Perinatal predictors of clinical instability at birth in late-preterm and term infants.

To identify characteristics associated with delivery room clinical instability in at-risk infants. Prospective cohort study. Two perinatal centres in Melbourne, Australia. Infants born at ≥ 35+0 weeks' gestation with a first-line paediatric doctor requested to attend. Clinical instability defined as any one of heart rate < 100 beats per minute for ≥ 20 s in the first 10 min after birth, maximum fraction of inspired oxygen of ≥ 0.70 in the first 10 min after birth, 5-min Apgar score of < 7, intubated in the delivery room or admitted to the neonatal unit for respiratory support. Four hundred and seventy-three infants were included. The median (IQR) gestational age at birth was 39+4 (38+4-40+4) weeks. Eighty (17%) infants met the criteria for clinical instability. Independent risk factors for clinical instability were labour without oxytocin administration, presence of a medical pregnancy complication, difficult extraction at birth and unplanned caesarean section in labour. Decision tree analysis determined that infants at highest risk were those whose mothers did not receive oxytocin during labour (25% risk). Infants at lowest risk were those whose mothers received oxytocin during labour and did not have a medical pregnancy complication (7% risk). CONCLUSIONS: We identified characteristics associated with clinical instability that may be useful in alerting less experienced clinicians to call for senior assistance early. The decision trees provide intuitive visual aids but require prospective validation. WHAT IS KNOWN: • First-line clinicians attending at-risk births may need to call senior colleagues for assistance depending on the infant's condition. • Delays in effectively supporting a compromised infant at birth is an important cause of neonatal morbidity and infant-mother separation. WHAT IS NEW: • This study identifies risk factors for delivery room clinical instability in at-risk infants born at ≥ 35+0 weeks' gestation. • The decision trees presented provide intuitive visual tools to aid in determining the need for senior paediatric presence.

Physiologically based cord clamping for infants ≥32+0 weeks gestation: A randomised clinical trial and reference percentiles for heart rate and oxygen saturation for infants ≥35+0 weeks gestation.

BACKGROUND: Globally, the majority of newborns requiring resuscitation at birth are full term or late-preterm infants. These infants typically have their umbilical cord clamped early (ECC) before moving to a resuscitation platform, losing the potential support of the placental circulation. Physiologically based cord clamping (PBCC) is clamping the umbilical cord after establishing lung aeration and holds promise as a readily available means of improving early newborn outcomes. In mechanically ventilated lambs, PBCC improved cardiovascular stability and reduced hypoxia. We hypothesised that PBCC compared to ECC would result in higher heart rate (HR) in infants needing resuscitation, without compromising safety. METHODS AND FINDINGS: Between 4 July 2018 and 18 May 2021, infants born at ≥32+0 weeks' gestation with a paediatrician called to attend were enrolled in a parallel-arm randomised trial at 2 Australian perinatal centres. Following initial stimulation, infants requiring further resuscitation were randomised within 60 seconds of birth using a smartphone-accessible web link. The intervention (PBCC) was to establish lung aeration, either via positive pressure ventilation (PPV) or effective spontaneous breathing, prior to cord clamping. The comparator was early cord clamping (ECC) prior to resuscitation. The primary outcome was mean HR between 60 to 120 seconds after birth, measured using 3-lead electrocardiogram, extracted from video recordings blinded to group allocation. Nonrandomised infants had deferred cord clamping (DCC) ≥120 seconds in the observational study arm. Among 508 at-risk infants enrolled, 123 were randomised (n = 63 to PBCC, n = 60 to ECC). Median (interquartile range, IQR) for gestational age was 39.9 (38.3 to 40.7) weeks in PBCC infants and 39.6 (38.4 to 40.4) weeks in ECC infants. Approximately 49% and 50% of the PBCC and ECC infants were female, respectively. Five infants (PBCC = 2, ECC = 3, 4% total) had missing primary outcome data. Cord clamping occurred at a median (IQR) of 136 (126 to 150) seconds in the PBCC arm and 37 (27 to 51) seconds in the ECC arm. Mean HR between 60 to 120 seconds after birth was 154 bpm (beats per minute) for PBCC versus 158 bpm for ECC (adjusted mean difference -6 bpm, 95% confidence interval (CI) -17 to 5 bpm, P = 0.39). Among 31 secondary outcomes, postpartum haemorrhage ≥500 ml occurred in 34% and 32% of mothers in the PBCC and ECC arms, respectively. Two hundred ninety-five nonrandomised infants (55% female) with median (IQR) gestational age of 39.6 (38.6 to 40.6) weeks received DCC. Data from these infants was used to create percentile charts of expected HR and oxygen saturation in vigorous infants receiving DCC. The trial was limited by the small number of infants requiring prolonged or advanced resuscitation. PBCC may provide other important benefits we did not measure, including improved maternal-infant bonding and higher iron stores. CONCLUSIONS: In this study, we observed that PBCC resulted in similar mean HR compared to infants receiving ECC. The findings suggest that for infants ≥32+0 weeks' gestation who receive brief, effective resuscitation at closely monitored births, PBCC does not provide additional benefit over ECC (performed after initial drying and stimulation) in terms of key physiological markers of transition. PBCC was feasible using a simple, low-cost strategy at both cesarean and vaginal births. The percentile charts of HR and oxygen saturation may guide clinicians monitoring the transition of at-risk infants who receive DCC. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12618000621213.

