Feasibility for non-invasive prenatal fetal blood group and platelet genotyping by massively parallel sequencing: A single test system for multiple atypical red cell, platelet and quality control markers.

Non-invasive prenatal tests (NIPT) to predict fetal red cell or platelet antigen status for alloimmunised women are provided for select antigens. This study reports on massively parallel sequencing (MPS) using a red cell and platelet probe panel targeting multiple nucleotide variants, plus individual identification single nucleotide polymorphisms (IISNPs). Maternal blood samples were provided from 33 alloimmunised cases, including seven with two red cell antibodies. Cell-free and genomic DNA was sequenced using targeted MPS and bioinformatically analysed using low-frequency variant detection. The resulting maternal genomic DNA allele frequency was subtracted from the cell-free DNA counterpart. Outcomes were matched against validated phenotyping/genotyping methods, where available. A 2.5% subtractive allele frequency threshold was set after comparing MPS predictions for K, RhC/c, RhE/e and Fya /Fyb against expected outcomes. This threshold was used for subsequent predictions, including HPA-15a, Jka /Jkb , Kpa /Kpb and Lua . MPS outcomes were 97.2% concordant with validated methods; one RhC case was discordantly negative and lacked IISNPs. IISNPs were informative for 30/33 cases as controls. NIPT MPS is feasible for fetal blood group genotyping and covers multiple blood groups and control targets in a single test. Noting caution for the Rh system, this has the potential to provide a personalised service for alloimmunised women.

Safety and Immunogenicity of an Investigational Respiratory Syncytial Virus Vaccine (RSVPreF3) in Mothers and Their Infants: A Phase 2 Randomized Trial.

BACKGROUND: In a phase 1/2 study, a maternal respiratory syncytial virus vaccine candidate (RSVPreF3) demonstrated an acceptable safety profile and efficiently increased RSV-specific humoral immune responses in non-pregnant women. METHODS: In this phase 2 observer-blind, placebo-controlled, randomized clinical trial (NCT04126213), the safety of RSVPreF3 (60 or 120 µg), administered during late second or third trimester, was evaluated in 213 18- to 40-year-old healthy pregnant women through 6 months postdelivery and their offspring through infancy; immunogenicity was evaluated through day 43 postdelivery and day 181 postbirth, respectively. RESULTS: RSVPreF3 was well tolerated. No pregnancy-related or neonatal adverse events of special interest were considered vaccine/placebo related. In the 60 and 120 µg RSVPreF3 groups: (1) neutralizing antibody (nAb) titers in mothers increased 12.7- and 14.9-fold against RSV-A and 10.6- and 13.2-fold against RSV-B, respectively, 1 month postvaccination and remained 8.9-10.0-fold over prevaccination at day 43 postdelivery; (2) nAb titers were consistently higher compared to placebo recipients; (3) placental transfer ratios for anti-RSVPreF3 antibodies at birth were 1.62 and 1.90, respectively, and (4) nAb levels in infants were highest at birth and declined through day 181 postbirth. CONCLUSIONS: RSVPreF3 maternal vaccination had an acceptable safety risk profile and induced robust RSV-specific immune responses with successful antibody transfer to their newborns. CLINICAL TRIALS REGISTRATION: NCT04126213.

WHAT IS THE CONTEXT?: Infants, especially those less than 6 months of age, are at increased risk of lung infection caused by respiratory syncytial virus (RSV). However, this risk could be reduced with maternal vaccination against RSV during pregnancy. A previous clinical trial found that a vaccine candidate (named RSVPreF3) was well tolerated when given to non-pregnant women. WHAT IS NEW?: In pregnant women, RSVPreF3 was also well tolerated. Occurrence of unsolicited adverse events was similar between vaccine and placebo recipients. None of the serious adverse events or events of interest for pregnant women or newborns were considered related to the study intervention. One month after vaccination, mothers who received RSVPreF3 had 11­15 times higher levels of antibodies against RSV than before vaccination. These antibody levels remained similar until 43 days after delivery. In the infants born to mothers vaccinated during pregnancy with RSVPreF3, antibody levels were highest at birth, when levels were higher than in their mothers, and declined through day 181 postbirth. WHAT IS THE IMPACT?: RSVPreF3 had an acceptable safety risk profile in pregnant women and their babies. This vaccine induced potent immune responses against RSV, with maternal antibodies transferred to infants of the vaccinated mothers.

