Development and validation of prediction models for fetal growth restriction and birthweight: an individual participant data meta-analysis.

Background: Fetal growth restriction is associated with perinatal morbidity and mortality. Early identification of women having at-risk fetuses can reduce perinatal adverse outcomes. Objectives: To assess the predictive performance of existing models predicting fetal growth restriction and birthweight, and if needed, to develop and validate new multivariable models using individual participant data. Design: Individual participant data meta-analyses of cohorts in International Prediction of Pregnancy Complications network, decision curve analysis and health economics analysis. Participants: Pregnant women at booking. External validation of existing models (9 cohorts, 441,415 pregnancies); International Prediction of Pregnancy Complications model development and validation (4 cohorts, 237,228 pregnancies). Predictors: Maternal clinical characteristics, biochemical and ultrasound markers. Primary outcomes: fetal growth restriction defined as birthweight <10th centile adjusted for gestational age and with stillbirth, neonatal death or delivery before 32 weeks' gestation birthweight. Analysis: First, we externally validated existing models using individual participant data meta-analysis. If needed, we developed and validated new International Prediction of Pregnancy Complications models using random-intercept regression models with backward elimination for variable selection and undertook internal-external cross-validation. We estimated the study-specific performance (c-statistic, calibration slope, calibration-in-the-large) for each model and pooled using random-effects meta-analysis. Heterogeneity was quantified using τ2 and 95% prediction intervals. We assessed the clinical utility of the fetal growth restriction model using decision curve analysis, and health economics analysis based on National Institute for Health and Care Excellence 2008 model. Results: Of the 119 published models, one birthweight model (Poon) could be validated. None reported fetal growth restriction using our definition. Across all cohorts, the Poon model had good summary calibration slope of 0.93 (95% confidence interval 0.90 to 0.96) with slight overfitting, and underpredicted birthweight by 90.4 g on average (95% confidence interval 37.9 g to 142.9 g). The newly developed International Prediction of Pregnancy Complications-fetal growth restriction model included maternal age, height, parity, smoking status, ethnicity, and any history of hypertension, pre-eclampsia, previous stillbirth or small for gestational age baby and gestational age at delivery. This allowed predictions conditional on a range of assumed gestational ages at delivery. The pooled apparent c-statistic and calibration were 0.96 (95% confidence interval 0.51 to 1.0), and 0.95 (95% confidence interval 0.67 to 1.23), respectively. The model showed positive net benefit for predicted probability thresholds between 1% and 90%. In addition to the predictors in the International Prediction of Pregnancy Complications-fetal growth restriction model, the International Prediction of Pregnancy Complications-birthweight model included maternal weight, history of diabetes and mode of conception. Average calibration slope across cohorts in the internal-external cross-validation was 1.00 (95% confidence interval 0.78 to 1.23) with no evidence of overfitting. Birthweight was underestimated by 9.7 g on average (95% confidence interval -154.3 g to 173.8 g). Limitations: We could not externally validate most of the published models due to variations in the definitions of outcomes. Internal-external cross-validation of our International Prediction of Pregnancy Complications-fetal growth restriction model was limited by the paucity of events in the included cohorts. The economic evaluation using the published National Institute for Health and Care Excellence 2008 model may not reflect current practice, and full economic evaluation was not possible due to paucity of data. Future work: International Prediction of Pregnancy Complications models' performance needs to be assessed in routine practice, and their impact on decision-making and clinical outcomes needs evaluation. Conclusion: The International Prediction of Pregnancy Complications-fetal growth restriction and International Prediction of Pregnancy Complications-birthweight models accurately predict fetal growth restriction and birthweight for various assumed gestational ages at delivery. These can be used to stratify the risk status at booking, plan monitoring and management. Study registration: This study is registered as PROSPERO CRD42019135045. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/148/07) and is published in full in Health Technology Assessment; Vol. 28, No. 14. See the NIHR Funding and Awards website for further award information.