Medical termination of pregnancy for fetal anomaly at or beyond 20 weeks' gestation-What are the maternal risks?

OBJECTIVE: To evaluate the common and severe maternal morbidities associated with medical termination of pregnancy (MTOP) for fetal anomaly ≥20 weeks' gestation. METHODS: A 10-year retrospective cohort study (January 2010-December 2019) analyzing 407 consecutive singleton pregnancies MTOP for fetal anomaly ≥20 weeks' gestation, at a quaternary maternity centre in Australia (Royal Women's Hospital, Melbourne). RESULTS: The cohort comprised of 191 primiparous and 216 multiparous women, of whom 75 (34.7%) had at least one prior Cesarean; 13 women had a low-lying placenta or placenta praevia. The average gestation was 23 weeks (interquartile range 22-26 weeks). A spontaneous unassisted vaginal delivery was achieved by the majority (n = 403, 99.0%). The most common maternal morbidities were transferred to the theater for manual removal of retained placental tissue (n = 65, 16.0%) and postpartum haemorrhage (PPH) (n = 45, 11.1%). Severe maternal morbidity occurred in six cases (1.3%) and included amniotic fluid embolism, cardiac arrest, major obstetric haemorrhage, uterine rupture and intensive care unit admission. There were no maternal deaths. CONCLUSIONS: The most common complications of MTOP for fetal anomaly ≥20 weeks' gestation were manual removal of placenta and PPH. Severe maternal morbidity affected 1 in 81 women.

Disparities between perceived and true outcomes of infants born at 23-25 weeks' gestation.

BACKGROUND: Decision-making for infants born at 23-25 weeks involves counselling parents about survival and major disability risks. Accurate information is needed for parents to make informed decisions about their baby's care. AIMS: To determine if perinatal clinicians had accurate perceptions of outcomes of infants born at 23-25 weeks' gestation, and if accuracy had changed over a decade. MATERIALS AND METHODS: A web-based survey was sent to midwives, nurses, neonatologists, and obstetricians working in tertiary and non-tertiary hospitals, and the neonatal retrieval service in the state of Victoria in 2020. A similar survey had been completed in 2010. Clinicians' estimates of survival and major neurodevelopmental disability rates were compared with true rates for actively managed infants overall, and by infant birthplace and gestational age, and professional workplace and discipline. Accuracy of outcomes was compared between eras. RESULTS: Overall, 165 surveys were received. Participants underestimated survival (absolute mean difference [%] -14.4%; [95% confidence interval (CI) -16.6 to -12.3]; P < 0.001) and overestimated major disability (absolute mean difference 32.7%; [95% CI 29.7 to 35.8]; P < 0.001) rates overall, and at each week of gestation, and were worse for outborn compared with inborn infants. Perceptions of clinicians in tertiary centres were similar to those of non-tertiary clinicians. Nurses/midwives were more pessimistic, and paediatricians were more optimistic. Clinicians' perceptions of outcome were less accurate in 2020 than in 2010. CONCLUSIONS: Most perinatal clinicians underestimate survival and overestimate major disability of infants born at 23-25 weeks' gestation, which may translate into overly pessimistic counselling of parents.

The addition of fetal scalp blood lactate measurement as an adjunct to cardiotocography to reduce caesarean sections during labour: The Flamingo randomised controlled trial.

