{"paper_id":"06f05fce-e8a3-4145-a761-94fa4195c846","body_text":"Perinatal outcomes after a prenatal diagnosis of a fetal copy number variant: A retrospective population-based cohort study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Perinatal outcomes after a prenatal diagnosis of a fetal copy number variant: A retrospective population-based cohort study Cecilia Pynaker, Jacqui McCoy, Jane Halliday, Sharon Lewis, David J Amor, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4285240/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 Aug, 2024 Read the published version in BMC Pediatrics → Version 1 posted You are reading this latest preprint version Abstract Background There are no established guidelines for the follow up of infants born after a prenatal diagnosis of a genomic copy number variant (CNV), despite their increased risk of developmental issues. The aims of this study were (i) to determine the perinatal outcomes of fetuses diagnosed with and without a CNV, and (ii) to establish a population-based paediatric cohort for long term developmental follow up. Methods An Australian state-wide research database was screened for pregnant individuals who had a prenatal chromosomal microarray (CMA) between 2013–2019 inclusive. Following linkage to laboratory records and clinical referrer details, hospital records were manually reviewed for study eligibility. Eligible participants were mother-child pairs where the pregnancy resulted in a livebirth, the mother was able to provide informed consent in English (did not require a translator) and the mother was the primary caregiver for the child at hospital discharge after birth. Research invitations were sent by registered post at an average of six years after the prenatal diagnostic test. Statistical analysis was performed in Stata17. Results Of 1832 prenatal records examined, 1364 (74.5%) mother-child pairs were eligible for recruitment into the follow up cohort. Of the 468 ineligible, 282 (60.3%) had ‘no live pregnancy outcome’ (209 terminations of pregnancy (TOP) and 73 miscarriages, stillbirths, and infant deaths), 157 (33.5%) required a translator, and 29 (6.2%) were excluded for other reasons. TOP rates varied by the type of fetal CNV detected: 49.3% (109/221) for pathogenic CNVs, 18.2% (58/319) for variants of uncertain significance and 3.3% (42/1292) where no clinically significant CNV was reported on CMA. Almost 77% of invitation letters were successfully delivered (1047/1364), and the subsequent participation rate in the follow up cohort was 19.2% (201/1047). Conclusions This study provides Australia’s first population-based data on perinatal outcomes following prenatal diagnostic testing with CMA. The relatively high rates of pregnancy loss for those with a prenatal diagnosis of a CNV presented a challenge for establishing a paediatric cohort to examine long term outcomes. Recruiting a mother-child cohort via prenatal ascertainment is a complex and resource-intensive process, but an important step in understanding the impact of a CNV diagnosis in pregnancy and beyond. Trial registration: ACTRN12620000446965p; Registered on April 6, 2020. Obstetrics & Gynecology Pediatrics Medical Genetics prenatal diagnosis chromosomal microarray analysis copy number variants variant of uncertain significance perinatal outcomes cohort studies paediatric population feasibility studies Figures Figure 1 BACKGROUND Chromosomal microarray analysis (CMA) can interrogate the human genome to a higher resolution than G-banded karyotyping. 1 This has enabled the detection of submicroscopic deletions and duplications, termed copy number variants (CNVs), which can be benign or pathogenic depending on their location and gene content. CMA is well-established as the gold-standard first-tier diagnostic test for paediatric patients with an unexplained developmental disability, intellectual disability or congenital anomalies, providing 15–20% higher diagnostic yield than G-banded karyotyping. 2 – 4 Alongside paediatric care, CMA has also revolutionised prenatal care. It has been 10 years since CMA replaced G-banded karyotyping as the recommended diagnostic test for fetuses with an ultrasound abnormality because of its superior diagnostic yield. 5 – 7 CMAs can detect pathogenic copy number variants (pCNV) linked to established syndromes, but also CNV of uncertain clinical significance (VUS). VUS are CNVs that often involve non-disease causing genes, may not have been previously identified or described, or for which there is limited information on genotype-phenotype correlation due to incomplete penetrance and variable expressivity. In the Australian state of Victoria, there has been an increase in the proportion of prenatal diagnostic tests analysed with CMA, from 39.4% in 2013 to 93.1% in 2021, regardless of indication for testing. 8 Concurrently, the proportion of fetuses diagnosed with a pCNV has increased over the past decade, from 1.0% in 2013 to 4.4% in 2022. 8 The most frequent pCNVs in our population are 22q11.2 deletion (DiGeorge syndrome), 4p16.3 deletion (Wolf-Hischhorn syndrome), and 5p15.33 deletion (cri-du-chat syndrome). 