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1.  Risk Factors for Excessive Gestational Weight Gain in a Healthy, Nulliparous Cohort 
Journal of Obesity  2014;2014:148391.
Objective. Excessive gestational weight gain (GWG) is associated with adverse maternal and child outcomes and contributes to obesity in women. Our aim was to identify early pregnancy factors associated with excessive GWG, in a contemporary nulliparous cohort. Methods. Participants in the SCOPE study were classified into GWG categories (“not excessive” versus “excessive”) based on pregravid body mass index (BMI) using 2009 Institute of Medicine (IOM) guidelines. Maternal characteristics and pregnancy risk factors at 14–16 weeks were compared between categories and multivariable analysis controlled for confounding factors. Results. Of 1950 women, 17% gained weight within the recommended range, 74% had excessive and 9% inadequate GWG. Women with excessive GWG were more likely to be overweight (adjOR 2.9 (95% CI 2.2–3.8)) or obese (adjOR 2.5 (95% CI 1.8–3.5)) before pregnancy compared to women with a normal BMI. Other factors independently associated with excessive GWG included recruitment in Ireland, younger maternal age, increasing maternal birthweight, cessation of smoking by 14–16 weeks, increased nightly sleep duration, high seafood diet, recent immigrant, limiting behaviour, and decreasing exercise by 14–16 weeks. Fertility treatment was protective. Conclusions. Identification of potentially modifiable risk factors for excessive GWG provides opportunities for intervention studies to improve pregnancy outcome and prevent maternal obesity.
PMCID: PMC4065732  PMID: 24995130
2.  Clinical Prediction in Early Pregnancy of Infants Small for Gestational Age by Customised Birthweight Centiles: Findings from a Healthy Nulliparous Cohort 
PLoS ONE  2013;8(8):e70917.
Small for gestational age (SGA) infants comprise up to 50% of all stillbirths and a minority are detected before birth. We aimed to develop and validate early pregnancy predictive models for SGA infants.
5628 participants from SCOPE, a prospective study of nulliparous pregnant women, were interviewed at 15±1 weeks’ gestation. Fetal anthropometry, uterine and umbilical Doppler studies were performed at 20±1 weeks’. The cohort was divided into training (n = 3735) and validation datasets (n = 1871). All-SGA (birthweight <10th customised centile), Normotensive-SGA (SGA with normotensive mother) and Hypertensive-SGA (SGA with mother who developed hypertension) were the primary outcomes. Multivariable analysis was performed using stepwise logistic regression firstly using clinical variables and then with clinical and ultrasound variables. Receiver operator curves were constructed and areas under the curve (AUC) calculated.
633 infants (11.3%) in the whole cohort were SGA; 465 (8.3%) Normotensive-SGA and 165 (3.0%) Hypertensive-SGA. In the training dataset risk factors for All-SGA at 15±1 weeks’ included: family history of coronary heart disease, maternal birthweight <3000 g and 3000 g to 3499 g compared with ≥3500 g, >12 months to conceive, university student, cigarette smoking, proteinuria, daily vigorous exercise and diastolic blood pressure ≥80. Recreational walking ≥4 times weekly, rhesus negative blood group and increasing random glucose were protective. AUC for clinical risk factors was 0.63. Fetal abdominal or head circumference z scores <10th centile and increasing uterine artery Doppler resistance at 20±1 weeks’ were associated with increased risk. Addition of these parameters increased the AUC to 0.69. Clinical predictors of Normotensive and Hypertensive-SGA were sub-groups of All-SGA predictors and were quite different. The combined clinical and ultrasound AUC for Normotensive and Hypertensive-SGA were 0.69 and 0.82 respectively.
Predictors for SGA of relevance to clinical practice were identified. The identity and predictive potential differed in normotensive women and those who developed hypertension.
PMCID: PMC3733741  PMID: 23940665
3.  The association of maternal ACE A11860G with small for gestational age babies is modulated by the environment and by fetal sex: a multicentre prospective case–control study 
Molecular Human Reproduction  2013;19(9):618-627.