BACKGROUND: Fetal scalp blood sampling for lactate measurement (FBSLM) is sometimes used to assist in identification of the need for expedited birth in the presence of an abnormal cardiotocograph (CTG). However, there is no randomised controlled trial evidence to support this. AIM: To determine whether adding FBSLM reduces the risk of birth by emergency caesarean section in labours complicated by an abnormal CTG, compared with CTG without FBS. MATERIAL AND METHODS: Labouring women at a tertiary maternity hospital in Melbourne, Australia with a singleton, cephalic presentation, at ≥37 weeks gestation with an abnormal CTG pattern were randomised to the intervention (n = 61), with intermittent FBSLM in addition to CTG monitoring, or control (CTG without FBS, n = 62). The primary outcome was rate of birth by caesarean section. Secondary outcomes included overall operative birth and fetal and neonatal safety endpoints. TRIAL REGISTRATION: ACTRN12611000172909. RESULTS: The smaller than anticipated sample was unable to demonstrate an effect from adding FBSLM to CTG monitoring on birth by caesarean section vs monitoring by CTG without FBS (25/61 and 28/62 respectively, P = 0.64, risk ratio 0.91, 95% confidence intervals 0.60-1.36). One newborn infant in the CTG group met the criteria for the composite neonatal outcome of death or serious outcome, neonatal encephalopathy, five-minute Apgar score < 4, neonatal resuscitation, admission to neonatal intensive care unit for 96 h or more. CONCLUSION: We were unable to provide robust evidence of the effectiveness of FBSLM to improve the specificity of the CTG in the assessment of fetal wellbeing.

Heart Disease and Pregnancy: The Need for a Twenty-First Century Approach to Care .

Pregnancy and childbirth present a specific challenge to the maternal cardiovascular system. Pre-existing cardiac diseases, or cardiac diseases that occur during pregnancy, are associated with a significant risk of morbidity and mortality for both mother and baby. In recent decades, cardiac disease has emerged as a leading cause of maternal death in most high income countries, including Australia and New Zealand. The burden of cardiac disease in pregnancy is likely to be growing due to an increase in adult survivors with congenital heart disease embarking on pregnancy coupled with demographic shifts in the age and cardiovascular risk factors of women giving birth and the persisting high incidence of acute rheumatic fever in First Nations women. There is widespread consensus that the best obstetric and neonatal outcomes in women with cardiac disease are delivered by a strategy of carefully coordinated multidisciplinary care. Australia and New Zealand currently lack nationally agreed strategies for clinical practice and service delivery for women with heart disease in pregnancy. This state-of-the-art review summarises some of the key issues faced in relation to prevention, diagnosis, treatment and health service delivery in this patient group and concludes with suggested priorities for policy and research.

Circulating mRNAs are differentially expressed in pregnancies with severe placental insufficiency and at high risk of stillbirth.

BACKGROUND: Fetuses affected by placental insufficiency do not receive adequate nutrients and oxygenation, become growth restricted and acidemic, and can demise. Preterm fetal growth restriction is a severe form of placental insufficiency with a high risk of stillbirth. We set out to identify maternal circulating mRNA transcripts that are differentially expressed in preterm pregnancies complicated by very severe placental insufficiency, in utero fetal acidemia, and are at very high risk of stillbirth. METHODS: We performed a cohort study across six hospitals in Australia and New Zealand, prospectively collecting blood from 128 pregnancies complicated by preterm fetal growth restriction (delivery < 34 weeks' gestation) and 42 controls. RNA-sequencing was done on all samples to discover circulating mRNAs associated with preterm fetal growth restriction and fetal acidemia in utero. We used RT-PCR to validate the associations between five lead candidate biomarkers of placental insufficiency in an independent cohort from Europe (46 with preterm fetal growth restriction) and in a third cohort of pregnancies ending in stillbirth. RESULTS: In the Australia and New Zealand cohort, we identified five mRNAs that were highly differentially expressed among pregnancies with preterm fetal growth restriction: NR4A2, EMP1, PGM5, SKIL, and UGT2B1. Combining three yielded an area under the receiver operative curve (AUC) of 0.95. Circulating NR4A2 and RCBTB2 in the maternal blood were dysregulated in the presence of fetal acidemia in utero. We validated the association between preterm fetal growth restriction and circulating EMP1, NR4A2, and PGM5 mRNA in a cohort from Europe. Combining EMP1 and PGM5 identified fetal growth restriction with an AUC of 0.92. Several of these genes were differentially expressed in the presence of ultrasound parameters that reflect placental insufficiency. Circulating NR4A2, EMP1, and RCBTB2 mRNA were differentially regulated in another cohort destined for stillbirth, compared to ongoing pregnancies. EMP1 mRNA appeared to have the most consistent association with placental insufficiency in all cohorts. CONCLUSIONS: Measuring circulating mRNA offers potential as a test to identify pregnancies with severe placental insufficiency and at very high risk of stillbirth. Circulating mRNA EMP1 may be promising as a biomarker of severe placental insufficiency.

