Fetal hydrops and the Incremental yield of Next-generation sequencing over standard prenatal Diagnostic testing (FIND) study: prospective cohort study and meta-analysis.

OBJECTIVE: To determine the incremental yield of exome sequencing (ES) over chromosomal microarray analysis (CMA) or karyotyping in prenatally diagnosed non-immune hydrops fetalis (NIHF). METHODS: A prospective cohort study (comprising an extended group of the Prenatal Assessment of Genomes and Exomes (PAGE) study) was performed which included 28 cases of prenatally diagnosed NIHF undergoing trio ES following negative CMA or karyotyping. These cases were combined with data from a systematic review of the literature. MEDLINE, EMBASE, CINAHL and ClinicalTrials.gov databases were searched electronically (January 2000 to October 2020) for studies reporting on the incremental yield of ES over CMA or karyotyping in fetuses with prenatally detected NIHF. Inclusion criteria for the systematic review were: (i) at least two cases of NIHF undergoing sequencing; (ii) testing initiated based on prenatal ultrasound-based phenotype; and (iii) negative CMA or karyotyping result. The incremental diagnostic yield of ES was assessed in: (i) all cases of NIHF; (ii) isolated NIHF; (iii) NIHF associated with an additional fetal structural anomaly; and (iv) NIHF according to severity (i.e. two vs three or more cavities affected). RESULTS: In the extended PAGE study cohort, the additional diagnostic yield of ES over CMA or karyotyping was 25.0% (7/28) in all NIHF cases, 21.4% (3/14) in those with isolated NIHF and 28.6% (4/14) in those with non-isolated NIHF. In the meta-analysis, the pooled incremental yield based on 21 studies (306 cases) was 29% (95% CI, 24-34%; P < 0.00001; I2 = 0%) in all NIHF, 21% (95% CI, 13-30%; P < 0.00001; I2 = 0%) in isolated NIHF and 39% (95% CI, 30-49%; P < 0.00001; I2 = 1%) in NIHF associated with an additional fetal structural anomaly. In the latter group, congenital limb contractures were the most prevalent additional structural anomaly associated with a causative pathogenic variant, occurring in 17.3% (19/110) of cases. The incremental yield did not differ significantly according to hydrops severity. The most common genetic disorders identified were RASopathies, occurring in 30.3% (27/89) of cases with a causative pathogenic variant, most frequently due to a PTPN11 variant (44.4%; 12/27). The predominant inheritance pattern in causative pathogenic variants was autosomal dominant in monoallelic disease genes (57.3%; 51/89), with most being de novo (86.3%; 44/51). CONCLUSIONS: Use of prenatal next-generation sequencing in both isolated and non-isolated NIHF should be considered in the development of clinical pathways. Given the wide range of potential syndromic diagnoses and heterogeneity in the prenatal phenotype of NIHF, exome or whole-genome sequencing may prove to be a more appropriate testing approach than a targeted gene panel testing strategy. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Variants of uncertain significance in prenatal microarrays: a retrospective cohort study.

OBJECTIVE: To categorise the variants of uncertain significance found with prenatal chromosomal microarray and determine the proportion of such variants that are associated with a well-known phenotype in order to establish how often they remain truly of uncertain significance. DESIGN: Retrospective cohort study. SETTING: The University of California, San Francisco. POPULATION: All patients with a variant of uncertain significance on prenatal microarray between 2014 and 2018. METHODS: Each variant was classified as a copy number variant that (a) contains Online Mendelian Inheritance in Man (OMIM)-annotated disease-causing genes ('OMIM morbid genes'); (b) confers autosomal recessive carrier status; (c) is associated with incomplete penetrance; (d) is >1 Mb in size without OMIM morbid genes; (e) demonstrates mosaicism; or (f) contains significant regions of homozygosity. For each variant of uncertain significance, we examined the existing literature to determine whether the predicted phenotype(s) was known. MAIN OUTCOME MEASURE: Prevalence and classification of variants and how much information is available regarding the likelihood of an affected phenotype. RESULTS: Of 970 prenatal microarrays, 55 (5.8%) had at least one variant of uncertain significance. The most common were copy number variants containing OMIM morbid genes (36.8%). In all, 48 (84.2%) were associated with a known phenotype; 55 (96.5%) had data available regarding the likelihood of an affected phenotype. CONCLUSIONS: The prevalence of variants of uncertain significance with prenatal microarray was 5.8%. In the large majority of cases, data were available regarding the predicted phenotype. TWEETABLE ABSTRACT: Variants of uncertain significance occur in 5.8% of prenatal microarrays. In the overwhelming majority of cases, outcome information is available.

