New Australian birthweight centiles.

OBJECTIVES: To prepare more accurate population-based Australian birthweight centile charts by using the most recent population data available and by excluding pre-term deliveries by obstetric intervention of small for gestational age babies. DESIGN: Population-based retrospective observational study. SETTING: Australian Institute of Health and Welfare National Perinatal Data Collection. PARTICIPANTS: All singleton births in Australia of 23-42 completed weeks' gestation and with spontaneous onset of labour, 2004-2013. Births initiated by obstetric intervention were excluded to minimise the influence of decisions to deliver small for gestational age babies before term. MAIN OUTCOME MEASURES: Birthweight centile curves, by gestational age and sex. RESULTS: Gestational age, birthweight, sex, and labour onset data were available for 2 807 051 singleton live births; onset of labour was spontaneous for 1 582 137 births (56.4%). At pre-term gestational ages, the 10th centile was higher than the corresponding centile in previous Australian birthweight charts based upon all births. CONCLUSION: Current birthweight centile charts probably underestimate the incidence of intra-uterine growth restriction because obstetric interventions for delivering pre-term small for gestational age babies depress the curves at earlier gestational ages. Our curves circumvent this problem by excluding intervention-initiated births; they also incorporate more recent population data. These updated centile curves could facilitate more accurate diagnosis of small for gestational age babies in Australia.

Effects of sample processing and storage on the integrity of cell-free miRNAs in maternal plasma.

BACKGROUND: Cell-free fetal miRNAs have been identified as potential biomarkers for fetal abnormalities and/or placental function. Factors affecting the stability of cell-free fetal miRNA samples (type of collection tube and time interval between sampling and analysis) have not previously been reported. METHODS: Blood from pregnant women (n = 12, 18 ± 4 weeks' gestation) was collected into two types of tube (EDTA and RNA BCT) and was stored at different temperatures for up to 72 h. Expression of seven apparently placental specific miRNAs was then measured to compare the effects of sampling and storage. These miRNAs were also assessed in non-pregnant women (n = 9). RESULTS: The quantity of miRNA extracted was not affected by time or tube. Three miRNAs (miR-518b, miR-525 and miR-526a*) were measureable only in pregnant women, but miR-518b was not always present. Detailed study of the two pregnancy specific miRNAs showed no effect of tube type at 4 h. However, variability in miRNA level was observed with increased time and was significant for one miRNA in the BCT tube at >48 h (p < 0.005). CONCLUSION: Some cffmiRNAs are placental specific, and these samples are stable when analyzed within 48 h of collection in either tube type. © 2017 John Wiley & Sons, Ltd.

Noninvasive fetal RHD genotyping of RhD negative pregnant women for targeted anti-D therapy in Australia: A cost-effectiveness analysis.

OBJECTIVE: To undertake a cost-effectiveness analysis of noninvasive fetal RHD genotyping to target pregnant women for antenatal anti-D prophylaxis therapy. METHOD: A decision-analytic model was constructed to compare RHD testing and targeted anti-D prophylaxis, with current universal anti-D prophylaxis among pregnant women with RhD negative blood type. Model estimates were derived from national perinatal statistics, published literature, donor program records, and national cost sources. One-way sensitivity analyses addressed the uncertainty of variables on the main findings. RESULTS: The unit cost for RHD genotyping was estimated at AU$45.48 (US$31.84). The "mean cost per healthy baby" was AU$7495 (US$5247) for universal prophylaxis and AU$7471 (US$5230) for targeted prophylaxis. The findings were sensitive to the unit costs of anti-D 625 IU (AU$59-AU$88) (US$41-US$62), the genetic test (AU$36-AU$55) (US$25-US$39), and packaging/transport costs of the samples for testing (AU$15-AU$40, US$11-US$28 per sample). With RHD genotyping, 13 938 women would avoid antenatal anti-D prophylaxis at a total cost savings to the National Blood Authority of AU$2.1 million (US$1.5 million) per year. To the health system, net cost savings of AU$159 701 (US$111 791) per year (0.05%) were predicted for total health care costs. CONCLUSIONS: Given the vulnerable supply of donor plasma and other health concerns, RHD genotyping is an economically sound option for Australia.

Strategy for managing maternal variant RHD alleles in Rhesus D negative obstetric populations during fetal RHD genotyping.