The rhesus incompatible pregnancy and its consequences for affected fetuses and neonates.

Rhesus incompatibility in pregnancy may result in haemolytic disease of the fetus and newborn (HDFN). This review discusses the fetal, neonatal and long-term consequences of HDFN and its management. Untreated, the fetal and neonatal prognosis of HDFN is poor. Provision of intravascular intrauterine transfusion (IUT) in a dedicated referral centre significantly reduces perinatal loss. Early-onset, severe fetal anaemia carries a greater risk of adverse fetal and neonatal outcomes and is less amenable to treatment with IUT. Interventions to prevent and treat severe, early onset disease have been investigated, however evidence from randomised controlled trials is required. Neonatal consequences of Rhesus haemolytic disease include early and late postnatal anaemia, and hyperbilirubinaemia leading to bilirubin-induced neurological dysfunction. Neurodevelopmental impairment and adult cardiovascular disease are long-term complications that have been reported in association with severe fetal anaemia. Strategies to prevent fetal hydrops, and further research into the long-term impacts of fetal anaemia may improve health outcomes for adult survivors of HDFN.

Cervical length surveillance for predicting spontaneous preterm birth in women with uterine anomalies: A cohort study.

INTRODUCTION: Uterine anomalies occur in an estimated 5% of women and have been shown to confer a higher risk of spontaneous preterm birth (SPTB). A sonographically short cervix (<25 mm) is a risk indicator for SPTB, although its predictive utility has been little studied in this specific high-risk population. We aimed to assess the pregnancy outcomes and predictive ability of short cervix in a cohort of women with uterine anomalies attending a high-risk antenatal clinic. MATERIAL AND METHODS: This historical cohort study assessed all pregnancies in women with congenital uterine anomalies referred to the Preterm labor Clinic at the Royal Women's Hospital, Melbourne, Australia, between 2004 and 2013. Logistic and linear regressions and receiver-operator curves were used to examine associations between cervical length and preterm birth. RESULTS: SPTB (<37 weeks' gestation) occurred in 23% of the 86 pregnancies (n = 20); rates by subgroup were: unicornuate uterus 60% (n = 3/5), uterus didelphys 40% (n = 6/15), bicornuate uterus 18% (n = 9/51), septate uterus 13% (n = 2/15). Preterm prelabor rupture of membranes occurred in 55% of spontaneous preterm births and was not independently associated with the presence of cervical cerclage or ureaplasma urealyticum. Short cervical length was associated with SPTB in women with septate uterus. Short cervix at 24 weeks (not at 16 or 20 weeks) was moderately predictive of SPTB < 34 weeks. CONCLUSIONS: Women with uterine anomalies are at increased risk of spontaneous preterm birth, particularly those with unicornuate uterus or uterus didelphys, but cervical surveillance did not identify these cases. Short cervix may be associated with SPTB in women with septate uterus. Preterm prelabor rupture of membranes occurred in 55% of SPTB. More research is required into etiology to help determine appropriate monitoring and treatment.

Prediction of preterm pre-eclampsia at midpregnancy using a multivariable screening algorithm.

