Impact of analysis technique on our understanding of the natural history of labour: a simulation study.

OBJECTIVE: To evaluate the discrepancy between historical and more recent descriptions of the first stage of labour by testing whether the statistical techniques used recently (repeated-measures polynomial and interval-censored regression) were appropriate for detection of periods of rapid acceleration of cervical dilatation as might occur at the time of transition from a latent to an active phase of labour. DESIGN AND SETTING: A simulation study using regression techniques. SAMPLE: We created a simulated data set for 500 000 labours with clearly defined latent and active phases using the parameters described by Friedman. Additionally, we created a data set comprising 500 000 labours with a progressively increasing rate of cervical dilatation. METHODS: Repeated-measures polynomial regression was used to create summary labour curves based on simulated cervical examinations. Interval-censored regression was used to create centimetre-by-centimetre estimates of rates of cervical dilatation and their 95th centiles. MAIN OUTCOME MEASURES: Labour summary curves and rates of cervical dilatation. RESULTS: Repeated-measures polynomial regression did not detect the rapid acceleration in cervical dilatation (i.e. acceleration phase) and overestimated lengths of labour, especially at smaller cervical dilatations. There was a two-fold overestimation in the mean rate of cervical dilatation from 4 to 6 cm. Interval-censored regression overestimated median transit times, at 4- to 5-cm cervical dilatation or when cervical examinations occurred less frequently than 0.5- to 1.5-hourly. CONCLUSION: Repeated-measures polynomial regression and interval-censored regression should not be routinely used to define labour progress because they do not accurately reflect the underlying data. TWEETABLE ABSTRACT: Repeated-measures polynomial and interval-censored regression techniques are not appropriate to model first stage of labour.

Performance of six birth-weight and estimated-fetal-weight standards for predicting adverse perinatal outcome: a 10-year nationwide population-based study.

OBJECTIVE: To evaluate three birth-weight (BW) standards (Australian population-based, Fenton and INTERGROWTH-21st ) and three estimated-fetal-weight (EFW) standards (Hadlock, INTERGROWTH-21st and WHO) for classifying small-for-gestational age (SGA) and large-for-gestational age (LGA) and predicting adverse perinatal outcomes in preterm and term babies. METHODS: This was a nationwide population-based study conducted on a total of 2.4 million singleton births that occurred from 24 + 0 to 40 + 6 weeks' gestation between 2004 and 2013 in Australia. The performance of the growth charts was evaluated according to SGA and LGA classification, and relative risk (RR) and diagnostic accuracy based on the areas under the receiver-operating-characteristics curves (AUCs) for stillbirth, neonatal death, perinatal death, composite morbidity and a composite of perinatal death and morbidity outcomes. The analysis was stratified according to gestational age at delivery (< 37 + 0 vs ≥ 37 + 0 weeks). RESULTS: Following exclusions, 2 392 782 singleton births were analyzed. There were significant differences in the SGA and LGA classification and risk of adverse outcomes between the six BW and EFW standards evaluated. For the term group, compared with the other standards, the INTERGROWTH-21st BW and EFW standards classified half the number of SGA (< 10th centile) babies (3-4% vs 7-11%) and twice the number of LGA (> 90th centile) babies (24-25% vs 8-15%), resulting in a smaller cohort of term SGA at higher risk of adverse outcome and a larger LGA cohort at lower risk of adverse outcome. For term SGA (< 3rd centile) babies, the RR of perinatal death using the two INTERGROWTH-21st standards was up to 1.5-fold higher than those of the other standards (including the WHO-EFW and Hadlock-EFW), while the INTERGROWTH-21st -EFW standard indicated a 12-26% reduced risk of perinatal death for LGA cases across centile thresholds. Conversely, for the preterm group, the WHO-EFW and Hadlock-EFW standards identified a higher SGA classification rate than did the other standards (18-19% vs 10-11%) and a 20-65% increased risk of perinatal death in term LGA babies. All BW and EFW charts had similarly poor performance in predicting adverse outcomes, including the composite outcome (AUC range, 0.49-0.62) for both preterm (AUC range, 0.58-0.62) and term (AUC range, 0.49-0.50) cases and across centiles. Furthermore, specific centile thresholds for identifying adverse outcomes varied markedly by chart between BW and EFW standards. CONCLUSIONS: This study addresses the recurrent problem of identifying fetuses at risk of morbidity and perinatal mortality associated with growth disorders and provides new insights into the applicability of international growth standards. Our findings of marked variation in classification and the similarly poor performance of prescriptive international standards and the other commonly used standards raise questions about whether the prescriptive international standards that were constructed for universal adoption are indeed applicable to a multiethnic population such as that of Australia. Thus, caution is needed when adopting universal standards for clinical and epidemiological use. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Ultrasound features prior to 11 weeks' gestation and first-trimester maternal factors in prediction of hypertensive disorders of pregnancy.