One in ten babies is born small for their age. A third of such small babies are considered to be 'growth-restricted' as they have complications such as dying in the womb (stillbirth) or after birth (newborn death), cerebral palsy, or needing long stays in hospital. When growth restriction is suspected in fetuses, they are closely monitored and often delivered early to avoid complications. Hence, it is important that we identify growth-restricted babies early to plan care. Our goal was to provide personalised and accurate estimates of the mother's chances of having a growth-restricted baby and predict the baby's weight if delivered at various time points in pregnancy. To do so, first we tested how accurate existing risk calculators ('prediction models') were in predicting growth restriction and birthweight. We then developed new risk-calculators and studied their clinical and economic benefits. We did so by accessing the data from individual pregnant women and their babies in our large database library (International Prediction of Pregnancy Complications). Published risk-calculators had various definitions of growth restriction and none predicted the chances of having a growth-restricted baby using our definition. One predicted baby's birthweight. This risk-calculator performed well, but underpredicted the birthweight by up to 143 g. We developed two new risk-calculators to predict growth-restricted babies (International Prediction of Pregnancy Complications-fetal growth restriction) and birthweight (International Prediction of Pregnancy Complications-birthweight). Both calculators accurately predicted the chances of the baby being born with growth restriction, and its birthweight. The birthweight was underpredicted by <9.7 g. The calculators performed well in both mothers predicted to be low and high risk. Further research is needed to determine the impact of using these calculators in practice, and challenges to implementing them in practice. Both International Prediction of Pregnancy Complications-fetal growth restriction and International Prediction of Pregnancy Complications-birthweight risk calculators will inform healthcare professionals and empower parents make informed decisions on monitoring and timing of delivery.

Development and validation of a prognostic model to predict birth weight: individual participant data meta-analysis.

Objective: To predict birth weight at various potential gestational ages of delivery based on data routinely available at the first antenatal visit. Design: Individual participant data meta-analysis. Data sources: Individual participant data of four cohorts (237 228 pregnancies) from the International Prediction of Pregnancy Complications (IPPIC) network dataset. Eligibility criteria for selecting studies: Studies in the IPPIC network were identified by searching major databases for studies reporting risk factors for adverse pregnancy outcomes, such as pre-eclampsia, fetal growth restriction, and stillbirth, from database inception to August 2019. Data of four IPPIC cohorts (237 228 pregnancies) from the US (National Institute of Child Health and Human Development, 2018; 233 483 pregnancies), UK (Allen et al, 2017; 1045 pregnancies), Norway (STORK Groruddalen research programme, 2010; 823 pregnancies), and Australia (Rumbold et al, 2006; 1877 pregnancies) were included in the development of the model. Results: The IPPIC birth weight model was developed with random intercept regression models with backward elimination for variable selection. Internal-external cross validation was performed to assess the study specific and pooled performance of the model, reported as calibration slope, calibration-in-the-large, and observed versus expected average birth weight ratio. Meta-analysis showed that the apparent performance of the model had good calibration (calibration slope 0.99, 95% confidence interval (CI) 0.88 to 1.10; calibration-in-the-large 44.5 g, -18.4 to 107.3) with an observed versus expected average birth weight ratio of 1.02 (95% CI 0.97 to 1.07). The proportion of variation in birth weight explained by the model (R2) was 46.9% (range 32.7-56.1% in each cohort). On internal-external cross validation, the model showed good calibration and predictive performance when validated in three cohorts with a calibration slope of 0.90 (Allen cohort), 1.04 (STORK Groruddalen cohort), and 1.07 (Rumbold cohort), calibration-in-the-large of -22.3 g (Allen cohort), -33.42 (Rumbold cohort), and 86.4 g (STORK Groruddalen cohort), and observed versus expected ratio of 0.99 (Rumbold cohort), 1.00 (Allen cohort), and 1.03 (STORK Groruddalen cohort); respective pooled estimates were 1.00 (95% CI 0.78 to 1.23; calibration slope), 9.7 g (-154.3 to 173.8; calibration-in-the-large), and 1.00 (0.94 to 1.07; observed v expected ratio). The model predictions were more accurate (smaller mean square error) in the lower end of predicted birth weight, which is important in informing clinical decision making. Conclusions: The IPPIC birth weight model allowed birth weight predictions for a range of possible gestational ages. The model explained about 50% of individual variation in birth weights, was well calibrated (especially in babies at high risk of fetal growth restriction and its complications), and showed promising performance in four different populations included in the individual participant data meta-analysis. Further research to examine the generalisability of performance in other countries, settings, and subgroups is required. Trial registration: PROSPERO CRD42019135045.

Feto-maternal indicators of cardiac dysfunction as a justification for the cardiac origins for pre-eclampsia.