My Baby's Movements: An assessment of the effectiveness of the My Baby's Movements phone program in reducing late-gestation stillbirth rates.

BACKGROUND: Delayed reporting of decreased fetal movements (DFM) could represent a missed opportunity to prevent stillbirth. Mobile phone applications (apps) have the potential to improve maternal awareness and reporting of DFM and contribute to stillbirth prevention. AIMS: To evaluate the effectiveness of the My Baby's Movements (MBM) app on late-gestation stillbirth rates. MATERIALS AND METHODS: The MBM trial evaluated a multifaceted fetal movements awareness package across 26 maternity services in Australia and New Zealand between 2016 and 2019. In this secondary analysis, generalised linear mixed models were used to compare rates of late-gestation stillbirth, obstetric interventions, and neonatal outcomes between app users and non-app users including calendar time, cluster, primiparity and other potential confounders as fixed effects, and hospital as a random effect. RESULTS: Of 140 052 women included, app users comprised 9.8% (n = 13 780). The stillbirth rate was not significantly lower among app users (1.67/1000 vs 2.29/1000) (adjusted odds ratio (aOR) 0.79; 95% CI 0.51-1.23). App users were less likely to have a preterm birth (aOR 0.81; 0.75-0.88) or a composite adverse neonatal outcome (aOR 0.87; 0.81-0.93); however, they had higher rates of induction of labour (IOL) (aOR 1.27; 1.22-1.32) and early term birth (aOR 1.08; 1.04-1.12). CONCLUSIONS: The MBM app had low uptake and its use was not associated with stillbirth rates but was associated with some neonatal benefit, and higher rates of IOL and early term birth. Use and acceptability of tools designed to promote fetal movement awareness is an important knowledge gap. The implications of increased IOL and early term births warrant consideration in future studies.

Decreased fetal movements-the utility of ultrasound to identify infants at risk and prevent stillbirth is poor.

BACKGROUND: Despite a paucity of evidence, it is widely accepted that a perceived reduction in fetal movements is associated with an increased risk of stillbirth and poor obstetrical outcome. Consequently, many international guidelines recommend urgent ultrasound assessment of fetal well-being in women presenting with decreased fetal movements. OBJECTIVE: This study aimed to compare rates of abnormal ultrasound findings reflective of fetal compromise between women presenting with decreased fetal movements and gestation-matched controls in the third trimester. STUDY DESIGN: This was a retrospective cohort study performed at the Mater Mothers' Hospital in Brisbane between 2017 and 2020. We undertook propensity score matching analysis comparing abnormal ultrasound parameters in women with singleton, nonanomalous pregnancies presenting with decreased fetal movements after 28 weeks' gestation. The primary outcome was a composite of any abnormal scan parameter: umbilical artery pulsatility index >95th centile, middle cerebral artery pulsatility index <5th centile, cerebroplacental ratio <10th centile, estimated fetal weight <10th centile for gestation, middle cerebral artery peak systolic velocity >1.5 multiples of the median, or deepest vertical pocket of amniotic fluid <2 or >8 cm. RESULTS: After propensity score matching, the study cohort comprised 1466 cases and 2207 controls. The rate of the primary composite outcome was not significantly different between the 2 cohorts (20.2% vs 21.3%; P=.42). There were 30 new cases of small-for-gestational-age detected in the decreased fetal movements cohort, giving a number needed to scan of 48 in the decreased fetal movements group to detect 1 case of small-for-gestational-age. However, the frequency of the composite outcome was higher (13.0% vs 5.4%) at the final scan before birth in women with multiple decreased fetal movement presentations. Despite this, there was no significant difference in clinical outcomes between the 2 cohorts. CONCLUSION: Ultrasound abnormalities are not increased in women with decreased fetal movements compared with controls.