OBJECTIVES: Maternal hypertensive disorders (MHD), including pregnancy-induced hypertension and pre-eclampsia, are estimated to occur in 7-10% of pregnancies worldwide and have significant short- and long-term implications for both mother and fetus. This study aimed to determine the association of conventional and novel early first-trimester ultrasound measures with MHD and whether these ultrasound measures, combined with maternal characteristics and biochemistry, improve the prediction of MHD. METHODS: This was a prospective cohort study of consecutive women with a singleton pregnancy, attending for an early (5 + 1 to 11 + 0 weeks' gestation) ultrasound examination at a private obstetric ultrasound practice between February 2016 and August 2018. Recorded ultrasound measurements included mean sac diameter, yolk sac diameter, crown-rump length, fetal heart rate (FHR), trophoblast thickness, trophoblast volume (TV) and mean uterine artery pulsatility index. Maternal biochemistry was assessed at 10-14 weeks and included beta-human chorionic gonadotropin, pregnancy-associated plasma protein-A (PAPP-A), placental growth factor (PlGF) and maternal serum alpha-fetoprotein. Regression models were fitted for each ultrasound parameter and multiples of the median (MoM) were calculated. All measures were compared between women who had a normotensive outcome and those who subsequently developed MHD. Logistic regression analysis was used to create a prediction model for MHD based on maternal characteristics, ultrasound measurements at 5 + 1 to 11 + 0 weeks' gestation and maternal biochemistry at 10-14 weeks. RESULTS: In total, 1141 women were included in the analysis, of whom 1086 (95.2%) were normotensive at delivery and 55 (4.8%) developed MHD. Women who developed MHD weighed significantly more than did normotensive women (P < 0.0001). Mean MoM values for TV (P = 0.006), PAPP-A (P = 0.031) and PlGF (P = 0.044) were decreased significantly in pregnancies that subsequently developed MHD. The proposed logistic regression model includes maternal weight and height and MoM values for TV, FHR and PlGF, resulting in an area under the receiver-operating-characteristics curve of 0.80 (95% CI, 0.75-0.86). CONCLUSION: The combination of maternal weight and height, TV and FHR, measured prior to 11 weeks' gestation, and first-trimester PlGF appears to have good predictive value for development of MHD later in pregnancy. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Assessing quality standards in measurement of uterine artery pulsatility index at 11 to 13 + 6 weeks' gestation.