Maternal arrhythmia and perinatal outcomes.

OBJECTIVE: The objective of this study was to determine whether arrhythmia in the setting of maternal cardiac disease (MCD) affects perinatal outcomes. STUDY DESIGN: This is a retrospective cohort study of pregnant women with MCD who delivered during 2008 to 2013. Perinatal outcomes among women with an arrhythmia were compared with those without. RESULTS: Among 143 women, 36 (25%) had an arrhythmia. Those with an arrhythmia were more likely to have a spontaneous vaginal delivery (64 vs 43%, P<0.05) and required fewer operative vaginal births (8 vs 27%, P=0.02). Pregnancies were more likely to be complicated by intrauterine growth restriction (IUGR) (17 vs 5%, P<0.05), although there were no differences in the rate of small for gestational age. The risk of IUGR remained increased after controlling for confounding (adjusted odds ratio 6.98, 95% confidence interval 1.59 to 30.79, P=0.01). Two cases of placental abruption were identified among mothers with arrhythmia while none were identified in the controls (P<0.05). CONCLUSION: Patients with arrhythmias were more likely to have a spontaneous vaginal delivery. Our data suggest that these pregnancies were an increased risk for IUGR.

Impending macrosomia: will induction of labour modify the risk of caesarean delivery?

OBJECTIVE: To compare the annual incidence rates of caesarean delivery between induction of labour and expectant management in the setting of macrosomia. DESIGN: This is a retrospective cohort study. SETTING: Deliveries in the USA in 2003. POPULATION: Singleton births of macrosomic neonates to low-risk nulliparous women at 39 weeks of gestation and beyond. METHODS: Women who had induction of labour at 39 weeks of gestation with a neonatal birthweight of 4000 ± 125 g (3875-4125 g) were compared with women who delivered (either induced or spontaneous labour) at 40, 41 or 42 weeks (i.e. expectant management), assuming an intrauterine fetal weight gain of 200 g per additional week of gestation. Similar comparisons were made at 40 and 41 weeks of gestation. Chi-square test and multivariable logistic regression analysis were used for statistical comparison. MAIN OUTCOME MEASURES: Method of delivery, 5-minute Apgar scores, neonatal injury. RESULTS: There were 132,112 women meeting the study criteria. In women whose labours were induced at 39 weeks and who delivered a neonate with a birthweight of 4000 ± 125 g, the frequency of caesarean was lower compared with women who delivered at a later gestational age (35.2% versus 40.9%; adjusted OR 1.25, 95% CI 1.17-1.33). This trend was maintained at both 40 weeks (36.1% versus 42.6%; adjusted OR 1.31, 95% CI 1.23-1.40) and 41 weeks (38.9% versus 41.8%; adjusted OR 1.16, 95% CI 1.06-1.28) of gestation. CONCLUSIONS: In the setting of known birthweight, it appears that induction of labour may reduce the risk of caesarean delivery. Future research should concentrate on clinical and radiological methods to better estimate birthweight to facilitate improved clinical care. These findings deserve examination in a large, prospective, randomised trial.

Diagnosis and morbidity of placenta accreta.

OBJECTIVE: To examine the diagnostic precision of ultrasound examination for placenta accreta in women with placenta previa and to compare the morbidity associated with accreta to that of previa alone. METHODS: This was a retrospective cohort study of all women with previa with/without accreta examined at the University of California, San Francisco (UCSF) between 2002 and 2008. The sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) of ultrasound examination for the diagnosis of accreta were calculated and compared with results from similar studies in the literature. Univariable analysis was used to compare clinical outcomes. RESULTS: The PPV of an ultrasound diagnosis of accreta was 68% and NPV was 98%. Ultrasound had a sensitivity of 89.5%. Compared with previa alone, accreta had an odds ratio (OR) of 89.6 (95% CI, 19.44-412.95) for estimated blood loss > 2 L, an OR of 29.6 (95% CI, 8.20-107.00) for transfusion and an OR of 8.52 (95% CI, 2.58-28.11) for length of hospital stay > 4 days. CONCLUSION: Placenta accreta is associated with greater morbidity than is placenta previa alone. Ultrasound examination is a good diagnostic test for accreta in women with placenta previa. This is consistent with most other studies in the literature.