0.4-3.6). The population attributable risk (PAR) of SGA-related perinatal death was higher for full (49.8%) than for ultrasound-and-gender (43.0%) customisation. CONCLUSIONS: Updating the New Zealand customised birthweight centile calculator resulted in revised coefficients that better reflect a contemporary birth cohort. Inclusion of maternal characteristics in a birthweight customisation model increases the detection of SGA infants at risk of perinatal death.

The impact of maternal body mass index on the phenotype of pre-eclampsia: a prospective cohort study.

OBJECTIVE: We hypothesised that among nulliparous women with pre-eclampsia, overweight or obese women would have a different phenotype of pre-eclampsia compared with normal weight women with pre-eclampsia. Specifically, they are more likely to develop term pre-eclampsia and less likely to have indicators of impaired placental perfusion, e.g. abnormal uterine artery Doppler or a small-for-gestational-age (SGA) infant. DESIGN: Prospective, multicentre, cohort SCOPE study (n = 3170). SETTING: New Zealand and Australia. POPULATION: Nulliparous women who developed pre-eclampsia. METHODS: Participants were interviewed at 14-16 weeks of gestation, uterine artery Doppler studies were performed at 19-21 weeks and pregnancy outcome was tracked prospectively. MAIN OUTCOME MEASURES: Rates of abnormal uterine artery Doppler indices, term/preterm birth and SGA infants were compared between normal, overweight and obese women with pre-eclampsia. Multivariable analysis was performed to examine the association between body mass index (BMI) and term pre-eclampsia. RESULTS: Of 178 women with pre-eclampsia, one underweight woman was excluded and 66 (37%) were normal weight, 52 (29%) were overweight and 59 (34%) were obese. Pre-eclampsia developed preterm in 26% of women and at term in 74% of women. There were no differences in the rates of term/preterm pre-eclampsia, abnormal uterine artery Doppler indices or SGA infants between BMI groups (P > 0.10). No independent association between BMI and term pre-eclampsia was found (P = 0.56). CONCLUSIONS: Among women with pre-eclampsia, those who are overweight or obese in early pregnancy are not more likely to have term pre-eclampsia compared with women with a normal BMI. Overweight and obese women require vigilant surveillance for the development of preterm as well as term pre-eclampsia.

Maternal Mid-Gestation Cytokine Dysregulation in Mothers of Children with Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a developmental disorder characterised by deficits in social interactions and communication, with stereotypical and repetitive behaviours. Recent evidence suggests that maternal immune dysregulation may predispose offspring to ASD. Independent samples t-tests revealed downregulation of IL-17A concentrations in cases, when compared to controls, at both 15 weeks (p = 0.02), and 20 weeks (p = 0.02), which persisted at 20 weeks following adjustment for confounding variables. This adds to the growing body of evidence that maternal immune regulation may play a role in foetal neurodevelopment.

Risk factors for small-for-gestational-age infants by customised birthweight centiles: data from an international prospective cohort study.

OBJECTIVE: To identify clinical and ultrasound variables associated with the birth of small-for-gestational-age (SGA) infants by customised centiles, subclassified according to whether their mothers were normotensive or developed hypertensive complications. DESIGN: Prospective, multicentre cohort study. SETTING: Participating centres of the Screening for Pregnancy Endpoints (SCOPE) study in Auckland, New Zealand, Adelaide, Australia, Manchester and London, UK, and Cork, Ireland. POPULATION: The 3513 nulliparous participants of the SCOPE study. METHODS: Women were interviewed at 15 ± 1 weeks, and had ultrasound growth measurements and umbilical and uterine Doppler studies at 20 ± 1 weeks. Variables associated with SGA infants were identified using logistic regression. MAIN OUTCOME MEASURES: Small for gestational age (i.e. a birthweight of less than the tenth customised centile), normotensive-SGA and hypertensive-SGA. Comparison groups for statistical analyses were non-SGA, normotensive non-SGA and hypertensive non-SGA. RESULTS: Among 376 (10.7%) SGA infants, 281 (74.7%) were normotensive-SGA and 95 (25.3%) were hypertensive-SGA. Independent risk factors for normotensive-SGA were low maternal birthweight, low fruit intake pre-pregnancy, cigarette smoking, increasing maternal age, daily vigorous exercise, being a tertiary student, head and abdominal circumference of less than the tenth centile and increasing uterine artery Doppler indices at the 20-week scan. Protective factors were: high green leafy vegetable intake pre-pregnancy, and rhesus-negative blood group. Risk factors for hypertensive-SGA were conception by in vitro fertilisation, previous early pregnancy loss and femur length of less than tenth centile at the 20-week scan. CONCLUSIONS: Risk factors for infants who are SGA by customised centiles have been identified in a cohort of healthy nulliparous women. A number of these factors are modifiable; however, further studies are needed to replicate these findings.