OBJECTIVES: To assess the effect of audit and feedback on the performance of first-trimester uterine artery pulsatility index (UtA-PI) measurement, to determine whether operator experience affects performance and whether an operator's measurement profile affects the screen-positive rate for early-onset pre-eclampsia (PE). METHODS: This was a prospective cohort study in which UtA-PI measurements were collected between 11 to 13 + 6 weeks' gestation by 12 operators and were entered into individualized calculators to convert them to multiples of a locally-derived median (MoM). Individual sonographer cumulative sum (CUSUM) and target charts were generated to assess central tendency and dispersion to identify systematic measurement errors and deviation from expected measurement performance. Six of the operators received regular feedback whilst the remaining six received no feedback. Each group consisted of four experienced operators and two relatively inexperienced operators. The average MoM for each operator was compared with their respective screen-positive rates for early-onset PE. RESULTS: The group that received feedback performed better than that which received none, with results more closely matching the expected measurement distribution. UtA-PI measurements were comparable between the experienced and inexperienced sonographers (mean log10 lowest PI MoM, -0.0089 vs 0.0124, respectively); however the inexperienced sonographers had a higher overall screen-positive rate for early-onset PE (10.0% vs 2.7%, respectively). There was a significant positive correlation between the mean MoM for each operator and the screen-positive rate (r = 0.63). CONCLUSIONS: CUSUM and target graphs are an effective method of audit for first-trimester UtA-PI measurement. Feedback to operators resulted in improved measurement performance, which will ultimately result in improved screening accuracy for PE.

Identification of submicroscopic chromosomal aberrations in fetuses with increased nuchal translucency and apparently normal karyotype.

OBJECTIVE: Fetal nuchal translucency (NT) is assessed by ultrasonography as a screening tool for aneuploidy at 11 to 13 + 6 weeks' gestation. Fetuses with increased NT but apparently normal karyotype are still at higher risk of structural abnormality and a range of genetic syndromes, which may be related to major and submicroscopic chromosomal abnormalities. The aim of this study was to report the prevalence of submicroscopic chromosomal abnormalities in a cohort of apparently euploid fetuses that presented with increased NT. METHODS: DNA was extracted from stored chorionic villus samples from fetuses found to have increased NT (> 3.5 mm) during first-trimester screening. These samples were examined by microarray-based comparative genomic hybridization (aCGH) using a 44K oligonucleotide array specifically constructed for prenatal screening. Variations in copy number (CNVs) were reported after excluding known non-pathogenic variants and after validation with multiplex ligation-dependent probe amplification (MLPA) or real-time quantitative polymerase chain reaction (qPCR). The prevalence of pathogenic CNVs is reported and the association with NT and other ultrasound findings described. RESULTS: CNVs were reported in 6/48 (12.5%) cases by aCGH and the microdeletions or microduplications ranged from 1.1 to 7.9 Mb. Five of these were validated by MLPA/real-time qPCR and four (8.3%) were considered to be pathogenic and clinically significant. The incidence of pathogenic CNVs was 20.0% (2/10) among those cases with other sonographic anomalies and 5.3% (2/38) among those without. CONCLUSION: aCGH allows detection of submicroscopic chromosomal abnormalities, the prevalence of which may be increased in fetuses with NT > 3.5 mm and an apparently normal karyotype.

Non-invasive first trimester determination of fetal gender: a new approach for prenatal diagnosis of haemophilia.

Ten carriers of haemophilia referred for prenatal diagnosis were offered first trimester non-invasive fetal gender determination by ultrasound and analysis of free fetal DNA (ffDNA) in maternal plasma in an attempt to reduce the need for an invasive diagnostic procedure in female pregnancies. Although repeat testing was required in three cases, fetal gender was determined correctly in all cases (four females, six males) at a median gestation of 12(+3) (11(+2) to 14(+1)) using both methods. In all cases of a female fetus, the mothers opted not to have invasive testing. Both methods provide a reliable option of avoiding invasive testing in female pregnancies.

Increased nuchal translucency as a prenatal manifestation of congenital adrenal hyperplasia.

We present two cases of pregnant women with a previous history of congenital adrenal hyperplasia. In both cases the only abnormal feature in the initial pregnancy had been increased nuchal translucency at 10-14 weeks of gestation. The fetal karyotype was normal and a diagnosis of congenital adrenal hyperplasia was made after delivery. In their current pregnancies, both fetuses also had increased nuchal translucency and normal fetal karyotype. Diagnosis of 21-hydroxylase deficiency was made prenatally by DNA analysis. These findings in four affected fetuses suggest that congenital adrenal hyperplasia should be added to the list of genetic anomalies associated with an increase in nuchal translucency.