BACKGROUND: Competing risk models used for midpregnancy prediction of preterm pre-eclampsia have shown detection rates (DR) of 85%, at fixed false-positive rate (FPR) of 10%. The full algorithm used between 19+0 and 24+6  weeks includes maternal factors, mean arterial pressure (MAP), mean uterine artery pulsatility index (UtAPI), serum placental growth factor (PlGF) level in multiples of the median (MoM), and soluble Fms-like tyrosine kinase-1 (sFlt-1) level in MoM. AIMS: To assess performance of the Fetal Medicine Foundation (FMF) algorithm at midpregnancy to screen for preterm (<37 weeks) pre-eclampsia. The outcome measured was preterm pre-eclampsia. MATERIALS AND METHODS: This is a prospective study including singleton pregnancies at 19-22 weeks gestation. Maternal bloods were collected and analysed using three different immunoassay platforms. Maternal characteristics, medical history, MAP, mean UtAPI, serum PlGF MoM and serum sFlt-1 MoM were used for risk assessment. DR and FPR were calculated, and receiver operating characteristic curves produced. RESULTS: Five hundred and twelve patients were included. Incidence of preterm pre-eclampsia was 1.6%. Using predicted risk of pre-eclampsia of one in 60 or more and one in 100 or higher, as given by the FMF predictive algorithm, the combination with the best predictive performance for preterm pre-eclampsia included maternal factors, MAP, UtAPI and PlGF MoM, giving DRs of 100% and 100%, respectively, and FPRs of 9.3 for all platforms and 12.9-13.5, respectively. Addition of sFlt-1 to the algorithm did not appear to improve performance. sFlt-1 MoM and PlGF MoM values obtained on the different platforms performed very similarly. CONCLUSIONS: Second trimester combined screening for preterm pre-eclampsia by maternal history, MAP, mean UtAPI and PlGF MoM using the FMF algorithm performed very well in this patient population.

The Utility of the Congenital Pulmonary Airway Malformation-Volume Ratio in the Assessment of Fetal Echogenic Lung Lesions: A Systematic Review.

Although relatively uncommon, the incidence of fetal echogenic lung lesions - a heterogeneous group of anomalies that includes congenital pulmonary airway malformations (CPAM) and bronchopulmonary sequestrations (BPS) - has increased recently. Two decades ago, the CPAM-volume ratio (CVR) was first described as a tool to predict the development of hydrops, with this outcome found to be unlikely in fetuses with CVRs of ≤1.6 cm2. Since then, no clear international consensus has evolved as to the optimal CVR thresholds for the prediction of fetal/neonatal outcomes. This systematic review aimed to assess all original research studies that reported on the predictive utility of the CVR. Potentially relevant papers were identified through searching for citations of the paper that originally described the CVR, in addition to keyword searches of electronic databases. Fifty-two original research papers were included in the final review. Of these, 34 used the CVR for descriptive purposes only, 5 assessed the validity of established thresholds in different populations, and 13 proposed new thresholds. The evidence identified in this review would suggest that a threshold much lower than 1.6 cm2 is likely to be of greater utility in most populations for many outcomes of perinatal relevance. For neonatal outcomes (mostly respiratory compromise at birth), a CVR on the initial ultrasound scan ranging from 0.5 to 1.0 cm2 appears to have the greatest predictive value. Although a number of studies concurred that 1.6 cm2 was a useful threshold for the prediction of hydrops, many others were unable to assess this due to the rarity of this complication. For this reason, thresholds as low as 0.4 cm2 may be more useful for the prediction of a broader range of fetal concerns, including mediastinal shift and fluid collections. Further large-scale studies are required to determine the true utility of this well-established index.

How clinically important are non-D Rh antibodies?

INTRODUCTION: The advent of RhD immunoglobulin prophylaxis to prevent maternal RhD alloimmunization has reduced the incidence of this condition and its associated poor outcomes. Consequently, non-D Rh antibodies now account for a greater proportion of alloimmunized pregnancies. These antibodies have been the subject of comparatively little research. This study investigated the incidence and clinical outcome of pregnancies affected by non-D Rh alloimmunization at an Australian tertiary maternity service. MATERIAL AND METHODS: This was a retrospective study of all pregnancies with non-D Rh antibodies (namely anti-C, -E, -c, -e, -Cw as well as the compound antibodies anti-CD, -cE and -ce) managed at the Royal Women's Hospital, Victoria, Australia, from 2009 to 2013 inclusive. Information collected included maternal demographics, details of the antibodies, course of the pregnancy and neonatal outcomes. RESULTS: During the study period, 115 non-D Rh alloimmunized pregnancies were identified in 102 mothers. Forty-nine pregnancies reached the critical titer (> 16) from non-D Rh alone and 11 fetuses received intrauterine red blood cell transfusion. Labor was induced or cesarean section performed in 38 cases. Forty-three neonates were admitted to the special care nursery and 59 received phototherapy. Nine received treatment for anemia and 10 neonates received intravenous immunoglobulin. CONCLUSIONS: Non-D Rh alloimmunization is a relatively uncommon complication of pregnancy, occurring in only .33% of pregnancies in the study period. It can lead to significant fetal/neonatal morbidity (and may lead to mortality). The most severe outcomes (including perinatal deaths) were mostly associated with the compound antibodies anti-CD and anti-cE, or a non-D Rh antibody in conjunction with anti-D.