While the pathophysiology of pre-eclampsia has been postulated as being secondary to placental dysfunction, a cardiac origin has more recently been proposed. Although an association between fetal congenital cardiovascular disease and pre-eclampsia has been demonstrated, no precise pathophysiologic mechanism for this association has been described. This review highlights the current biophysical (including echocardiography and Doppler indices) and biochemical (including proteomic, metabolomic and genetic/transcriptomic) markers of cardiac dysfunction that have been investigated in maternal and fetal cardiac disease and their overlap with predictors of pre-eclampsia.   Common pathways of inflammatory and anti-angiogenesis imbalance, endothelial damage, and oxidative stress have been demonstrated in both cardiovascular disease and pre-eclampsia and further investigation into these pathways could help to elucidate the common pathophysiologic mechanisms linking these disorders.

Trial of labour following two previous caesarean sections - A UK cohort study.

OBJECTIVES: To assess the (i) predictors of and associated rates of success and; (ii) maternal and perinatal outcomes of women undergoing trial of labour after two previous caesarean sections (TOLA2C). STUDY DESIGN: This retrospective cohort study collected data from two regional obstetric centres with 12,000 deliveries per annum collectively. The population included singleton pregnancies undergoing (i) TOLA2C, (ii) elective repeat caesarean section following two caesarean sections (ERCS) and (iii) trial of labour after one caesarean section (TOLA1C). Data was collected electronically from 2013 to 2021. Statistical analysis included Fisher exact and Kruskal-Wallis test to compare unpaired samples alongside univariate and multivariable logistic regression. The primary outcome measure was maternal and perinatal outcome. RESULTS: The three groups included; n = 146 TOLA2C, n = 206 ERCS and n = 99 TOLA1C. TOLA2C had a success rate of 65 % compared to 74 % for TOLA1C (p = 0.16). The optimal predictor of successful TOLA2C was previous successful TOLA1C OR 8.65 (95 % CI 2.75-38.41). TOLA2C was associated with greater risk of endometritis and/or sepsis postnatally compared to the other two groups [10.3 % (n = 15) versus 0.5 % (n = 1) and 3 % (n = 3) for ERCS and TOLA1C respectively p < 0.01]. It was also associated with longer maternal hospital stay [2.4 days (+/-1.8) versus 1.8 (+/-0.8) and 1.8 (+/-1.7) p < 0.01], a greater proportion of neonates with Apgar scores less than 7 (p=<0.01) and higher rates of neonatal unit admission [14 % (n = 20) versus 5 % (n = 11) versus 4 % (n = 4) (p=<0.01)]. CONCLUSION: Women considering trial of labour following two caesarean sections should be counselled regarding the potential increased risk of endometritis, sepsis and adverse neonatal outcome.

Monogenic conditions and central nervous system anomalies: A prospective study, systematic review and meta-analysis.

OBJECTIVES: Determine the incremental diagnostic yield of prenatal exome sequencing (pES) over chromosome microarray (CMA) or G-banding karyotype in fetuses with central nervous system (CNS) abnormalities. METHODS: Data were collected via electronic searches from January 2010 to April 2022 in MEDLINE, Cochrane, Web of Science and EMBASE. The NHS England prenatal exome cohort was also included. Incremental yield was calculated as a pooled value using a random-effects model. RESULTS: Thirty studies were included (n = 1583 cases). The incremental yield with pES for any CNS anomaly was 32% [95%CI 27%-36%; I2 = 72%]. Subgroup analysis revealed apparent incremental yields in; (a) isolated CNS anomalies; 27% [95%CI 19%-34%; I2 = 74%]; (b) single CNS anomaly; 16% [95% CI 10%-23%; I2 = 41%]; (c) more than one CNS anomaly; 31% [95% Cl 21%-40%; I2 = 56%]; and (d) the anatomical subtype with the most optimal yield was Type 1 malformation of cortical development, related to abnormal cell proliferation or apoptosis, incorporating microcephalies, megalencephalies and dysplasia; 40% (22%-57%; I2 = 68%). The commonest syndromes in isolated cases were Lissencephaly 3 and X-linked hydrocephalus. CONCLUSIONS: Prenatal exome sequencing provides a high incremental diagnostic yield in fetuses with CNS abnormalities with optimal yields in cases with multiple CNS anomalies, particularly those affecting the midline, posterior fossa and cortex.