Cardiac gene expression of GATA-4 transcription factor in human trisomy 21 fetuses with increased nuchal translucency.

This study examines GATA-4 gene expression in cardiac tissue from fetuses with trisomy 21 presenting with increased nuchal translucency thickness at 10-14 weeks of gestation. mRNA was extracted from cardiac tissue after termination of pregnancy at 10-18 weeks of gestation in ten trisomy 21 fetuses and 29 normal controls. Northern and slot blots were performed and densitometric analysis of slot blots was used to determine the steady-state levels of expression of GATA-4. GATA-4 transcript levels were also compared with ANP and BNP, which have previously been measured in the same panel of samples. GATA-4 expression increased significantly with gestation but there was no significant difference between fetuses with trisomy 21 and controls. There was no significant association between GATA-4 expression and the steady-state level of transcripts for the natriuretic peptides.

Cerebellar hypoplasia, facial dysmorphism and internal abnormalities: a new recessive syndrome?

Three female sibs had cerebellar hypoplasia, facial dysmorphism comprising a high forehead, lowset posteriorly rotated ears, a prominent upper lip and receding chin, and variable internal abnormalities. Two of the cases had deficient lobulation of the lungs, two had an atrial septal defect of the heart and developmental abnormalities of the urinary system or internal genitalia, one had holoprosencephaly. All had normal chromosomes. This syndrome does not seem to have been reported before and may be inherited in an autosomal recessive manner.

Increased nuchal translucency at 10-14 weeks of gestation as a marker for major cardiac defects.

Screening for fetal cardiac defects is traditionally based on the ultrasonographic examination of the four-chamber view of the fetal heart at mid-gestation, which has been shown to identify 26% of major cardiac defects. Pathological studies in fetuses with increased nuchal translucency at 10-14 weeks of gestation, a sonographic marker for chromosomal abnormalities, have shown an association between increased nuchal translucency and congenital abnormalities of the heart. This study reports the prevalence of cardiac defects in 1427 chromosomally normal fetuses with increased nuchal translucency thickness, and examines the potential value of this sonographic marker in screening for major cardiac defects. The diagnosis of cardiac defects was made either by postmortem examination in terminations of pregnancy and intrauterine or neonatal deaths or by clinical examination and appropriate investigations in live births. The prevalence of major cardiac defects was 17 per 1000 (24 of 1427 fetuses) and increased with translucency thickness from 5.4 per 1000 for translucency of 2.5-3.4 mm to 233 per 1000 for translucency of > or = 5.5 mm. These findings suggest that measurement of nuchal translucency thickness at 10-14 weeks may prove to be a useful method of screening for abnormalities of the heart and great arteries in addition to its role in screening for chromosomal defects.

Cardiac expression of sarcoplasmic reticulum calcium ATPase in fetuses with trisomy 21 and trisomy 18 presenting with nuchal translucency.

At 10-14 weeks of gestation about 80% of fetuses with chromosomal defects have abnormal accumulation of subcutaneous fluid in the nuchal region that is visualized by ultrasonography as nuchal translucency. A possible cause for this translucency is cardiac dysfunction due to the associated defects in the heart and great arteries. The aim of this study was to investigate whether in cardiac tissue from trisomic fetuses, compared to normals, there is an alteration in the steady state levels of expression of the genes encoding sarcoplasmic reticulum calcium ATPase (calcium ATPase), which is known to be downregulated in postnatal heart failure. After termination of pregnancy at 10-18 weeks of gestation, mRNA was extracted from cardiac tissue in 11 trisomy 21 and 4 trisomy 18 fetuses. Densitometric analysis of the Northern and slot blots was used to determine the steady state levels of expression of calcium ATPase and the values from the trisomic fetuses were compared to those of 30 normal controls at 10-18 weeks. Calcium ATPase gene expression did not change significantly with gestation at 10-18 weeks. In trisomic fetuses there was no significant decrease in calcium ATPase expression and expression levels of calcium ATPase were not related to increased nuchal translucency. However, the levels expressed in fetuses are already very low and cardiac dysfunction as a potential etiological factor cannot be excluded.