Maternal complications and pregnancy outcome in women with mechanical prosthetic heart valves treated with enoxaparin.

OBJECTIVE: To determine maternal and fetal outcomes in women with mechanical heart valves managed with therapeutic dose enoxaparin during pregnancy. DESIGN: Retrospective audit. SETTING: Hospital-based high-risk antenatal clinics. POPULATION: Pregnant women with mechanical heart valves attending high-risk antenatal clinics, treated with enoxaparin (1 mg/kg twice daily) during pregnancy. METHODS: Women with mechanical heart valves treated with enoxaparin at any stage during pregnancy (1997-2008) identified using a database of women with mechanical heart valves attending the high-risk clinics and a prospective database of women prescribed enoxaparin for any indication during pregnancy. MAIN OUTCOME MEASURES: Maternal outcomes included thromboembolic and haemorrhagic complications. Pregnancy and fetal outcomes included miscarriage, stillbirth, baby death and live birth, small-for-gestational-age infants, warfarin embryopathy and warfarin-related fetal loss. RESULTS: Thirty-one women underwent 47 pregnancies. In 34 pregnancies (72.3%), anticoagulation was with predominantly enoxaparin and 13 (27.7%) pregnancies women received mainly warfarin, with enoxaparin given in the first trimester and/or peri-delivery. Seven (14.9%) thrombotic complications occurred, of which five (10.6%) were associated with enoxaparin treatment. Non-compliance or sub-therapeutic anti-Xa levels contributed in each case. Antenatal and postpartum haemorrhagic complications occurred in eight (17%) and 15 (32%) pregnancies respectively. Of 35 pregnancies continuing after 20 weeks' gestation, 96% (22/23) of women taking predominantly enoxaparin had a surviving infant compared with 75% (9/12) in women taking primarily warfarin. Four perinatal deaths occurred, three attributable to warfarin. CONCLUSIONS: Compliance with therapeutic dose enoxaparin and aspirin during pregnancy in women with mechanical heart valves is associated with a low risk of valve thrombosis and good fetal outcomes, but close monitoring is essential.

Changes in Doppler flow velocity waveforms and fetal size at 20 weeks gestation among cigarette smokers.

OBJECTIVES: To compare umbilical and uterine artery Doppler waveforms and fetal size at 20 weeks between smokers and nonsmokers. DESIGN: Prospective cohort study. SETTING: Auckland, New Zealand and Adelaide, Australia. POPULATION: Nulliparous participants in the Screening for Pregnancy Endpoints (SCOPE) study. METHODS: Self-reported smoking status was determined at 15 +/- 1 weeks' gestation. At the 20 +/- 1 week anatomy scan, uterine and umbilical Doppler resistance indices (RI) and fetal measurements were compared between smokers and nonsmokers. MAIN OUTCOMES MEASURES: Umbilical and mean uterine artery Doppler RI values, abnormal umbilical and uterine Doppler (RI > 90th centile) and fetal biometry. RESULTS: Among the 2459 women, 248 (10%) were smokers. Smokers had higher umbilical RI [0.75 (SD 0.06) versus 0.73 (0.06), P < 0.0001] and mean uterine RI [0.59 (0.09) versus 0.56 (0.10), P < 0.0001]. They were twice as likely to have an abnormal umbilical Doppler at 20 weeks compared with nonsmokers [n = 35 (14.6%) versus n = 156 (7.2%), OR 2.21, 95% CI 1.49-3.27]. This effect remained significant after adjusting for age, ethnicity, marital status, employment and BMI (adjusted OR 1.62, 95% CI 1.03-2.54). Smokers were more likely to have an abnormal mean uterine RI [n = 33 (13.7%) versus n = 198 (9.2%), OR 1.57, 95% CI 1.06-2.33], but this association was not significant after adjusting for confounders. Fetuses of women who smoked had a small reduction in femur length and estimated weight compared with nonsmokers. CONCLUSIONS: At 20 weeks' gestation, women who smoke have higher umbilical artery RI, a surrogate measure for an abnormal placental villous vascular tree. This may contribute to later fetal growth restriction among smokers. Further research is needed to explore the clinical significance of these findings.