The role of non-invasive prenatal testing (NIPT) for fetal blood group typing in Australia.

Maternal alloimmunisation against red blood cell antigens can cause haemolytic disease of the fetus and newborn (HDFN). Although most frequently caused by anti-D, since the implementation of rhesus D (RhD) immunoglobulin prophylaxis, other alloantibodies have become more prevalent in HDFN. Recent advances in non-invasive prenatal testing (NIPT) have allowed early prediction of HDFN risk in alloimmunised pregnancies and allow clinicians to focus health resources on those pregnancies that require intervention. This article aims to provide updates on the current status of NIPT in Australia as both a diagnostic and screening tool in pregnancy.

The randomized Tracheal Occlusion To Accelerate Lung growth (TOTAL)-trials on fetal surgery for congenital diaphragmatic hernia: reanalysis using pooled data.

BACKGROUND: Two randomized controlled trials compared the neonatal and infant outcomes after fetoscopic endoluminal tracheal occlusion with expectant prenatal management in fetuses with severe and moderate isolated congenital diaphragmatic hernia, respectively. Fetoscopic endoluminal tracheal occlusion was carried out at 27+0 to 29+6 weeks' gestation (referred to as "early") for severe and at 30+0 to 31+6 weeks ("late") for moderate hypoplasia. The reported absolute increase in the survival to discharge was 13% (95% confidence interval, -1 to 28; P=.059) and 25% (95% confidence interval, 6-46; P=.0091) for moderate and severe hypoplasia. OBJECTIVE: Data from the 2 trials were pooled to study the heterogeneity of the treatment effect by observed over expected lung-to-head ratio and explore the effect of gestational age at balloon insertion. STUDY DESIGN: Individual participant data from the 2 trials were reanalyzed. Women were assessed between 2008 and 2020 at 14 experienced fetoscopic endoluminal tracheal occlusion centers and were randomized in a 1:1 ratio to either expectant management or fetoscopic endoluminal tracheal occlusion. All received standardized postnatal management. The combined data involved 287 patients (196 with moderate hypoplasia and 91 with severe hypoplasia). The primary endpoint was survival to discharge from the neonatal intensive care unit. The secondary endpoints were survival to 6 months of age, survival to 6 months without oxygen supplementation, and gestational age at live birth. Penalized regression was used with the following covariates: intervention (fetoscopic endoluminal tracheal occlusion vs expectant), early balloon insertion (yes vs no), observed over expected lung-to-head ratio, liver herniation (yes vs no), and trial (severe vs moderate). The interaction between intervention and the observed over expected lung-to-head ratio was evaluated to study treatment effect heterogeneity. RESULTS: For survival to discharge, the adjusted odds ratio of fetoscopic endoluminal tracheal occlusion was 1.78 (95% confidence interval, 1.05-3.01; P=.031). The additional effect of early balloon insertion was highly uncertain (adjusted odds ratio, 1.53; 95% confidence interval, 0.60-3.91; P=.370). When combining these 2 effects, the adjusted odds ratio of fetoscopic endoluminal tracheal occlusion with early balloon insertion was 2.73 (95% confidence interval, 1.15-6.49). The results for survival to 6 months and survival to 6 months without oxygen dependence were comparable. The gestational age at delivery was on average 1.7 weeks earlier (95% confidence interval, 1.1-2.3) following fetoscopic endoluminal tracheal occlusion with late insertion and 3.2 weeks earlier (95% confidence interval, 2.3-4.1) following fetoscopic endoluminal tracheal occlusion with early insertion compared with expectant management. There was no evidence that the effect of fetoscopic endoluminal tracheal occlusion depended on the observed over expected lung-to-head ratio for any of the endpoints. CONCLUSION: This analysis suggests that fetoscopic endoluminal tracheal occlusion increases survival for both moderate and severe lung hypoplasia. The difference between the results for the Tracheal Occlusion To Accelerate Lung growth trials, when considered apart, may be because of the difference in the time point of balloon insertion. However, the effect of the time point of balloon insertion could not be robustly assessed because of a small sample size and the confounding effect of disease severity. Fetoscopic endoluminal tracheal occlusion with early balloon insertion in particular strongly increases the risk for preterm delivery.