Fetal heart rate in trisomy 21 and other chromosomal abnormalities at 10-14 weeks of gestation.

Fetal heart rate was measured routinely as part of a prospective study examining the efficacy of screening for trisomy 21 by fetal nuchal translucency thickness and maternal age. In 6903 normal singleton pregnancies the fetal heart rate decreased from a mean of 171 bpm at 10 weeks of gestation to 156 bpm at 14 weeks (r = 0.413, p < 0.0001). In 85 trisomy 21 pregnancies, the mean heart rate was significantly higher than in the normal group (mean difference 0.67 SD, 95% confidence interval 0.42-0.92, t = 5.3, p < 0.001). The fetal heart rate in trisomy 18 and triploid fetuses was significantly lower and in trisomy 13 and Turner syndrome was higher than normal. There was no significant association between delta fetal heart rate and delta nuchal translucency thickness in either the normal (r = -0.018) or the trisomy 21 (r = -0.031) pregnancies. Consequently, the risk for chromosomal defects can be derived by combining data from maternal age, fetal nuchal translucency and fetal heart rate. The effectiveness of screening by this method was examined in a self-selected population with completed pregnancies that had undergone first-trimester scanning. This population contained 6903 normal and 29 trisomy 21 fetuses. For a false-positive rate of about 5%, the sensitivity for trisomy 21 was 48% by maternal age, 26% by fetal heart rate, 72% by nuchal translucency thickness, 59% by maternal age and fetal heart rate, 76% by maternal age and nuchal translucency thickness and 83% by a combination of maternal age, nuchal translucency thickness and fetal heart rate.

Cardiac gene expression of atrial natriuretic peptide and brain natriuretic peptide in trisomic fetuses.

OBJECTIVE: To investigate whether the increased nuchal translucency of trisomic fetuses is the consequence of heart failure by examining cardiac expression of atrial natriuretic peptide and brain natriuretic peptide genes. METHODS: Cardiac atrial natriuretic peptide and brain natriuretic peptide messenger RNA (mRNA) levels were measured in fetal hearts from 15 pregnancies affected by trisomy 21 or 18 at 12-16 weeks' gestation and from 30 normal controls at 10-20 weeks. RESULTS: In normal fetuses, mRNA levels of atrial natriuretic peptide decreased, but levels of brain natriuretic peptide did not change significantly with gestation. In trisomic fetuses, mRNA levels of both atrial natriuretic peptide and brain natriuretic peptide were significantly higher than in gestational age-matched normal controls. CONCLUSION: These data demonstrate that atrial natriuretic peptide and brain natriuretic peptide genes are transcribed prenatally, and the findings in trisomic fetuses suggest that the increased translucency of trisomic fetuses may be the consequence of heart failure.

Intrauterine lethality of trisomy 21 fetuses with increased nuchal translucency thickness.

This study investigates whether first-trimester screening for trisomy 21 by fetal nuchal translucency thickness preferentially identifies those fetuses destined to die in utero and examines the potential impact of such a method of screening on the live birth incidence of trisomy 21. In 70 pregnancies, trisomy 21 was diagnosed at 12 (range 11-14) weeks of gestation and the parents opted for elective termination which was carried out at 14 (12-20) weeks. In all cases, viability was established by ultrasound scan at the time of chorion villus sampling (CVS) and just before termination of pregnancy. Eight (11.4%) fetuses died in the interval between CVS and termination of pregnancy and this rate of lethality was higher than the 6.9% estimated rate for an unselected population of trisomy 21 fetuses. This 4.5% increase may, in part, be attributed to the effects of CVS and may also be due to patient selection on the basis of increased nuchal translucency. The rate of lethality increased with translucency thickness from 5.3% for those with translucency of 1-3 mm to 23.5% for translucency of > 7 mm. In trisomy 21, the rate of intrauterine lethality is associated with nuchal translucency thickness. Nevertheless, a policy of screening by maternal age and fetal nuchal translucency followed by selective termination of affected fetuses would still result in a more than 70% reduction in the live birth incidence of trisomy 21.