Paternal contributions to large-for-gestational-age term babies: findings from a multicenter prospective cohort study.

We assessed whether paternal demographic, anthropometric and clinical factors influence the risk of an infant being born large-for-gestational-age (LGA). We examined the data on 3659 fathers of term offspring (including 662 LGA infants) born to primiparous women from Screening for Pregnancy Endpoints (SCOPE). LGA was defined as birth weight >90th centile as per INTERGROWTH 21st standards, with reference group being infants ⩽90th centile. Associations between paternal factors and likelihood of an LGA infant were examined using univariable and multivariable models. Men who fathered LGA babies were 180 g heavier at birth (P<0.001) and were more likely to have been born macrosomic (P<0.001) than those whose infants were not LGA. Fathers of LGA infants were 2.1 cm taller (P<0.001), 2.8 kg heavier (P<0.001) and had similar body mass index (BMI). In multivariable models, increasing paternal birth weight and height were independently associated with greater odds of having an LGA infant, irrespective of maternal factors. One unit increase in paternal BMI was associated with 2.9% greater odds of having an LGA boy but not girl; however, this association disappeared after adjustment for maternal BMI. There were no associations between paternal demographic factors or clinical history and infant LGA. In conclusion, fathers who were heavier at birth and were taller were more likely to have an LGA infant, but maternal BMI had a dominant influence on LGA.

Activated endothelial cells resist displacement by trophoblast in vitro.

BACKGROUND: Transformation of the spiral arteries by invading trophoblasts is an essential prerequisite to the development of a healthy fully grown fetus. Reduced transformation of the spiral arteries is a characteristic feature of pregnancies complicated by several diseases of pregnancy including preeclampsia. The aim of this study was to investigate further the hypothesis that spiral artery endothelial cells can contribute to the mechanism of shallow trophoblast invasion. METHOD: Fluorescently labeled Jar cells were added to monolayers of fluorescently-labeled endothelial cells that had been activated by treatment with TNFalpha, INF gamma or necrotic cell bodies. The ability of the Jars to displace endothelial cells from the monolayers was quantified by measuring the area of Jar cells "islands" formed in the endothelial cell monolayers by confocal microscopy and digital image. RESULTS: The area of Jar cell islands formed in monolayers of activated endothelial cells was significantly smaller that the area of islands formed in control resting/non-activated endothelial cell monolayers regardless of the activator. DISCUSSION: This work demonstrates that activated endothelial cells are more resistant to trophoblast displacement than resting endothelial cells and adds weight to the suggestion that endothelial cells could contribute to shallow invasion of the spiral arteries by trophoblasts in diseases such as preeclampsia.

Socio-economic status influences the relationship between obesity and antenatal depression: Data from a prospective cohort study.

