The impact of CREBRF rs373863828 Pacific-variant on infant body composition.

In Maori and Pacific adults, the CREBRF rs373863828 minor (A) allele is associated with increased body mass index (BMI) but reduced incidence of type-2 and gestational diabetes mellitus. In this prospective cohort study of Maori and Pacific infants, nested within a nutritional intervention trial for pregnant women with obesity and without pregestational diabetes, we investigated whether the rs373863828 A allele is associated with differences in growth and body composition from birth to 12-18 months' corrected age. Infants with and without the variant allele were compared using generalised linear models adjusted for potential confounding by gestation length, sex, ethnicity and parity, and in a secondary analysis, additionally adjusted for gestational diabetes. Carriage of the rs373863828 A allele was not associated with altered growth and body composition from birth to 6 months. At 12-18 months, infants with the rs373863828 A allele had lower whole-body fat mass [FM 1.4 (0.7) vs. 1.7 (0.7) kg, aMD -0.4, 95% CI -0.7, 0.0, P = 0.05; FM index 2.2 (1.1) vs. 2.6 (1.0) kg/m2 aMD -0.6, 95% CI -1.2,0.0, P = 0.04]. However, this association was not significant after adjustment for gestational diabetes, suggesting that it may be mediated, at least in part, by the beneficial effect of CREBRF rs373863828 A allele on maternal glycemic status.

Detection of small for gestational age babies and perinatal outcomes following implementation of the Growth Assessment Protocol at a New Zealand tertiary facility: An observational intervention study.

BACKGROUND: Timely detection of small for gestational age (SGA) fetuses is important for reducing severe perinatal morbidity and mortality, and better tools are needed to detect SGA in maternity care. AIM: We evaluated the effect of the introduction of the Perinatal Institute's Growth Assessment Protocol (GAP) in the Counties Manukau Health region, South Auckland, New Zealand, on antenatal detection of SGA and maternal and perinatal outcomes. MATERIALS AND METHODS: Uncontrolled before and after study in women booked under hospital community midwife care with a singleton, non-anomalous pregnancy. Antenatal detection of SGA (birthweight <10th customised centile) was compared pre-GAP (2012, N = 1105) and post-GAP (2017, N = 1082). Composite adverse neonatal outcome was defined as neonatal unit admission >48 h, five-minute Apgar score <7, and/or any ventilation. Analyses were adjusted for maternal age, body mass index, deprivation, smoking and ethnicity. RESULTS: SGA rates were similar across epochs (13.8% vs 12.9%) but antenatal detection of SGA increased from 22.9% (35/153) to 57.9% (81/140) post-GAP (adjusted odds ratio (aOR) = 4.8, 95% CI 2.82-8.18). Rates of induction of labour and caesarean section increased between epochs but were similar in SGA, non-SGA, and detected and non-detected SGA subgroups. Among SGA babies, there was some evidence that antenatal detection of SGA may be associated with lower composite adverse neonatal outcome (detected SGA: aOR 0.44 95% CI 0.17-1.15; non-detected SGA: aOR = 1.81 95% CI 0.73-4.48; interaction P = 0.03). Pre-term birth did not appear to be influenced by GAP. CONCLUSION: Implementation of GAP was associated with a nearly five-fold increase in SGA detection without increasing obstetric intervention for SGA.

The Pacific-specific CREBRF rs373863828 allele protects against gestational diabetes mellitus in Maori and Pacific women with obesity.

AIMS/HYPOTHESIS: The CREBRF rs373863828 minor (A) allele is associated with increased BMI but reduced prevalence of type 2 diabetes in Maori and Pacific people. Given the shared aetiology of type 2 diabetes and gestational diabetes mellitus (GDM), we tested for an association between the CREBRF rs373863828 variant and GDM. METHODS: We conducted a prospective cohort study of Maori and Pacific women nested within a nutritional intervention study for pregnant women with obesity. Women were enrolled at 12-17 weeks' gestation and underwent anthropometry and collection of buffy coats for later genetic testing. GDM was diagnosed by 75 g OGTT at 24-28 weeks' gestation using the International Association of Diabetes and Pregnancy Study Groups criteria. Genotyping was performed by real-time PCR with a custom CREBRF rs373863828 probe-set. The association between CREBRF rs373863828 and GDM was analysed separately by ethnic group using logistic regression, with effect estimates combined in a meta-analysis. RESULTS: Of 112 Maori and Pacific pregnant women with obesity, 31 (28%) carried the CREBRF rs373863828 A allele (A/G or A/A) and 35 (31%) developed GDM. Women who carried the CREBRF rs373863828 A allele did not differ in BMI when compared with non-carriers (G/G). There was a fivefold reduction in the likelihood of GDM per CREBRF rs373863828 A allele (OR 0.19 [95% CI 0.05, 0.69], p = 0.01), independent of age, BMI and family history of diabetes (adjusted OR 0.13 [95% CI 0.03, 0.53], p = 0.004). GDM was diagnosed in 10% and 40% of women with and without the CREBRF rs373863828 A allele, respectively (no woman with the A/A genotype developed GDM). CONCLUSIONS/INTERPRETATION: The CREBRF rs373863828 (A) allele is associated with reduced likelihood of GDM in Maori and Pacific women with obesity and may improve GDM risk prediction. Graphical abstract.

Accuracy of point-of-care HbA1c testing in pregnant women.