Gene expression of human pregnancy-associated plasma protein-A in placenta from trisomic pregnancies.

Placental pregnancy-associated plasma protein-A (PAPP-A) mRNA expression, placental PAPP-A protein concentration and maternal serum levels of PAPP-A were examined in pregnancies affected by trisomy 21 (n=8), trisomy 18 (n=7) and 15 normal controls at 12-15 weeks of gestation. The maternal serum concentration of PAPP-A in the trisomic group of pregnancies was significantly lower than in the normal controls. However there were no significant differences between the three groups in PAPP-A mRNA expression or PAPP-A protein concentration in the placental tissues. There was no significant association between the level of placental mRNA and either placental protein or maternal serum PAPP-A concentrations in the normal or trisomic pregnancies. There was however a significant association between placental protein and maternal serum PAPP-A concentrations in the normal and trisomy 21 pregnancies but not in those affected by trisomy 18. These findings suggest that the decrease in maternal serum PAPP-A in trisomic pregnancies is due to alternations in post-translational events such as protein stability, alterations in the release mechanism of the protein, impaired protein transport across the placenta or modified serum stability of PAPP-A.

Cardiac defects in 1st-trimester fetuses with trisomy 18.

In trisomy 18, echocardiographic studies of affected neonates and pathological studies of stillbirths and infants have demonstrated a high incidence of cardiac defects. Fetal trisomy 18 can now be detected at 11-14 weeks of gestation, providing the opportunity to examine the incidence of cardiac defects at this gestational age. In 19 fetuses with trisomy 18 pathological examination of heart and great vessels was carried out after termination of pregnancy at 11-14 weeks of gestation. The abnormal karyotype was diagnosed by chorion villus sampling in pregnancies with increased fetal nuchal translucency thickness. All 19 fetuses had cardiac defects, and the commonest were ventricular septal defects in 16 (84%) and valvular abnormalities in 16 (84%). In 14 of the 16 cases with valvular abnormalities more than one valve was affected. The great vessels were available for examination in 18 of the 19 cases, and in 10 there was a hypoplastic aortic isthmus or pulmonary trunk. In 6 (32%) cases there was persistence of the left superior vena cava. In 1st-trimester fetuses with trisomy 18, the frequency of perimembranous ventricular septal defects and valvular abnormalities is similar to that in affected neonates. Haemodynamic changes due to the valvular abnormalities, especially imperforate valves, and hypoplasia of the great vessels may be the underlying mechanisms for the increased nuchal translucency of trisomic fetuses. Persistence of the left superior vena cava may result from venous congestion of head and neck.

Increased first trimester nuchal translucency as a prenatal manifestation of Smith-Lemli-Opitz syndrome.

Routine ultrasound examination at 11 weeks of gestation in a woman with no family history of genetic disease demonstrated increased accumulation of fluid in the fetal nuchal region. In view of the association of this defect with chromosomal abnormalities, fetal karyotyping was performed by chorion villus sampling and this demonstrated a normal 46,XY karyotype. Subsequent scans showed resolution of the nuchal fluid, and at the 20-week scan the fetal genitalia appeared to be female. Fetal blood sampling confirmed a normal male karyotype and fetoscopy confirmed the presence of female external genitalia. The parents elected to terminate the pregnancy, and postmortem findings were indicative of Smith-Lemli-Opitz syndrome. This was confirmed by the finding of increased levels of 7-dehydrocholesterol in cultured skin fibroblasts.