Optic nerve sonography and ophthalmic artery Doppler velocimetry in healthy pregnant women: an Australian cohort study.

PURPOSE: Maternal ocular sonography offers a window into cerebrovascular and intracranial pressure changes in pregnancy. This study aimed to determine the Doppler velocimetric variables of the ophthalmic artery, and the mean diameter of the optic nerve sheath (ONSD), in an Australian cohort of healthy pregnant women. METHODS: A prospective observational cohort study of healthy women with uncomplicated singleton pregnancies in the third trimester was undertaken in a tertiary maternity service. A single prenatal ultrasonographic examination was performed on all participants, with a postnatal examination performed on a subgroup with uncomplicated deliveries. RESULTS: Fifty women were examined at a mean gestation of 35 weeks. The mean ± SD Doppler variables in the ophthalmic artery were peak systolic velocity (PSV) 41.89 ± 13.13 cm/s, second peak velocity 20.63 ± 8.97 cm/s, end diastolic velocity 9.29 ± 5.13 cm/s, pulsatility index 1.97 ± 0.53, resistive index 0.78 ± 0.07, peak ratio (second peak velocity/PSV) 0.49 ± 0.12, while the mean ONSD was 4.34 ± 0.4 mm. None of these variables had a demonstrable relationship with gestation or mean arterial pressure (MAP), nor did the sheath diameter have a relationship with any of the Doppler variables. CONCLUSIONS: The ocular sonographic variables observed in this population are similar to those reported in other cohorts. No clear relationship could be identified in this cohort between ophthalmic artery Doppler variables and the ONSD, and between each of these variables and gestation or MAP.

Enoxaparin for the prevention of preeclampsia and intrauterine growth restriction in women with a history: a randomized trial.

BACKGROUND: Preeclampsia and small-for-gestational-age pregnancy are major causes of maternal and perinatal morbidity and mortality. Women with a previous pregnancy affected by these conditions are at an increased risk of recurrence in a future pregnancy. Past trials evaluating the effect of low-molecular-weight heparin for the prevention of recurrence of preeclampsia and small-for-gestational-age pregnancy have shown conflicting results with high levels of heterogeneity displayed when trials were compared. OBJECTIVE: We sought to assess the effectiveness of enoxaparin in addition to high-risk care for the prevention of preeclampsia and small-for-gestational-age pregnancy in women with a history of these conditions. STUDY DESIGN: This was an open-label randomized controlled trial in 5 tertiary care centers in 3 countries. Women with a viable singleton pregnancy were invited to participate between >6+0 and <16+0 weeks if deemed to be at high risk of preeclampsia and/or small for gestational age based on their obstetric history. Eligible participants were randomly assigned in a 1-to-1 ratio to standard high-risk care or standard high-risk care plus enoxaparin 40 mg (4000 IU) by subcutaneous injection daily from recruitment until 36+0 weeks or delivery, whichever occurred sooner. Standard high-risk care was defined as care coordinated by a high-risk antenatal clinic service, aspirin 100 mg daily until 36+0 weeks, and-for women with prior preeclampsia-calcium 1000-1500 mg daily until 36+0 weeks. In a subgroup of participants serum samples were taken at recruitment and at 20 and 30 weeks' gestation and later analyzed for soluble fms-like tyrosine kinase-1, soluble endoglin, endothelin-1, placental growth factor, and soluble vascular cell adhesion molecule 1. The primary outcome was a composite of preeclampsia and/or small-for-gestational-age <5th customized birthweight percentile. All data were analyzed on an intention-to-treat basis. The trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12609000699268). RESULTS: Between July 26, 2010, and Oct. 28, 2015, a total of 156 participants were enrolled and included in the analysis. In all, 149 participants were included in the outcome analysis (72 receiving standard high-risk care plus enoxaparin and 77 receiving standard high-risk care only). Seven women who miscarried <16 weeks' gestation were excluded. The majority of participants (151/156, 97%) received aspirin. The addition of enoxaparin had no effect on the rate of preeclampsia and/or small-for-gestational-age <5th customized birthweight percentile: enoxaparin 18/72 (25%) vs no enoxaparin 17/77 (22.1%) (odds ratio, 1.19; 95% confidence interval, 0.53-2.64). There was also no difference in any of the secondary outcome measures. Levels of soluble fms-like tyrosine kinase-1 and soluble endoglin increased among those who developed preeclampsia, but there was no difference in levels of these antiangiogenic factors (nor any of the other serum analytes measured) among those treated with enoxaparin compared to those receiving standard high-risk care only. CONCLUSION: The use of enoxaparin in addition to standard high-risk care does not reduce the risk of recurrence of preeclampsia and small-for-gestational-age infants in a subsequent pregnancy.