9 These account for 13.5%, 3.9%, 3.0% of pregnancies with a pCNV respectively. However, the vast majority of pCNVs are rare, which makes counselling on long term childhood outcomes difficult, especially when ascertained before birth when the phenotype is incomplete. A VUS is diagnosed in approximately 5% of fetuses following chorionic villus sampling or amniocentesis. 8 These VUS can be challenging as there is often no prenatal phenotype to guide CNV interpretation. The limited data available are commonly skewed towards cases diagnosed postnatally, possibly biased towards the more severe end of the phenotypic spectrum. 10 – 12 In Australia, there are currently no guidelines for the routine follow up and assessment of children with a prenatally diagnosed VUS. Furthermore, as genomic databases and clinical interpretation guidelines are updated some prenatal VUS are subsequently reclassified as either pathogenic or benign. 13 This highlights the challenge of providing appropriate long term care, as children may not only be lost to follow up after the newborn period, but may also carry a nonextant genetic diagnosis throughout childhood due to changes in scientific knowledge. 12 , 14 The PrenatAL Microarray (PALM) is a nationally-funded cohort study of mother-child pairs who have had a prenatal diagnosis with a chromosomal microarray (CMA) from 2013 to 2019 in the Australian state of Victoria. In brief, this cohort study of children- with and without a prenatally-ascertained CNV- aims to examine their developmental, social-emotional and health outcomes in early childhood through a range of parent completed questions, in person cognitive assessments, and clinical paediatric review. 15 The full protocol has been previously published in this journal. 15 In this paper, we report the perinatal outcomes of fetuses that had a prenatal chromosomal microarray (potential PALM participants, with and without a CNV), including rates of termination of pregnancy (TOP) and spontaneous perinatal losses following prenatal diagnosis. We also present the challenges of creating a representative paediatric cohort of children from a prenatal cohort. METHODS Study population This was a population-based study set in the Australian state of Victoria. Victoria has approximately 78,000 births per year with a median maternal age of 31.5 years. 16 All pregnant individuals are offered screening for fetal structural anomalies and chromosomal conditions, with an uptake of 83.6% state-wide. 17 Between 2013–2021, 80.9% of prenatal diagnostic tests were analysed by CMA. 8 TOP is lawful on maternal request up to 24 weeks, and after 24 weeks if two medical practitioners deem it “appropriate in all the circumstances”. 18 Eligibility criteria for paediatric cohort Participants were eligible if: the pregnancy resulted in a livebirth, they were the primary-caregiver for the child at hospital discharge, resident in the Australian state of Victoria, and able to provide informed consent in English (did not require a translator). Data sources Multiple sources were utilised to identify and pre-screen potential study participants. Victorian Prenatal Diagnosis Database The Victorian Prenatal Diagnosis Database (VPDD) is a population-based research dataset that collects all chromosome testing results from amniotic fluid and chorionic villus samples (CVS). 8 The VPDD was screened for pregnant individuals who underwent prenatal diagnosis with CMA from January 2013 to December 2019. Clinical laboratories classified prenatal CNVs in accordance with established guidelines. 19 – 21 ‘Cases’ included pregnancies with a pathogenic or likely pathogenic CNV (pCNV) and variant of uncertain significance (VUS). ‘Controls’ were pregnancies that had a primary clinical indication other than an ultrasound abnormality and had ‘no clinically significant genomic imbalance’ reported on CMA. These included positive (‘high chance) screening result (non-invasive prenatal testing, combined first trimester screening, or second trimester serum screening), and other testing indications (such as advanced maternal age, maternal request). There were also some controls where the ultrasound abnormality was a secondary indication after a primary indication of a positive screening result. Due to the modifier of a structural anomaly or known genetic condition on childhood outcomes, ‘controls’ with a clinical indication of a fetal structural abnormality, family history of a chromosomal condition or a single gene condition were excluded. Further details will be available in the next phase of the PALM study and any controls with a major structural abnormality on antenatal ultrasound excluded from analysis. Clinical laboratories that submitted the cases and controls to the VPDD internally reidentified records and obtained the name of the public maternity hospital or private clinical referrer. Follow up was different for these two groups: a) Public hospital medical record review Hospital medical records were manually reviewed for perinatal outcome and study eligibility. Perinatal outcomes were coded as either miscarriage (spontaneous pregnancy loss < 20 weeks’ gestation), stillbirth (infant born with no signs of life ≥ 20 weeks’ gestation), TOP, neonatal death (death