When should we offer antenatal sequencing for urinary tract malformations? A systematic review, cohort study and meta-analysis.

OBJECTIVE: Determine the incremental yield of prenatal exome sequencing (PES) over chromosome microarray (CMA) and/or karyotype for urinary tract malformations (UTMs). METHOD: A prospective cohort study encompassing data from the English Genomic Medicine Service North Thames Laboratory Hub for fetuses with bilateral echogenic kidneys (BEKs) was combined with data from a systematic review. MEDLINE, EMBASE, Web of Science, MedRxiv and GreyLit were searched from 01/2010-02/2023 for studies reporting on the yield of PES over CMA or karyotype in fetuses with UTMs. Pooled incremental yield was determined using a random effects model. PROSPERO CRD42023364544. RESULTS: Fourteen studies (410 cases) were included. The incremental yield for multisystem UTMs, any isolated UTMs, and BEKs was 31% [95% CI, 18%-46%; I2  = 78%], 16% [95% CI, 6%-26%; I2  = 80%] and 51% [95% CI, 27%-75%; I2  = 34%]. The most common clinical diseases and syndromes identified, based on the variant genes detected, were Bardet-Biedl syndrome (BBS genes), dominant and recessive polycystic kidney diseases (PKD1, PKD2 and PKHD1) and renal cysts and diabetes syndrome (HNF1B). CONCLUSION: There was a notable incremental genetic diagnostic yield when PES was applied to multisystem UTMs and BEKs. There was a modest incremental yield when this technique was used for UTMs other than BEKs.

Prenatal next-generation sequencing in the fetus with congenital malformations: how can we improve clinical utility?

Fetal malformations have a variable prognosis that may be influenced by the detection of an underlying monogenic etiology. The careful detection and selection of fetal phenotypes and the use of prenatal next-generation sequencing with robust bioinformatic pathways and variant selection have improved the clinical utility and impact of genetic testing.

Should we offer prenatal exome sequencing for intrauterine growth restriction or short long bones? A systematic review and meta-analysis.

OBJECTIVE: This study aimed to determine the incremental yield of prenatal exome sequencing over chromosomal microarray or G-banding karyotype in fetuses with: (1) intrauterine growth restriction related to placental insufficiency or (2) short long bones, in isolated and nonisolated instances for both scenarios. DATA SOURCES: Data were collected via electronic searches for relevant citations from January 2010 to April 10, 2022 in MEDLINE, Embase, Web of Science, and Cochrane, and using relevant bibliographies and data generated in-house. STUDY ELIGIBILITY CRITERIA: Included were prospective or retrospective cohort studies and/or case series with: (1) n>5 cases of short long bones and/or intrauterine growth restriction undergoing prenatal sequencing with a clearly defined phenotype including assessment of placental function; (2) testing based on prenatal phenotype only; (3) a nondiagnostic chromosomal microarray/karyotype; and (4) known results of genetic testing. METHODS: Incremental yield was calculated for each study and as a pooled value for the aforementioned groups using a random-effects model. Results were displayed in forest plots with 95% confidence intervals. Heterogeneity was assessed statistically using Higgins' I2. Publication bias was assessed graphically using funnel plots. Quality assessment was performed using modified Standards for Reporting of Diagnostic Accuracy criteria (International Prospective Register of Systematic Reviews registration number CRD42022324680). RESULTS: Nineteen studies were included (n=452 cases). The apparent incremental yields with prenatal sequencing were: (1) 4% (95% confidence interval, -5.0 to 12; I2=0%) in isolated intrauterine growth restriction with evidence of placental insufficiency, (2) 30% (95% confidence interval, 13-47; I2=1%) in intrauterine growth restriction with additional structural anomalies, (3) 48% (95% confidence interval, 26-70; I2=73%) in isolated short long bones, and (4) 68% (95% confidence interval, 58-77; I2=51%) in short long bones with additional skeletal anomalies. Of the 37 short long bone cases with a diagnosis, 32 had a skeletal dysplasia, with thanatophoric dysplasia and osteogenesis imperfecta being the most common (both 21.6% [n=8/37]). In fetuses with short long bones and additional skeletal features, osteogenesis imperfecta was the most common diagnosis (28% [n=57/204]). Where documented, the inheritance patterns were de novo in 75.4% (n=150) of cases. CONCLUSION: Prenatal sequencing adds substantially to incremental yield over chromosomal microarray in fetuses with short long bones or multisystem intrauterine growth restriction. Robust studies are required to assess the utility of fetal sequencing in isolated intrauterine growth restriction with evidence of placental insufficiency, which cannot be recommended on the basis of current evidence.