Management of Fetal Supraventricular Tachycardia: Case Series from a Tertiary Perinatal Cardiac Center.

BACKGROUND: Fetal supraventricular tachycardia is a relatively uncommon cardiac rhythm abnormality which is often associated with adverse perinatal outcomes if untreated. Although there are several treatment modalities and protocols in use globally, there is no consensus as to the most effective antiarrhythmic to manage this condition. AIM: This study aimed to evaluate perinatal outcomes following prenatal maternal therapy for fetal supraventricular tachycardia. MATERIALS AND METHODS: This was a 20-year retrospective cohort study. Institutional records were reviewed for antenatal therapy choice and maternal and fetal outcomes. RESULTS: Sixty-nine cases met diagnostic criteria for fetal SVT, of which 56 (81%) received maternal antiarrhythmic therapy. Digoxin was the most common, but least effective, first-line therapy in 28 patients, achieving successful rate reversion in 35.7%. Thirty-one patients (55%) required second-line therapy, and this was most successful with digoxin and flecainide polytherapy achieving rate reversion in 17 of 18 cases (94.5%) at a median of 3 days (1.5-7). Hydrops was present in 23 (33%) cases at initial presentation, 16 of which achieved rate reversion. There was minimal difference in treatment efficacy comparing single- or multiple-agent treatment in the setting of hydrops (50% vs. 42.8%). Side effects occurred in 14/56 treated patients (25%) but were severe in only 8 (14.3%) women, most commonly with digoxin and flecainide polytherapy (6 of 8 cases). There were 3 (4%) fetal deaths amongst the study cohort. CONCLUSIONS: Digoxin and flecainide polytherapy were well tolerated and successfully achieved rhythm and rate control in fetuses with prenatally diagnosed supraventricular tachycardia. The presence of hydrops was a poor prognostic feature.

Randomized Trial of Fetal Surgery for Moderate Left Diaphragmatic Hernia.

BACKGROUND: Fetoscopic endoluminal tracheal occlusion (FETO) has been associated with increased postnatal survival among infants with severe pulmonary hypoplasia due to isolated congenital diaphragmatic hernia on the left side, but data are lacking to inform its effects in infants with moderate disease. METHODS: In this open-label trial conducted at many centers with experience in FETO and other types of prenatal surgery, we randomly assigned, in a 1:1 ratio, women carrying singleton fetuses with a moderate isolated congenital diaphragmatic hernia on the left side to FETO at 30 to 32 weeks of gestation or expectant care. Both treatments were followed by standardized postnatal care. The primary outcomes were infant survival to discharge from a neonatal intensive care unit (NICU) and survival without oxygen supplementation at 6 months of age. RESULTS: In an intention-to-treat analysis involving 196 women, 62 of 98 infants in the FETO group (63%) and 49 of 98 infants in the expectant care group (50%) survived to discharge (relative risk , 1.27; 95% confidence interval [CI], 0.99 to 1.63; two-sided P = 0.06). At 6 months of age, 53 of 98 infants (54%) in the FETO group and 43 of 98 infants (44%) in the expectant care group were alive without oxygen supplementation (relative risk, 1.23; 95% CI, 0.93 to 1.65). The incidence of preterm, prelabor rupture of membranes was higher among women in the FETO group than among those in the expectant care group (44% vs. 12%; relative risk, 3.79; 95% CI, 2.13 to 6.91), as was the incidence of preterm birth (64% vs. 22%, respectively; relative risk, 2.86; 95% CI, 1.94 to 4.34), but FETO was not associated with any other serious maternal complications. There were two spontaneous fetal deaths (one in each group) without obvious cause and one neonatal death that was associated with balloon removal. CONCLUSIONS: This trial involving fetuses with moderate congenital diaphragmatic hernia on the left side did not show a significant benefit of FETO performed at 30 to 32 weeks of gestation over expectant care with respect to survival to discharge or the need for oxygen supplementation at 6 months. FETO increased the risks of preterm, prelabor rupture of membranes and preterm birth. (Funded by the European Commission and others; TOTAL ClinicalTrials.gov number, NCT00763737.).