We aimed to determine whether the ACE A11860G genotype is associated with small for gestational age babies (SGA) and to determine whether the association is affected by environmental factors and fetal sex. Overall, 3234 healthy nulliparous women with singleton pregnancies, their partners and babies were prospectively recruited in Adelaide, Australia and Auckland, New Zealand. Data analyses were confined to 2121 Caucasian parent–infant trios, among which 216 were pregnancies with SGA infants and 1185 were uncomplicated pregnancies. Women with the ACE A11860G GG genotype in the combined and Adelaide cohorts had increased risk for SGA [odds ratios (OR) 1.5, 95% confidence interval (CI) 1.1–2.1 and OR 2.0, 95% CI 1.3–3.3, respectively) and delivered lighter babies (P = 0.02; P = 0.007, respectively) compared with those with AA/AG genotypes. The maternal ACE A11860G GG genotype was associated with higher maternal plasma ACE concentration at 15 weeks' gestation than AA/AG genotypes (P < 0.001). When the Adelaide cohort was stratified by maternal socio-economic index (SEI) and pre-pregnancy green leafy vegetable intake, the ACE A11860G GG genotype was only associated with an increased risk for SGA (OR 4.9, 95% CI 1.8–13.4 and OR 3.3, 95% CI 1.6–7.0, respectively) and a reduction in customized birthweight centile (P = 0.006 and P = 0.03) if superimposed on maternal SEI <34 or pre-pregnancy green leafy vegetable intake <1 serve/day. Furthermore, the associations of maternal ACE A11860G with customized birthweight centile observed among Adelaide women with SEI <34 or pre-pregnancy green leafy vegetable intake <1 serve/day were female specific. The current study identified a novel association of maternal ACE A11860G with SGA. More interestingly, this association was modified by environmental factors and fetal sex, suggesting ACE A11860G–environment–fetal sex interactions.
Trial Registry Name: Screening nulliparous women to identify the combinations of clinical risk factors and/or biomarkers required to predict pre-eclampsia, SGA babies and spontaneous preterm birth.
Registration number: ACTRN12607000551493.
PMCID: PMC3749805  PMID: 23615722
ACE A11860G; small for gestational age; socio-economic index; pre-pregnancy green leafy vegetable intake; fetal sex
4.  Maternal obesity and postpartum haemorrhage after vaginal and caesarean delivery among nulliparous women at term: a retrospective cohort study 
Increasing rates of postpartum haemorrhage in developed countries over the past two decades are not explained by corresponding changes in risk factors and conjecture has been raised that maternal obesity may be responsible. Few studies investigating risk factors for PPH have included BMI or investigated PPH risk among nulliparous women. The aim of this study was to determine in a cohort of nulliparous women delivering at term whether overweight and obesity are independent risk factors for major postpartum haemorrhage (PPH ≥1000ml) after vaginal and caesarean section delivery.
The study population was nulliparous singleton pregnancies delivered at term at National Women’s Hospital, Auckland, New Zealand from 2006 to 2009 (N=11,363). Multivariable logistic regression was adjusted for risk factors for major PPH.
There were 7238 (63.7%) women of normal BMI, 2631 (23.2%) overweight and 1494 (13.1%) obese. Overall, PPH rates were increased in overweight and obese compared with normal-weight women (n=255 [9.7%], n=233 [15.6%]), n=524 [7.2%], p <.001) respectively. There was an approximate twofold increase in risk in obese nulliparous women that was independent of confounders, adjusted odds ratio [aOR (95% CI)] for all deliveries 1.86 (1.51-2.28). Being obese was a risk factor for major PPH following both caesarean 1.73 (1.32-2.28) and vaginal delivery 2.11 (1.54-2.89) and the latter risk was similar after exclusion of women with major perineal trauma and retained placentae. Three additional factors were consistently associated with risk for major PPH regardless of mode of delivery: increasing infant birthweight, antepartum haemorrhage and Asian ethnicity.
Nulliparous obese women have a twofold increase in risk of major PPH compared to women with normal BMI regardless of mode of delivery. Higher rates of PPH among obese women are not attributable to their higher rates of caesarean delivery. Obesity is an important high risk factor for PPH, and the risk following vaginal delivery is emphasised. We recommend in addition to standard practice of active management of third stage of labour, there should be increased vigilance and preparation for PPH management in obese women.
PMCID: PMC3495044  PMID: 23078042
Nulliparity obesity postpartum haemorrhage
5.  Risk Factors for Preterm Birth in an International Prospective Cohort of Nulliparous Women 
PLoS ONE  2012;7(7):e39154.
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.
Prospective international multicentre cohort.
3234 healthy nulliparous women with a singleton pregnancy, follow up was complete in 3184 of participants (98.5%).