Chorionic villus sampling in the cell-free DNA aneuploidy screening era: careful selection criteria can maximise the clinical utility of screening and invasive testing.

OBJECTIVES: To quantify the impact of cell-free DNA (cfDNA) screening on chorionic villus sampling (CVS) test indications and outcomes in a tertiary maternity service. METHODS: Retrospective cohort study of all CVS procedures performed for any indication on singleton pregnancies at The Royal Women's Hospital, Melbourne, and at Women's Ultrasound Melbourne, Australia, between August 2008 and February 2015. Karyotypes were classified according to pathogenicity and detectability by standard cfDNA screening panels. RESULTS: A total of 2051 CVS procedures, 25 373 twelve-week scans and 2394 cfDNA tests were performed. The CVS rate per 12-week scan fell from 9.8 to 3.9% following introduction of cfDNA screening. The yield of pathogenic chromosomal anomalies per CVS increased from 12.9 to 25.2%, with 70% of pathogenic results now comprising T21, up from 52%. Sixteen (5.3%) of the pathogenic chromosomal abnormalities identified on CVS would not have been predicted by current cfDNA tests. CONCLUSIONS: There is an evolving tension between improved screening performance for common aneuploidies offered by cfDNA testing, and the increasing diagnostic utility of molecular karyotyping. However, the risk of not identifying pathogenic chromosomal abnormalities is low if cfDNA screening is offered in the absence of a structural fetal anomaly, increased nuchal translucency or relevant family history. © 2017 John Wiley & Sons, Ltd.

A review of the mechanisms and evidence for typical and atypical twinning.

The mechanisms responsible for twinning and disorders of twin gestations have been the subject of considerable interest by physicians and scientists, and cases of atypical twinning have called for a reexamination of the fundamental theories invoked to explain twin gestations. This article presents a review of the literature focusing on twinning and atypical twinning with an emphasis on the phenomena of chimeric twins, phenotypically discordant monozygotic twins, mirror-image twins, polar body twins, complete hydatidiform mole with a coexistent twin, vanishing twins, fetus papyraceus, fetus in fetu, superfetation, and superfecundation. The traditional models attributing monozygotic twinning to a fission event, and more recent models describing monozygotic twinning as a fusion event, are critically reviewed. Ethical restrictions on scientific experimentation with human embryos and the rarity of cases of atypical twinning have limited opportunities to elucidate the exact mechanisms by which these phenomena occur. Refinements in the modeling of early embryonic development in twin pregnancies may have significant clinical implications. The article includes a series of figures to illustrate the phenomena described.

Renal Interlobar Vein Impedance Index as a First-Trimester Marker Does Not Predict Hypertensive Disorders of Pregnancy.