Prospective cohort study: Causes of stillbirth in Australia 2013-2018.

BACKGROUND: Stillbirth is a major public health problem that is slow to improve in Australia. Understanding the causes of stillbirth through appropriate investigation is the cornerstone of prevention and important for parents to understand why their baby died. AIM: The aim of this study is to assess compliance with the Perinatal Society of Australia and New Zealand (PSANZ) Perinatal Mortality Clinical Practice Guidelines (2009) for stillbirths. METHODS: This is a prospective multi-centred cohort study of stillbirths at participating hospitals (2013-2018). Data were recorded into a purpose-built database. The frequency of the recommended core investigations was calculated, and χ2 test was performed for subgroup analyses by gestational age groups and timing of fetal death. A 70% compliance threshold was defined for investigations. The cause of death categories was provided according to PSANZ Perinatal Death Classification. RESULTS: Among 697 reported total stillbirths, 562 (81%) were antepartum, and 101 (15%) were intrapartum. The most common cause of death categories were 'congenital abnormality' (12.5%), 'specific perinatal conditions' (12.2%) and 'unexplained antepartum death' (29%). According to 2009 guidelines, there were no stillbirths where all recommended investigations were performed (including or excluding autopsy). A compliance of 70% was observed for comprehensive history (82%), full blood count (94%), cytomegalovirus (71%), toxoplasmosis (70%), renal function (75%), liver function (79%), external examination (86%), post-mortem examination (84%) and placental histopathology (92%). The overall autopsy rate was 52%. CONCLUSIONS: Compliance with recommended investigations for stillbirth was suboptimal, and many stillbirths remain unexplained. Education on the value of investigations for stillbirth is needed. Future studies should focus on understanding the yield and value of investigations and service delivery gaps that impact compliance.

Spontaneous twin anemia polycythemia sequence: diagnosis, management, and outcome in an international cohort of 249 cases.

