Neurogenetic fetal akinesia and arthrogryposis: genetics, expanding genotype-phenotypes and functional genomics.

BACKGROUND: Fetal akinesia and arthrogryposis are clinically and genetically heterogeneous and have traditionally been refractive to genetic diagnosis. The widespread availability of affordable genome-wide sequencing has facilitated accurate genetic diagnosis and gene discovery in these conditions. METHODS: We performed next generation sequencing (NGS) in 190 probands with a diagnosis of arthrogryposis multiplex congenita, distal arthrogryposis, fetal akinesia deformation sequence or multiple pterygium syndrome. This sequencing was a combination of bespoke neurogenetic disease gene panels and whole exome sequencing. Only class 4 and 5 variants were reported, except for two cases where the identified variants of unknown significance (VUS) are most likely to be causative for the observed phenotype. Co-segregation studies and confirmation of variants identified by NGS were performed where possible. Functional genomics was performed as required. RESULTS: Of the 190 probands, 81 received an accurate genetic diagnosis. All except two of these cases harboured class 4 and/or 5 variants based on the American College of Medical Genetics and Genomics guidelines. We identified phenotypic expansions associated with CACNA1S, CHRNB1, GMPPB and STAC3. We describe a total of 50 novel variants, including a novel missense variant in the recently identified gene for arthrogryposis with brain malformations-SMPD4. CONCLUSIONS: Comprehensive gene panels give a diagnosis for a substantial proportion (42%) of fetal akinesia and arthrogryposis cases, even in an unselected cohort. Recently identified genes account for a relatively large proportion, 32%, of the diagnoses. Diagnostic-research collaboration was critical to the diagnosis and variant interpretation in many cases, facilitated genotype-phenotype expansions and reclassified VUS through functional genomics.

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.

A survey of clinician and patient attitudes towards the use of progesterone for women at risk of preterm birth.

BACKGROUND AND AIMS: To assess the current use of vaginal progesterone in women at increased risk of preterm birth among practitioners within Australia and New Zealand, and the willingness of both clinicians and women to participate in a randomised controlled trial to further evaluate the role of progesterone in preterm birth. METHODS: A survey of fellows and members of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists, and women who had a spontaneous preterm birth at less than 34 weeks gestation, at the Women's and Children's Hospital was conducted. RESULTS: A total of 1430 surveys were distributed to members and fellows, of which 738 (52%) were returned. Of these, 490 were from currently practising obstetricians (34% of total college membership). Twelve of the 490 (2%) respondents indicated that they currently use progesterone in women with a previous spontaneous preterm birth at less than 34 weeks gestation. Of the respondents, 317 (65%) indicated a willingness to participate in a multicentred randomised controlled trial assessing the use of progesterone in women with a previous spontaneous preterm birth at less than 34 weeks gestation. A total of 207 eligible women identified from the hospital database were sent a questionnaire, with responses obtained from 119 women (57%). Overall, women were satisfied with their preterm birth experience. Fifty-two women (44%) indicated a willingness to consider participation in a randomised trial of vaginal progesterone. CONCLUSIONS: Progesterone is not widely used in Australia and New Zealand for women considered at increased risk of preterm birth. Conducting a randomised trial of vaginal progesterone is feasible.

Care of women at risk of preterm birth: a survey of reported practice in Australia and New Zealand.

A mail-out questionnaire on management of women considered at high risk of preterm birth was sent to all members and fellows of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists. While the survey suggested that there is general consensus among practitioners as to what constitutes an increased risk of preterm birth, there is some variation in investigations and treatment currently undertaken.