Platelet response to aspirin in UK and Irish pregnancy cohorts: a genome-wide approach.

A multi-center prospective cross-sectional and genome-wide association study (GWAS) recruited pregnant women taking low dose aspirin. Objectives were to (i) develop pregnancy-specific 95% reference intervals for a range of laboratory based platelet function tests (PFTs); (ii) select an optimal and acceptable PFT that reflected aspirin's COX-1 inhibition in women with confirmed aspirin adherence in pregnancy; and (iii) identify genomic variants that may influence pregnant women's platelet response to aspirin.The study included two independent cohorts of pregnant women. A range of PFTs and matched phenotyping with urinary 11-dehydrothromboxane B2 (11DTXB2) and nuclear magnetic resonance (NMR) spectroscopy detection of urinary salicyluric acid as a measure of aspirin adherence were performed. Genome-wide data was acquired from the UK Biobank Axiom® (Thermo Fisher Scientific). 11DTXB2 in combination with adherence testing with NMR salicyluric acid was an accurate and acceptable testing strategy for detecting biochemical aspirin responsiveness in pregnant women, with the provision of relevant reference ranges. GWAS meta-analysis found no significant single nucleotide polymorphisms in association with response to aspirin in pregnancy. Further evaluation in relation to effective dosing of aspirin in pregnancy and optimizing the benefits to specific subgroups should now be a priority for future research.

The Diagnostic Yield of Prenatal Genetic Technologies in Congenital Heart Disease: A Prospective Cohort Study.

INTRODUCTION: The objective was to evaluate: (i) the proportion of prenatally diagnosed congenital heart disease (CHD) associated with an abnormal quantitative fluorescence-PCR (QF-PCR), chromosome microarray (CMA), and exome sequencing (ES) result; and (ii) the diagnostic yield of these technologies based on CHD category and presence of extra-cardiac anomalies (ECAs). METHODS: This prospective cohort study was set across 12 UK foetal medicine centres. All cases underwent QF-PCR, CMA, and ES, and the diagnostic yield in n = 147 cases of prenatally diagnosed CHD was assessed. RESULTS: In 34.7% (n = 51/147), a genetic diagnosis was obtained. Using a stepwise testing strategy, the diagnostic yield for QF-PCR, CMA, and ES was 15.6% (n = 23/147), 13.7% (n = 17/124), and 10.2% (n = 11/107), respectively. Abnormal QF-PCR/shunt (septal) defects 31.4% (n = 11/35), p = 0.046, and abnormal CMA/conotruncal anomalies 22.7% (n = 10/44), p = 0.04, had significant associations. Monogenic variants were commonest in complex CHD 36.4% (n = 4/11). Multisystem CHD had a greater diagnostic yield overall compared to isolated OR 2.41 (95% CI, 1.1-5.1), particularly in association with brain and gastrointestinal tract anomalies. The proportion of variants of uncertain significance was 4.7% (n = 5/107) with ES, with none in the CMA group. CONCLUSION: In the era of prenatal ES, there remains an important role for QF-PCR and CMA. Identification of monogenic pathologic variants further allows delineation of prognosis in CHD.

Diagnostic and perinatal outcomes in consanguineous couples with a structural fetal anomaly: A cohort study.