BACKGROUND: Twin anemia polycythemia sequence is a chronic form of unbalanced fetofetal transfusion through minuscule placental anastomoses in monochorionic twins, leading to anemia in the donor and polycythemia in the recipient. Owing to the low incidence of twin anemia polycythemia sequence, data on diagnosis, management, and outcome are limited. OBJECTIVE: This study aimed to investigate the diagnosis, management, and outcome in a large international cohort of spontaneous twin anemia polycythemia sequence. STUDY DESIGN: Data from the international twin anemia polycythemia sequence registry, retrospectively collected between 2014 and 2019, were used for this study. A total of 17 fetal therapy centers contributed to the data collection. The primary outcomes were perinatal mortality and severe neonatal morbidity. Secondary outcomes included a risk factor analysis for perinatal mortality and severe neonatal morbidity. RESULTS: A total of 249 cases of spontaneous twin anemia polycythemia sequence were included in this study, 219 (88%) of which were diagnosed antenatally and 30 (12%) postnatally. Twin anemia polycythemia sequence was diagnosed antenatally at a median gestational age of 23.7 weeks (interquartile range, 9.7-28.8; range, 15.1-35.3). Antenatal management included laser surgery in 39% (86 of 219), expectant management in 23% (51 of 219), delivery in 16% (34 of 219), intrauterine transfusion (with partial exchange transfusion) in 12% (26 of 219), selective feticide in 8% (18 of 219), and termination of pregnancy in 1% (3 of 219) of cases. Perinatal mortality rate was 15% (72 of 493) for the total group, 22% (54 of 243) for donors, and 7% (18 of 242) for recipients (P<.001). Severe neonatal morbidity occurred in 33% (141 of 432) of twins with twin anemia polycythemia sequence and was similar for donors (32%; 63 of 196) and recipients (33%; 75 of 228) (P=.628). Independent risk factors for spontaneous perinatal mortality were donor status (odds ratio, 3.8; 95% confidence interval, 1.9-7.5; P<.001), antenatal twin anemia polycythemia sequence stage (odds ratio, 6.3; 95% confidence interval, 1.4-27.8; P=.016 [stage 2]; odds ratio, 9.6; 95% confidence interval, 2.1-45.5; P=.005 [stage 3]; odds ratio, 20.9; 95% confidence interval, 3.0-146.4; P=.002 [stage 4]), and gestational age at birth (odds ratio, 0.8; 95% confidence interval, 0.7-0.9; P=.001). Independent risk factors for severe neonatal morbidity were antenatal twin anemia polycythemia sequence stage 4 (odds ratio, 7.9; 95% confidence interval, 1.4-43.3; P=.018) and gestational age at birth (odds ratio, 1.7; 95% confidence interval, 1.5-2.1, P<.001). CONCLUSION: Spontaneous twin anemia polycythemia sequence can develop at any time in pregnancy from the beginning of the second trimester to the end of the third trimester. Management for twin anemia polycythemia sequence varies considerably, with laser surgery being the most frequent intervention. Perinatal mortality and severe neonatal morbidity were high, the former especially so in the donor twins.

Non-invasive prenatal testing for management of haemolytic disease of the fetus and newborn induced by maternal alloimmunisation.

Anti-D immunoglobulin prophylaxis reduces the risk of RhD negative women becoming alloimmunised to the RhD antigen and is a major preventative strategy in reducing the burden of haemolytic disease of the fetus and newborn (HDFN). HDFN also arises from other maternal red cell antibodies, with the most clinically significant, after anti-D, being anti-K, anti-c and anti-E. Among the 39 human blood group systems advanced genomic technologies are still revealing novel or rare antigens involved in maternal alloimmunisation. Where clinically significant maternal antibodies are detected in pregnancy, non-invasive prenatal testing (NIPT) of cell-free fetal DNA provides a safe way to assess the fetal blood group antigen status. This provides information as to the risk for HDFN and thus guides management strategies. In many countries, NIPT fetal RHD genotyping as a diagnostic test using real-time PCR has already been integrated into routine clinical care for the management of women with allo-anti-D to assess the risk for HDFN. In addition, screening programs have been established to provide antenatal assessment of the fetal RHD genotype in non-alloimmunised RhD negative pregnant women to target anti-D prophylaxis to those predicted to be carrying an RhD positive baby. Both diagnostic and screening assays exhibit high accuracy (over 99 %). NIPT fetal genotyping for atypical (other than RhD) blood group antigens presents more challenges as most arise from a single nucleotide variant. Recent studies show potential for genomic and digital technologies to provide a personalised medicine approach with NIPT to assess fetal blood group status for women with other (non-D) red cell antibodies to manage the risk for HDFN.

Post-Laser Twin Anemia Polycythemia Sequence: Diagnosis, Management, and Outcome in an International Cohort of 164 Cases.