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.
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 ACTRN12607000551493
PMCID: PMC3398037  PMID: 22815699
6.  Association between maternal sleep practices and risk of late stillbirth: a case-control study 
Objectives To determine whether snoring, sleep position, and other sleep practices in pregnant women are associated with risk of late stillbirth.
Design Prospective population based case-control study.
Setting Auckland, New Zealand
Participants Cases: 155 women with a singleton late stillbirth (≥28 weeks’ gestation) without congenital abnormality born between July 2006 and June 2009 and booked to deliver in Auckland. Controls: 310 women with single ongoing pregnancies and gestation matched to that at which the stillbirth occurred. Multivariable logistic regression adjusted for known confounding factors.
Main outcome measure Maternal snoring, daytime sleepiness (measured with the Epworth sleepiness scale), and sleep position at the time of going to sleep and on waking (left side, right side, back, and other).
Results The prevalence of late stillbirth in this study was 3.09/1000 births. No relation was found between snoring or daytime sleepiness and risk of late stillbirth. However, women who slept on their back or on their right side on the previous night (before stillbirth or interview) were more likely to experience a late stillbirth compared with women who slept on their left side (adjusted odds ratio for back sleeping 2.54 (95% CI 1.04 to 6.18), and for right side sleeping 1.74 (0.98 to 3.01)). The absolute risk of late stillbirth for women who went to sleep on their left was 1.96/1000 and was 3.93/1000 for women who did not go to sleep on their left. Women who got up to go to the toilet once or less on the last night were more likely to experience a late stillbirth compared with women who got up more frequently (adjusted odds ratio 2.28 (1.40 to 3.71)). Women who regularly slept during the day in the previous month were also more likely to experience a late stillbirth than those who did not (2.04 (1.26 to 3.27)).
Conclusions This is the first study to report maternal sleep related practices as risk factors for stillbirth, and these findings require urgent confirmation in further studies.
PMCID: PMC3114953  PMID: 21673002
7.  Clinical risk prediction for pre-eclampsia in nulliparous women: development of model in international prospective cohort 
Objectives To develop a predictive model for pre-eclampsia based on clinical risk factors for nulliparous women and to identify a subgroup at increased risk, in whom specialist referral might be indicated.
Design Prospective multicentre cohort.
Setting Five centres in Auckland, New Zealand; Adelaide, Australia; Manchester and London, United Kingdom; and Cork, Republic of Ireland.
Participants 3572 “healthy” nulliparous women with a singleton pregnancy from a large international study; data on pregnancy outcome were available for 3529 (99%).
Main outcome measure Pre-eclampsia defined as ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg, or both, on at least two occasions four hours apart after 20 weeks’ gestation but before the onset of labour, or postpartum, with either proteinuria or any multisystem complication. Preterm pre-eclampsia was defined as women with pre-eclampsia delivered before 37+0 weeks’ gestation. In the stepwise logistic regression the comparison group was women without pre-eclampsia.
Results Of the 3529 women, 186 (5.3%) developed pre-eclampsia, including 47 (1.3%) with preterm pre-eclampsia. Clinical risk factors at 14-16 weeks’ gestation were age, mean arterial blood pressure, body mass index (BMI), family history of pre-eclampsia, family history of coronary heart disease, maternal birth weight, and vaginal bleeding for at least five days. Factors associated with reduced risk were a previous single miscarriage with the same partner, taking at least 12 months to conceive, high intake of fruit, cigarette smoking, and alcohol use in the first trimester. The area under the receiver operating characteristics curve (AUC), under internal validation, was 0.71. Addition of uterine artery Doppler indices did not improve performance (internal validation AUC 0.71). A framework for specialist referral was developed based on a probability of pre-eclampsia generated by the model of at least 15% or an abnormal uterine artery Doppler waveform in a subset of women with single risk factors. Nine per cent of nulliparous women would be referred for a specialist opinion, of whom 21% would develop pre-eclampsia. The relative risk for developing pre-eclampsia and preterm pre-eclampsia in women referred to a specialist compared with standard care was 5.5 and 12.2, respectively.
Conclusions The ability to predict pre-eclampsia in healthy nulliparous women using clinical phenotype is modest and requires external validation in other populations. If validated, it could provide a personalised clinical risk profile for nulliparous women to which biomarkers could be added.
Trial registration ACTRN12607000551493.