INTRODUCTION: Consanguineous unions occur when a couple are related outside marriage and is associated with adverse genetic and perinatal outcomes for affected offspring. The objectives of this study were to evaluate: (i) background characteristics, (ii) uptake of prenatal and postnatal investigation and (iii) diagnostic outcomes of UK consanguineous couples presenting with a fetal structural anomaly. MATERIAL AND METHODS: This was a retrospective and partly prospective cohort study comparing consanguineous (n = 62) and non-consanguineous (n = 218) pregnancies with current or previous fetal structural anomalies reviewed in a UK prenatal genetic clinic from 2008 to 2019. Outcomes were compared using odds ratios (OR). RESULTS: Most consanguineous couples were of Pakistani ethnicity (odds ratio [OR] 29, 95% confidence interval [95% CI] 13-62) and required use of an interpreter [OR 9, 95% CI 4-20). In the consanguineous group, the uptake of prenatal invasive testing was lower (OR 0.4, 95% CI 0.2-0.7) and the number declining follow up was greater (OR 10, 95% CI 3-34) than in the non-consanguineous group. This likely explained the lower proportion of consanguineous couples where a final definitive unifying diagnosis to explain the fetal structural anomalies was reached (OR 0.3, 95% CI 0.2-0.6). When a diagnosis was obtained in this group, it was always postnatal and most often using genomic sequencing technologies (OR 6, 95% CI 1-27). The risk of perinatal death was greater (OR 3, 95% CI 1-6) in the consanguineous group, as was the risk of fetal structural anomaly recurrence in a subsequent pregnancy (OR 4, 95% CI 1-13). There was no difference in the uptake of perinatal autopsy or termination of pregnancy between groups. CONCLUSIONS: Consanguineous couples are a vulnerable group in the prenatal setting. Although adverse perinatal outcomes in this group are more common secondary to congenital anomalies, despite the evolution of genomic sequencing technologies, due to a lower uptake of prenatal testing it is less likely that a unifying diagnosis is obtained and recurrence can occur. There is a need for proactive genetic counseling and education from the multidisciplinary team, addressing language barriers as well as religious and cultural beliefs in an attempt to optimize reproductive options.

Evolution of a prenatal genetic clinic-A 10-year cohort study.

OBJECTIVE: To (a) evaluate the proportion of women where a unifying genetic diagnosis was obtained following assessment of an observed pattern of fetal anomalies and (b) assess trends in genetic testing in a joint fetal-medicine genetic clinic. METHOD: Retrospective cohort study of all women attending the clinic. Outcomes included (a) indication for referral, (b) genetic test performed and (c) diagnoses obtained. RESULTS: From 2008 to 2019, 256 patients were referred and reviewed, of which 23% (n = 59) were consanguineous. The main indication for referral was the observed pattern of fetal anomalies. Over 10 years, the number of patients reviewed increased from 11 to 35 per annum. A unifying genetic diagnosis was obtained in 43.2% (n = 79/183), the majority of which were diagnosed prenatally (50.6% [n = 40/79]). The main investigation(s) that was the ultimate diagnostic test was targeted gene panel sequencing 34.2% (n = 27/79), with this and exome sequencing becoming the dominant genetic test by 2019. Pregnancies reviewed due to an abnormal karyotype or microarray decreased as an indication for referral during the study period (21.6% [n = 16/74] 2008-2012 vs 16.5% [n = 30/182] in 2012-2019). CONCLUSION: A prenatal genetic clinic with a structured multi-disciplinary team approach may be successful in obtaining a unifying prenatal genetic diagnosis.

The impact of fetal umbilical artery Doppler pulsatility index on childhood respiratory function and atopy: a prospective case-control study.

Objective: To determine if an elevated fetal umbilical artery Doppler pulsatility index is associated with abnormal respiratory function and atopy in children aged 12 years.Methods: This prospective case-control study compared children that had an elevated fetal umbilical artery Doppler pulsatility index (>90th centile) to those with a normal pulsatility index (<90th centile). All subjects were delivered at full-term and with appropriate growth for gestational age. Outcome measures included; (i) presence of asthma and/or atopy; (ii) spirometry measurements and (iii) serum C-reactive protein and leptin. Multiple regression was used to account for parental smoking, childhood age, gender and socioeconomic status.Results: 174 children with an average age of 12.1 (±0.6 SD), 48% of who were male were included in the analysis. Of the 174, 99 (57%) were in the normal umbilical artery Doppler pulsatility index group and 75 (43%) elevated umbilical artery Doppler pulsatility index groups. The overall proportion of subjects with asthma was 28% (48/174) and atopy 56% (98/174). No association was found between elevated fetal umbilical artery Doppler pulsatility index and asthma (p = .47) or atopy (p = .75) at age 12 years. Similarly there was no association between FEV1(%) (p = .96), forced vital capacity (FVC)(%) (p = .98), elevated serum C-reactive protein (p = .69) or leptin (p = .20) and an elevated fetal umbilical artery Doppler pulsatility index.Conclusions: An elevated umbilical artery Doppler at 28-weeks gestation in the absence of prematurity or fetal growth restriction is not associated with altered respiratory function or the presence of atopy in children aged 12 years. These findings support the theory that such disease has a multifactorial pathophysiology.