BACKGROUND: Obesity has been associated with increased risk of antenatal depression, but little is known about this relationship. This study tested whether socio-economic status (SES) influences the relationship between obesity and antenatal depression. METHODS: Data were taken from the Screening for Pregnancy Endpoints (SCOPE) cohort. BMI was calculated from measured height and weight at 15±1 weeks' gestation. Underweight women were excluded. SES was indicated by self-reported household income (dichotomised around the median: low SES ≤£45,000; high SES >£45,000). Antenatal depression was defined as scoring ≥13 on the Edinburgh Postnatal Depression Scale at both 15±1 and 20±1 weeks' gestation, to identify persistently elevated symptoms of depression. RESULTS: Five thousand five hundred and twenty two women were included in these analyses and 5.5% had persistently elevated antenatal depression symptoms. There was a significant interaction between SES and BMI on the risk of antenatal depression (p=0.042). Among high SES women, obese women had approximately double the odds of antenatal depression than normal weight controls (AOR 2.11, 95%CI 1.16-3.83, p=0.014, adjusted for confounders). Among low SES women there was no association between obesity and antenatal depression. The interaction effect was robust to alternative indicators of SES in sensitivity analyses. LIMITATIONS: 1) Antenatal depression was assessed with a self-reported screening measure; and 2) potential mediators such as stigma and poor body-image could not be examined. CONCLUSIONS: Obesity was only associated with increased risk of antenatal depression among high SES women in this sample. Healthcare professionals should be aware that antenatal depression is more common among low SES women, regardless of BMI category.

Long-term survival and valve-related complications in young women with cardiac valve replacements.

BACKGROUND: The type of cardiac valve replacement associated with the lowest health risks for young women who may undergo pregnancies is unknown. We investigated which valve type was associated with greatest patient and valve survival and the effect of pregnancy on valve loss. METHODS AND RESULTS: In this retrospective study, all women 12 to 35 years old who underwent valve replacements between 1972 and 1992 at Greenlane Hospital were identified, and follow-up was available in 93%. The 232 women were followed up for 1499 patient-years. Ten-year survival of women with mechanical (n=178), bioprosthetic (n=73), and homograft (n=72) valves was 70% (95% CI, 59% to 83%), 84% (95% CI, 72% to 99%), and 96% (95% CI, 91% to 100%), P=0.002. After adjustment for confounding variables, the relative risk (RR) of death with mechanical compared with bioprosthetic valves was 2.17 (95% CI, 0.78 to 5.88). Thromboembolic events occurred in 45% of women with mechanical valves within 5 years, compared with 13% with bioprosthetic valves, P=0.0001. Valve loss at 10 years was higher in bioprosthetic valves [82% (95% CI, 62% to 92%)] than in mechanical [29% (95% CI, 17% to 39%)] or homograft [28% (95% CI, 12% to 41%)] valves, P=0.0001. Pregnancy was not associated with increased bioprosthetic (RR, 0.96; 95% CI, 0.68 to 1. 35), homograft (RR, 0.65; 95% CI, 0.37 to 1.13), or mechanical (RR, 0.54; 95% CI, 0.27 to 1.08) valve loss. CONCLUSIONS: Although 10-year valve survival was greater with mechanical than bioprosthetic valves, mechanical valves may be associated with reduced patient survival in young women. Thromboembolic complications, often with long-term sequelae, were common with mechanical valves. Pregnancy did not increase structural deterioration or reduce survival of bioprosthetic valves.

Interaction of Jar choriocarcinoma cells with endothelial cell monolayers.

During human pregnancy the uterine spiral arteries are invaded by placental trophoblasts which replace the endothelial cells that line the non-pregnant spiral arteries and transform these vessels into large-bore conduits enabling adequate perfusion of the placenta with maternal blood. Failure of this process may predispose to preeclampsia and fetal growth restriction [Brosens I, Robertson WB, Dixon HG. The physiological response of the vessels of the placental bed to normal pregnancy. Journal of Pathology and Bacteriology 1967;93:569-79; Khong TY, De Wolf F, Robertson WB, Brosens I. Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants. British Journal of Obstetrics and Gynaecology 1986;93:1049-59]. There is a paucity of data on the role of maternal endothelial cells in this process. In this study we investigated the cellular interactions between trophoblast-derived Jar cells and endothelial cells (HUVECs and HMEC-1). The effect of coculturing Jar cells with endothelial cell monolayers was determined by confocal microscopy, DNA fragmentation assay and flow cytometry. We demonstrated that Jar cells migrate into focal areas in endothelial cell monolayers, where they induce endothelial cell death and, then phagocytose the dead endothelial cells. Our results suggest that endothelial cells may not simply be passive targets for invading trophoblasts during the remodeling of the spiral arteries.