PMCID: PMC3072235  PMID: 21474517
8.  Spontaneous preterm birth and small for gestational age infants in women who stop smoking early in pregnancy: prospective cohort study 
Objectives To compare pregnancy outcomes between women who stopped smoking in early pregnancy and those who either did not smoke in pregnancy or continued to smoke.
Design Prospective cohort study.
Setting Auckland, New Zealand and Adelaide, Australia.
Participants 2504 nulliparous women participating in the Screening for Pregnancy Endpoints (SCOPE) study grouped by maternal smoking status at 15 (±1) week’s gestation.
Main outcome measures Spontaneous preterm birth and small for gestational age infants (birth weight <10th customised centile). We compared odds of these outcomes between stopped smokers and non-smokers, and between current smokers and stopped smokers, using logistic regression, adjusting for demographic and clinical risk factors.
Results 80% (n=1992) of women were non-smokers, 10% (n=261) had stopped smoking, and 10% (n=251) were current smokers. We noted no differences in rates of spontaneous preterm birth (4%, n=88 v 4%, n=10; adjusted odds ratio 1.03, 95% confidence interval l0.49 to 2.18; P=0.66) or small for gestational age infants (10%, n=195 v 10%, n=27; 1.06, 0.67 to 1.68; P=0.8) between non-smokers and stopped smokers. Current smokers had higher rates of spontaneous preterm birth (10%, n=25 v 4%, n=10; 3.21, 1.42 to 7.23; P=0.006) and small for gestational age infants (17%, n=42 v 10%, n=27; 1.76, 1.03 to 3.02; P=0.03) than stopped smokers.
Conclusion In women who stopped smoking before 15 weeks’ gestation, rates of spontaneous preterm birth and small for gestational age infants did not differ from those in non-smokers, indicating that these severe adverse effects of smoking may be reversible if smoking is stopped early in pregnancy.
PMCID: PMC2661373  PMID: 19325177
9.  Exploration and confirmation of factors associated with uncomplicated pregnancy in nulliparous women: prospective cohort study 
Objective To identify factors at 15 and 20 weeks’ gestation associated with a subsequent uncomplicated pregnancy.
Design Prospective international multicentre observational cohort study.
Setting Auckland, New Zealand and Adelaide, Australia (exploration and local replication dataset) and Manchester, Leeds, and London, United Kingdom, and Cork, Republic of Ireland (external confirmation dataset).
Participants 5628 healthy nulliparous women with a singleton pregnancy.
Main outcome measure Uncomplicated pregnancy, defined as a normotensive pregnancy delivered at >37 weeks’ gestation, resulting in a liveborn baby not small for gestational age, and the absence of any other significant pregnancy complications. In a stepwise logistic regression the comparison group was women with a complicated pregnancy.
Results Of the 5628 women, 3452 (61.3%) had an uncomplicated pregnancy. Factors that reduced the likelihood of an uncomplicated pregnancy included increased body mass index (relative risk 0.74, 95% confidence intervals 0.65 to 0.84), misuse of drugs in the first trimester (0.90, 0.84 to 0.97), mean diastolic blood pressure (for each 5 mm Hg increase 0.92, 0.91 to 0.94), and mean systolic blood pressure (for each 5 mm Hg increase 0.95, 0.94 to 0.96). Beneficial factors were prepregnancy fruit intake at least three times daily (1.09, 1.01 to 1.18) and being in paid employment (per eight hours’ increase 1.02, 1.01 to 1.04). Detrimental factors not amenable to alteration were a history of hypertension while using oral contraception, socioeconomic index, family history of any hypertensive complications in pregnancy, vaginal bleeding during pregnancy, and increasing uterine artery resistance index. Smoking in pregnancy was noted to be a detrimental factor in the initial two datasets but did not remain in the final model.
Conclusions This study identified factors associated with normal pregnancy through adoption of a novel hypothesis generating approach, which has shifted the emphasis away from adverse outcomes towards uncomplicated pregnancies. Although confirmation in other cohorts is necessary, this study implies that individually targeted lifestyle interventions (normalising maternal weight, increasing prepregnancy fruit intake, reducing blood pressure, stopping misuse of drugs) may increase the likelihood of normal pregnancy outcomes.
Trial registration Australian New Zealand Clinical Trials Registry ACTRN12607000551493.
PMCID: PMC3898573  PMID: 24270055

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