Prenatal chromosomal microarray testing of fetuses with ultrasound structural anomalies: A prospective cohort study of over 1000 consecutive cases.

OBJECTIVE: Evaluate the diagnostic yield of prenatal submicroscopic chromosome anomalies using prenatal array comparative genomic hybridisation (aCGH). METHOD: Prospective cohort study conducted between March 2013 and June 2017 including fetuses where an elevated nuchal translucency (NT) or structural anomaly was identified on ultrasound and common aneuploidy testing was negative. aCGH was performed using an 8-plex oligonucleotide platform with a genome wide backbone resolution of greater than 200 kb and interpretation in line with American College of Medical Genetics guidance. RESULTS: One thousand one hundred twenty-nine fetuses were included; 371 fetuses with an increased NT (32.9%) and 758 with a structural anomaly (67.1%). The rate of pathogenic copy number variants (CNVs) and variant of uncertain significance (VUS) was 5.9% (n = 22) and 0.5% (n = 2) in the elevated NT group and 7.3% (n = 55) and 0.8% (n = 6) in the mid-trimester anomaly group. No pathogenic CNVs were identified in fetuses with an NT less than 4.0 mm. Multisystem and cardiac anomalies had the greatest yield of pathogenic CNV with a 22q11.2 microdeletion present in 40% (12/30). CONCLUSION: Prenatal aCGH is a useful diagnostic tool in the investigation of fetuses with a significantly elevated NT or structural anomaly. With time and experience, rates of pathogenic CNVs have increased, and VUS have reduced, supporting the prenatal application of increasingly high resolution aCGH platforms.

Exome sequencing in the assessment of congenital malformations in the fetus and neonate.

Major congenital anomalies are often associated with perinatal mortality, long-term morbidity and prolonged hospitalisation. Prenatal ultrasound remains the principle diagnostic test for many anomalies, but despite this up to one-third are only identified in the neonatal period. The primary step in determining underlying aetiology is to define accurately the phenotype by recognition of dysmorphology (both prenatally and postnatally). The potential introduction of next-generation sequencing, primarily through exome sequencing, into perinatal practice may improve the pathological diagnostic yield. However, clinicians must understand both the benefit and potential harms of this technology in facilitating the discovery of relevant pathogenic variants in the diagnosis and management of congenital malformations.

Evaluation of the Effect of Low-Dose Aspirin on Biochemical and Biophysical Biomarkers for Placental Disease in Low-Risk Pregnancy: Secondary Analysis of a Multicenter RCT.

OBJECTIVE: To assess the effect of aspirin use in low-risk pregnancy on: (1) pregnancy-associated plasma protein-A (PAPP-A) and placental-like growth factor (PLGF); (2) urinary albumin-to-creatinine ratio (ACR) and blood pressure; (3) fetal growth parameters; and (4) placental histopathology. STUDY DESIGN: This secondary analysis from the T rial of low-dose aspirin with an E arly S creening T est for preeclampsia and growth restriction randomized controlled trial was based on low-risk nulliparous women randomized at 11 weeks to (1) aspirin 75 mg; (2) no aspirin; and (3) aspirin based on the preeclampsia Fetal Medicine Foundation screening test. At baseline, women underwent assessment of blood pressure, PAPP-A, PLGF, and ACR, repeated 9 to 10 weeks postaspirin, in addition to fetal growth assessment. Gross and histopathological placental analyses were performed in line with Amsterdam criteria. RESULTS: A total of 445 subjects were included (aspirin n = 163 [36.6%]; no aspirin n = 282 [63.4%]). Although the fetal-to-placental weight ratio was significantly greater in the aspirin group (7.5 [±1.3] vs. 7.3 [±1.4], p = 0.045), as was change in ultrasound assessed estimated fetal weight from second to third trimesters (1,624.5 g [±235.1] vs. 1,606.2 [±189.4], p = 0.042), this was invalidated by the lack of a difference in birth weight. Aspirin did not significantly impact on change in serum or urine preeclampsia biomarkers, maternal blood pressure, or placental histopathology. CONCLUSION: Aspirin use in low-risk pregnancy does not appear to impact on preeclampsia biomarkers, fetal growth, or placental pathology.