OBJECTIVES: The purpose of this study was to examine whether the maternal renal interlobar vein impedance index as assessed by first-trimester sonography is able to predict the later development of hypertensive disorders of pregnancy. METHODS: Venous Doppler parameters of both maternal kidneys were studied in 214 pregnant women at gestational ages of 11 weeks to 13 weeks 6 days. Patients were classified according to outcomes related to hypertensive disorders. Detection rates and areas under receiver operating characteristic curves were determined for the maternal renal interlobar vein impedance index as a first-trimester predictor of preeclampsia and gestational hypertension. RESULTS: Among the 214 patients, 22 (10.3%) developed preeclampsia; 10 (4.7%) developed gestational hypertension; and 182 were unaffected by hypertensive disorders (controls; 85.0%). In the overall study population, there was no difference in the impedance index between the right (0.44; 95% confidence interval, 0.35-0.50) and left (0.43; 95% confidence interval, 0.35-0.53) sides (P = .86). The average impedance index did not differ among women destined to develop preeclampsia (0.46; 95% confidence interval, 0.38-0.57), gestational hypertension (0.39; 95% confidence interval, 0.33-0.46), or pregnancies uncomplicated by hypertensive disease (0.42; 95% confidence interval, 0.37-0.50; P = .15). Low detection rates and the area under the curve analysis demonstrated that the impedance index was not predictive of hypertensive disorders of pregnancy. CONCLUSIONS: The maternal renal interlobar vein impedance index should not be considered a first-trimester marker of hypertensive disorders of pregnancy.

Pre-Implantation Genetic Screening Techniques: Implications for Clinical Prenatal Diagnosis.

Chromosomal aneuploidy is responsible for a significant proportion of pregnancy failures, whether conceived naturally or through in vitro fertilization (IVF). In an effort to improve the success rate of IVF, screening embryos for aneuploidy - or pre-implantation genetic screening (PGS) - has been proposed as a means of ensuring only euploid embryos are selected for transfer. Early PGS approaches were based on fluorescence in situ hybridization testing, and have been shown not to improve live birth rates. Recent developments in genetic testing technologies - such as next-generation sequencing and quantitative polymerase chain reaction, coupled with embryo biopsy at the blastocyst stage - have shown promise in improving IVF outcomes, but they remain to be validated in adequately powered, prospective randomized trials. The extent to which IVF with PGS lowers the a priori risk of aneuploidy in ongoing pregnancies so conceived has been poorly described, rendering it difficult to incorporate the potential benefit of PGS into existing prenatal aneuploidy screening regimens such as cell-free DNA testing or conventional combined nuchal translucency and maternal biochemistry assessment. Further data on the sensitivity and specificity of various forms of molecular PGS testing would improve our understanding of the effectiveness and accuracy of these technologies. This, in addition to further research into methods of risk combination and assessment, would allow us to help our patients make better- informed decisions about whether or not to proceed with invasive diagnostic tests.

Protocol for a randomised controlled trial of fetal scalp blood lactate measurement to reduce caesarean sections during labour: the Flamingo trial [ACTRN12611000172909].

BACKGROUND: The rate of caesarean sections around the world is rising each year, reaching epidemic proportions. Although many caesarean sections are performed for concerns about fetal welfare on the basis of abnormal cardiotocography, the majority of babies are shown to be well at birth, meaning that the operation, with its inherent short and long term risks, could have been avoided without compromising the baby's health. Previously, fetal scalp blood sampling for pH estimation was performed in the context of an abnormal cardiotocograph, to improve the identification of babies in need of expedited delivery. This test has largely been replaced by lactate measurement, although its validity is yet to be established through a randomised controlled trial. This study aims to test the hypothesis that the performance of fetal scalp blood lactate measurement for women in labour with an abnormal cardiotocograph will reduce the rate of birth by caesarean section from 38 % to 25 % (a 35 % relative reduction). METHODS/DESIGN: Prospective unblinded randomised controlled trial conducted at a single tertiary perinatal centre. Women labouring with a singleton fetus in cephalic presentation at 37 or more weeks' gestation with ruptured membranes and with an abnormal cardiotocograph will be eligible. Participants will be randomised to one of two groups: fetal monitoring by cardiotocography alone, or cardiotocography augmented by fetal scalp blood lactate analysis. Decisions regarding the timing and mode of delivery will be made by the treating team, in accordance with hospital protocols. The primary study endpoint is caesarean section with secondary outcomes collected from maternal, fetal and neonatal clinical course and morbidities. A cost effectiveness analysis will also be performed. A sample size of 600 will provide 90 % power to detect the hypothesised difference in the proportion of women who give birth by caesarean section. DISCUSSION: This world-first trial is adequately powered to determine the impact of fetal scalp blood lactate measurement on rates of caesarean section. Preventing unnecessary caesarean sections will reduce the health and financial burdens associated with this operation, both in the index and any future pregnancies. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12611000172909.