The aim of this study was to investigate the management and outcome in the post-laser twin anemia polycythemia sequence (TAPS). Data of the international TAPS Registry, collected between 2014 and 2019, were used for this study. The primary outcomes were perinatal mortality and severe neonatal morbidity. Secondary outcomes included a risk factor analysis for perinatal mortality and severe neonatal morbidity. A total of 164 post-laser TAPS pregnancies were included, of which 92% (151/164) were diagnosed antenatally and 8% (13/164) postnatally. The median number of days between laser for TTTS and detection of TAPS was 14 (IQR: 7-28, range: 1-119). Antenatal management included expectant management in 43% (62/151), intrauterine transfusion with or without partial exchange transfusion in 29% (44/151), repeated laser surgery in 15% (24/151), selective feticide in 7% (11/151), delivery in 6% (9/151), and termination of pregnancy in 1% (1/151). The median gestational age (GA) at birth was 31.7 weeks (IQR: 28.6-33.7; range: 19.0-41.3). The perinatal mortality rate was 25% (83/327) for the total group, 37% (61/164) for donors, and 14% (22/163) for recipients (p < 0.001). Severe neonatal morbidity was detected in 40% (105/263) of the cohort and was similar for donors (43%; 51/118) and recipients (37%; 54/145), p = 0.568. Independent risk factors for spontaneous perinatal mortality were antenatal TAPS Stage 4 (OR = 3.4, 95%CI 1.4-26.0, p = 0.015), TAPS donor status (OR = 4.2, 95%CI 2.1-8.3, p < 0.001), and GA at birth (OR = 0.8, 95%CI 0.7-0.9, p = 0.001). Severe neonatal morbidity was significantly associated with GA at birth (OR = 1.5, 95%CI 1.3-1.7, p < 0.001). In conclusion, post-laser TAPS most often occurs within one month after laser for TTTS, but may develop up to 17 weeks after initial surgery. Management is mostly expectant, but varies greatly, highlighting the lack of consensus on the optimal treatment and heterogeneity of the condition. Perinatal outcome is poor, particularly due to the high rate of perinatal mortality in donor twins.

Interventions for investigating and identifying the causes of stillbirth.

BACKGROUND: Identification of the causes of stillbirth is critical to the primary prevention of stillbirth and to the provision of optimal care in subsequent pregnancies. A wide variety of investigations are available, but there is currently no consensus on the optimal approach. Given their cost and potential to add further emotional burden to parents, there is a need to systematically assess the effect of these interventions on outcomes for parents, including psychosocial outcomes, economic costs, and on rates of diagnosis of the causes of stillbirth. OBJECTIVES: To assess the effect of different tests, protocols or guidelines for investigating and identifying the causes of stillbirth on outcomes for parents, including psychosocial outcomes, economic costs, and rates of diagnosis of the causes of stillbirth. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (31 August 2017), ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) (15 May 2017). SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs), quasi-RCTs, and cluster-RCTs. We planned to include studies published as abstract only, provided there was sufficient information to allow us to assess study eligibility. We planned to exclude cross-over trials.Participants included parents (including mothers, fathers, and partners) who had experienced a stillbirth of 20 weeks' gestation or greater.This review focused on interventions for investigating and identifying the causes of stillbirth. Such interventions are likely to be diverse, but could include:* review of maternal and family history, and current pregnancy and birth history;* clinical history of present illness;* maternal investigations (such as ultrasound, amniocentesis, antibody screening, etc.);* examination of the stillborn baby (including full autopsy, partial autopsy or noninvasive components, such as magnetic resonance imaging (MRI), computerised tomography (CT) scanning, and radiography);* umbilical cord examination;* placental examination including histopathology (microscopic examination of placental tissue); and* verbal autopsy (interviews with care providers and support people to ascertain causes, without examination of the baby).We planned to include trials assessing any test, protocol or guideline (or combinations of tests/protocols/guidelines) for investigating the causes of stillbirth, compared with the absence of a test, protocol or guideline, or usual care (further details are presented in the Background, see Description of the intervention).We also planned to include trials comparing any test, protocol or guideline (or combinations of tests/protocols/guidelines) for investigating the causes of stillbirth with another, for example, the use of a limited investigation protocol compared with a comprehensive investigation protocol. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility independently. MAIN RESULTS: We excluded five studies that were not RCTs. There were no eligible trials for inclusion in this review. AUTHORS' CONCLUSIONS: There is currently a lack of RCT evidence regarding the effectiveness of interventions for investigating and identifying the causes of stillbirth. Seeking to determine the causes of stillbirth is an essential component of quality maternity care, but it remains unclear what impact these interventions have on the psychosocial outcomes of parents and families, the rates of diagnosis of the causes of stillbirth, and the care and management of subsequent pregnancies following stillbirth. Due to the absence of trials, this review is unable to inform clinical practice regarding the investigation of stillbirths, and the specific investigations that would determine the causes.Future RCTs addressing this research question would be beneficial, but the settings in which the trials take place, and their design, need to be given careful consideration. Trials need to be conducted with the utmost care and consideration for the needs, concerns, and values of parents and families. Assessment of longer-term psychosocial variables, economic costs to health services, and effects on subsequent pregnancy care and outcomes should also be considered in any future trials.