The Impact of Aspirin on Ultrasound Markers of Uteroplacental Flow in Low-Risk Pregnancy: Secondary Analysis of a Multicenter RCT.

OBJECTIVE: This article evaluates the effect of low-dose aspirin on uterine artery (UtA) Doppler, placental volume, and vascularization flow indices in low-risk pregnancy. STUDY DESIGN: In this secondary analysis of the TEST randomized controlled trial, low-risk nulliparous women were originally randomized at 11 weeks to: (1) routine aspirin 75 mg; (2) no aspirin; and (3) aspirin based upon the preeclampsia Fetal Medicine Foundation screening test. UtA Doppler, three-dimensional (3D) placental volume, and vascularization flow indices were assessed prior to and 6 weeks postaspirin commencement. RESULTS: A total of 546 women were included (aspirin n = 192, no aspirin n = 354). Between first and second trimesters, aspirin use was not associated with a change in UtA Doppler, placental volume, or vascular flow indices. There was no significant difference in the change in UtA Doppler pulsatility index (PI) Z-scores or notching (PI Z-score -0.2 vs. -0.2, p = 0.17), nor was there a significant change in placental volume Z-score and vascular flow indices (volume Z-score change: 0.74 vs. 0.62, p = 0.34). CONCLUSION: Low-dose aspirin commenced at 11 weeks in low-risk women does not appear to improve uterine and placental perfusion or placental volume. Any perceived effect on uteroplacental vasculature is not reflected in changes in placental volume nor uteroplacental flow as assessed by two-dimensional and 3D ultrasound.

Preeclampsia Prevention Using Routine Versus Screening Test-Indicated Aspirin in Low-Risk Women.

The objective was to evaluate whether routine aspirin 75 mg is more cost-effective than the Fetal Medicine Foundation screen-and-treat approach for preeclampsia prevention in low-risk nulliparous women. A health economic decision analytical model was devised to estimate the discounted net health and cost outcomes of routine aspirin versus Fetal Medicine Foundation screening test-indicated aspirin for a cohort of 100 000 low-risk nulliparous women. Both strategies were compared with no intervention. A subanalysis also compared disaggregated components of the algorithm. The analysis used data from hospital administration, literature, and a randomized controlled trial. Sensitivity analyses assessed the impact of aspirin adherence, test cost, and accuracy on study results. Presumed rates of preeclampsia were 3.75% with no intervention versus 0.45% with aspirin use. Results found that routine aspirin was the preferred strategy, in terms of greater health gains and larger cost savings. It provided 163 quality-adjusted life-years relative to no intervention, whereas the screen-and-treat policy achieved 108 quality-adjusted life-years. Routine aspirin would result in an estimated cost saving of €14.9 million annually relative to no intervention, whereas screen-and-treat approach would result in a smaller cost saving of €3.1 million. When the analysis was extended to consider alternative screen-and-treat strategies, routine aspirin remained the optimally cost-effective approach. In conclusion, routine aspirin use in low-risk nulliparous women has a greater health gain and cost saving compared with both the Fetal Medicine Foundation and other screen-and-treat approaches.

Clinical utility of exome sequencing in the prenatal diagnosis of congenital anomalies: A Review.

Advances in prenatal genomics have enabled the assessment of not only the sub-microscopic structure of chromosomes using chromosomal microarray analysis, but also the detection of "pathogenic variants" to the resolution of a single base pair with the use of next generation sequencing. Research is emerging on the additional prenatal diagnostic yield that exome sequencing offers when structural fetal anomalies are detected on ultrasound examination, in particular the identification of monogenic abnormalities defining prognosis and recurrence of anomalies. Primarily assessed using fetal DNA obtained by invasive techniques (amniocytes or chorionic villi), this technology is progressing into a non-invasive approach using maternal plasma. There are several challenges, to be addressed before this technology can be introduced into routine clinical practice. These are primarily technical and interpretational but also relate to service provision; cost-effectiveness; turn-around time; patient acceptability and ethical dilemmas. With adequate pre- and post-test counselling many of these challenges may be overcome and such counselling has to be multi-disciplinary, involving clinical geneticists, genetic scientists, paediatricians, perinatal pathologists and fetal medicine subspecialists. There is therefore a need for obstetricians to have an understanding of the clinical utility, application, advantages and challenges of such technologies before introduction into routine clinical practice.