OBJECTIVES: Fetal RHD screening programs that aim to reduce unnecessary antenatal anti-D prophylaxis are being introduced into clinical practice. Strategies to manage women serologically typed as Rhesus D negative who have maternal RHD variants are needed. This study describes maternal RHD allelic variants detected in nonselected and alloimmunised Rhesus D negative obstetric populations and explores a mathematical approach to identify these variants. METHODS: Fetal RHD status was defined by testing cell-free fetal DNA in maternal plasma. Women at risk of an RHD variant were identified by selection for C and E haplotypes or by recognition of low polymerase chain reaction cycle threshold on fetal RHD typing. Maternal RHD alleles were defined by SNP profiling or sequencing. RESULTS: The prevalence of RHD variants in nonselected and alloimmunised groups was 1% (6/603) and 5.5% (6/110), respectively (p < 0.001). An inverse association between RHD cycle threshold values and gestational age was described by a linear model (p < 0.001). Standard residual values with a Z score threshold of -3.00 would have detected all maternal variants with one (1/713) false positive. CONCLUSIONS: The prevalence of maternal RHD variants was significantly higher in alloimmunised cases. The causative mechanism for this needs further investigation. Mathematical modeling simplifies the detection of maternal RHD variants.

Anti-D in pregnant women with the RHD(IVS3+1G>A)-associated DEL phenotype.

BACKGROUND: Pregnant women with the DEL phenotype appear to be D- by routine serology. Women with DEL phenotypes that show a partial D-like epitope loss may develop anti-D. It has been proposed that this alloantibody could have a deleterious effect with respect to hemolytic disease in the fetus and newborn. CASE REPORTS: Two pregnant women, one in Australia and one in Germany, were serotyped as D- and were sensitized to the D antigen. Noninvasive fetal RHD genotyping was performed to plan pregnancy management. RESULTS: In both cases the fetal RHD status could not be assigned due to the presence of a maternal DEL allele. This was suspected through detection of high RHD amplicon levels during quantitative polymerase chain reaction. For both cases extended molecular typing of the maternal genomic DNA revealed a RHD(IVS3+1G>A) allele. For case one, the D+ infant developed a mild hemolytic disease requiring phototherapy. In the second case a D- (or DEL) newborn was unaffected. CONCLUSION: Fetal genotyping from maternal plasma reveals RHD variants in pregnant women with anti-D. Fetuses and newborns of sensitized pregnant women carrying the RHD(IVS3+1G>A) allele are at risk of hemolytic disease.

Combining early (<11 weeks' gestation) ultrasound features and maternal factors to predict small-for-gestational age neonates.

OBJECTIVES: Placental related adverse pregnancy outcomes such as fetal growth restriction have significant short- and long-term implications for both mother and fetus. This study aimed to determine if conventional and novel early first trimester ultrasound measures are associated with small for gestational age (SGA) neonates. In addition, we aimed to assess whether a combination of ultrasound measures, maternal characteristics and biochemistry improved the prediction of this adverse pregnancy outcome. METHODS: This was a prospective cohort study including ultrasound measurements: trophoblast thickness (TT), trophoblast volume (TV), mean uterine artery pulsatility index, crown-rump length, fetal heart rate, mean sac diameter (MSD) and yolk sac diameter. Biochemical markers considered in the analysis were placental growth factor (PIGF), pregnancy - associated plasma protein A (PAPP-A), beta human chorionic gonadotropin and alpha fetoprotein. Regression models were fitted for ultrasound parameters using multiples of the median (MoM). All measures were compared with normal birthweight (BW) ≥10th centile and SGA (BW < 10th centile). Logistic regression analysis was used to create a clinical prediction model for SGA based on maternal characteristics, ultrasound measurements at <11 weeks gestational age and maternal biochemistry collected at 10-14 weeks. RESULTS: As compared to pregnancies delivered of babies with normal BW (n = 1068), MoM values for TT, TV, MSD, PAPP-A and PIGF were significantly reduced (P < 0.05) in pregnancies delivered of SGA babies (n = 73). The proposed logistic regression model includes maternal height, TV and PIGF resulting in an area under the receiver operator curve 0.70 (95% CI 0.63-0.76) for the prediction of SGA. CONCLUSION: A significantly decreased TV, measured <11 weeks gestation, is predictive of BW < 10th centile. With addition of maternal height and PIGF, this three-marker algorithm provided a reasonable predictive value for the development of SGA later in pregnancy.