Fetoscopic endoluminal tracheal occlusion and reestablishment of fetal airways for congenital diaphragmatic hernia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a congenital anomaly with high mortality and morbidity mainly due to pulmonary hypoplasia and hypertension. Temporary fetal tracheal occlusion to promote prenatal lung growth may improve survival. Entrapment of lung fluid stretches the airways, leading to lung growth. METHODS: Fetal endoluminal tracheal occlusion (FETO) is performed by percutaneous sono-endoscopic insertion of a balloon developed for interventional radiology. Reversal of the occlusion to induce lung maturation can be performed by fetoscopy, transabdominal puncture, tracheoscopy, or by postnatal removal if all else fails. RESULTS: FETO and balloon removal have been shown safe in experienced hands. This paper deals with the technical aspects of balloon insertion and removal. While FETO is invasive, it has minimal maternal risks yet can cause preterm birth potentially offsetting its beneficial effects. CONCLUSION: For left-sided severe and moderate CDH, the procedure is considered investigational and is currently being evaluated in a global randomized clinical trial (https://www.totaltrial.eu/). The procedure can be clinically offered to fetuses with severe right-sided CDH.

Care of pregnant women with decreased fetal movements: Update of a clinical practice guideline for Australia and New Zealand.

The National Health and Medical Research Council (NHMRC) Centre of Research Excellence in Stillbirth and the Perinatal Society of Australia and New Zealand (PSANZ) have recently partnered in updating an important clinical practice guideline, Care of pregnant women with decreased fetal movements. This guideline offers 12 recommendations and a suggested care pathway, with the aim to improve the quality of care for women reporting decreased fetal movements through an evidence-based approach. Adoption of the guideline by clinicians and maternity hospitals could result in earlier identification of higher-risk pregnancies, improved perinatal health outcomes for women and their babies, and reduced stillbirth rates.

Application of Whole Genome Sequencing Technology in the Investigation of Genetic Causes of Fetal, Perinatal, and Early Infant Death.

Death in the fetal, perinatal, and early infant age-group has a multitude of causes, a proportion of which is presumed to be genetic. Defining a specific genetic aberration leading to the death is problematic at this young age, due to limited phenotype-genotype correlation inherent in the underdeveloped phenotype, the inability to assess certain phenotypic traits after death, and the problems of dealing with rare disorders. In this study, our aim was to increase the yield of identification of a defined genetic cause of an early death. Therefore, we employed whole genome sequencing and bioinformatic filtering techniques as a comprehensive, unbiased genetic investigation into 16 fetal, perinatal, and early infant deaths, which had undergone a full autopsy. A likely genetic cause was identified in two cases (in genes; COL2A1 and RYR1) and a speculative genetic cause in a further six cases (in genes: ARHGAP35, BBS7, CASZ1, CRIM1, DHCR7, HADHB, HAPLN3, HSPG2, MYO18B, and SRGAP2). This investigation indicates that whole genome sequencing is a significantly enabling technology when determining genetic causes of early death.