BACKGROUND: In New Zealand, it is recommended that all pregnant women have a haemoglobin A1c (HbA1c) test performed with their booking antenatal bloods to identify previously unrecognised diabetes. However, screening rates in some groups are low. Use of a point-of-care device may improve compliance with screening. AIM: To assess the accuracy of the COBAS b101 point-of-care system referenced against a laboratory method, for measurement of HbA1c levels in pregnant women. MATERIALS AND METHODS: Convenience sample of 40 obese pregnant women enrolled in a clinical trial. HbA1c was assayed in paired capillary and venous whole blood samples using the COBAS b101 point-of-care system and Primus Ultra2 high performance liquid chromatography laboratory analyser, respectively. The accuracy of the point-of-care system was assessed by Bland-Altman analysis. RESULTS: The mean (SD) laboratory HbA1c was 35.9 (2.0) mmol/mol. The COBAS b101 point-of-care system, compared with the laboratory reference method, had a small negative bias for HbA1c (-1.0 mmol/mol, 95% CI -2.0 to -0.03, P = 0.03) and relatively wide 95% limits of agreement (-7.2 to 5.1 mmol/mol). CONCLUSION: In conclusion, we found that in pregnancy, the COBAS b101 point-of-care system has a small negative bias and modest point accuracy for HbA1c. When used to screen for previously unrecognised diabetes in pregnancy, appropriate COBAS b101 HbA1c point-of-care HbA1c thresholds for a negative and positive result are 7 mmol/mol below and 5 mmol/mol above the clinical threshold, respectively. Values between these limits should be confirmed by laboratory testing.

Risk factors for excessive gestational weight gain in a healthy, nulliparous cohort.

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.

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.

Clinical prediction in early pregnancy of infants small for gestational age by customised birthweight centiles: findings from a healthy nulliparous cohort.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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 <10(th) 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. CONCLUSION: Predictors for SGA of relevance to clinical practice were identified. The identity and predictive potential differed in normotensive women and those who developed hypertension.

Antepartum haemorrhage of unknown origin and maternal cigarette smoking beyond the first trimester.

BACKGROUND: Antepartum haemorrhage of unknown origin (APHUO) is associated with preterm birth and perinatal mortality. AIM: To determine whether smoking beyond the first trimester of pregnancy was an independent risk factor for APHUO. METHODS: 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. RESULTS: 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 0.76­2.14), but vaginal bleeding in early pregnancy (adjusted OR = 2.98, 95% CI 2.12­4.18) and overweight/obesity (adjusted OR = 1.43, 95% CI 1.02­1.99) were independent risk factors. First trimester folic acid use was associated with a reduced risk (adjusted OR = 0.44, 95% CI 0.25­0.77). CONCLUSION: Smoking is not an independent risk factor for APHUO after adjustment for confounders, but other risk and protective factors have been identified.

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.

Maternal serum activin A is not elevated before preeclampsia in women who are at high risk.

OBJECTIVE: The purpose of this study was to determine whether, in women who are at high risk of the development of preeclampsia, serum activin A concentrations are elevated before the disease and whether activin A is a useful predictor of preeclampsia. STUDY DESIGN: Sera were collected on five occasions throughout pregnancy from women with chronic hypertension, renal disease, or previous early-onset preeclampsia (n = 80 women). Women were classified as control subjects (normotensive or stable chronic hypertension), gestational hypertensive, or preeclamptic (de novo or superimposed). Serum activin A concentrations were measured by immunoassay. Differences in activin A concentrations between groups were analyzed with the use of a mixed-models procedure; screening test characteristics were calculated. RESULTS: Twenty-six women (33%) had gestational hypertension, and 17 women (21%) had preeclampsia or superimposed preeclampsia. Serum activin A levels increased with gestation in all groups (P =.0001), but there were no significant difference in activin A levels between groups (P =.75). CONCLUSION: In women who were at high risk of the development of preeclampsia, serum activin A levels are not elevated with preeclampsia. Activin A is not a useful predictor of preeclampsia in this setting.

Longitudinal serum concentrations of placental growth factor: evidence for abnormal placental angiogenesis in pathologic pregnancies.

OBJECTIVE: Complicated pregnancies demonstrate abnormal decidual and placental villous vasculature. We examined maternal concentrations of vascular endothelial growth factor and placental growth factor in normal pregnancies and in pregnancies that were complicated by isolated idiopathic small-for-gestational-age (SGA) newborn infants, preeclampsia alone, or preeclampsia with SGA newborn infants at the time of clinical disease and before the onset of clinical signs. STUDY DESIGN: Serum vascular endothelial growth factor and placental growth factor were measured by enzyme-linked immunosorbent assay in cross-sectional and longitudinal cohorts of pregnant nulliparous women. The results were compared by Wilcoxon tests or a mixed-models method, respectively. RESULTS: In the cross-sectional study, serum placental growth factor was reduced in abnormal pregnancy relative to control subjects (SGA newborn infants, 18 [P =.04]; preeclampsia, 20; or preeclampsia with small- for-gestational-age newborn infants, 11 [P =.0001]) as early as 15 to 19 weeks of gestation in preeclampsia with SGA newborn infants. Vascular endothelial growth factor was <30 pg/mL in all serum specimens from pregnant women. CONCLUSION: We postulate that decreased placental growth factor production results in abnormalities of placental angiogenesis through direct and indirect effects on other vasculotropic growth factors.