within 28 days of birth), infant death (death within 2 years of birth), or live birth. A minimum de-identified dataset was collected for all individuals screened containing: hospital name, maternal postcode, test date, gestational age, clinical indication, CNV classification, perinatal outcome, parity, and study eligibility status. Maternal postcode was mapped to the corresponding local government area and assigned the relevant Index of Relative Socioeconomic Advantage and Disadvantage (IRSAD) allocated by the Australian Bureau of Statistics from 2016 Census data. 22 b) Private clinical referrers Private clinicians were contacted by phone and/or email and asked to pre-screen their patients for study eligibility and send an invitation letter to eligible participants. No minimum dataset was collected for these patients as pre-screening was performed at the clinician’s discretion. Study recruitment Study invitation letters were sent by registered post between November 2021 and June 2023. Each contained a participant information and consent form, hard-copy questionnaire booklet, and replied paid envelope. Registered post enabled tracking of research letters, including proof of mailing and signature on delivery. The public roll of the Australian Electoral Commission (AEC) was used to check the details of participants whose post were returned to sender. Participants had the option to complete a hard copy or online consent form and questionnaire. Completed hard copies were returned using the provided replied paid envelope, while the online version, hosted in Research Electronic Data Capture (REDCap), were accessed via a QR code in the invitation letter. 23 , 24 Protocol amendments Pandemic impacts In response to the COVID-19 pandemic in 2020, the study protocol was updated to include alternative online child assessments. Due to pandemic-related disruptions, a 12-month extension was requested due to delays in recruitment, participant assessments, and obtaining approvals for new regional sites. Low recruitment rate In response to a low recruitment rate, the study protocol was amended. Participants were: (i) sent two reminder letters, and (ii) offered an AUD$110 gift card in appreciation of their time. The first reminder was sent three weeks after the initial study invitation (if successfully delivered), and the second reminder three weeks after the first reminder. Ethics Committee approval for all amendments was obtained. Statistical analysis Statistical analysis was performed in Stata17 using chi-squared test for proportions with p < 0.05 considered significant. 25 Wilson score method was used to calculate 95% confidence intervals using Epitools. 26 Ethics approval This study received Human Research Ethics Committee approval from the Royal Children’s Hospital on April 8, 2020 (Reference no. 60542) and Mercy Health on September 15, 2020 (Reference no. 2020-046). RESULTS Pre-screening of potential participants During the 7-year study period 8184 prenatal diagnostic tests were performed by CMA; a fetal CNV was reported for 1029 samples (12.6%, 95%CI: 11.9–13.3%), and ‘no clinically significant CNV’ reported in 7155 samples (87.4%, 95%CI: 85.7–88.1%). Of these, 4316 with ‘no clinically significant CNV’ were excluded due to an indication of an ultrasound abnormality, family history of a chromosomal condition, or a single gene condition. Figure 1 illustrates the pre-screening and recruitment of participants with and without a copy number variant. The personal identifiers of the 2458 potential cases and controls were provided to the eight relevant hospitals and were manually reviewed for eligibility criteria. Only 74.5% (n = 1832) had a known birth outcome documented in the hospital records. The remaining missing birth outcome data was due to patients delivering in a different hospital to the one in which the prenatal diagnostic procedure was performed. Of those with a known birth outcome (n = 1832), 1364 (74.5%) were eligible for recruitment (‘potential participants’) and 468 (25.5%) were ineligible. Of the 468 ineligible, 282 (60.3%) had ‘no live pregnancy outcome’ (209 terminations of pregnancy (TOP) and 73 miscarriages, stillbirths, and infant deaths), 157 (33.5%) required a translator, and 29 (6.2%) were excluded for other reasons (Table 1 ). Table 1 Reasons for study ineligibility. Reason for study ineligibility Pathogenic copy number variant Variant of uncertain significance No clinically significant genomic imbalance Total n (% pCNVs) n (% VUS) n (% NAD) n (% total) Perinatal/infant death 128 (90.1) 75 (72.8) 79 (35.4) 282 (60.3) Translator required 12 (8.5) 22 (21.4) 123 (55.2) 157 (33.5) Mother (gestational carrier) not the intended primary caregiver 1 (0.7) 1 (1.0) 7 (3.1) 9 (1.9) Multifetal pregnancy 0 (0.0) 0 (0.0) 2 (0.9) 2 (0.4) Unable to provide informed consent 0 (0.0) 1 (1.0) 0 (0.0) 1 (0.2) Other † 1 (0.7) 4 (3.9) 12 (5.4) 17 (3.6) Total 142 (100.0) 103 (100.0) 223 (100.0) 468 (100.0) Abbreviations: pCNV, pathogenic copy number variant; VUS, variant of uncertain significance; NAD, no clinically significant genomic imbalance † Other reasons for study ineligibility were made at the discretion of the site Principle Investigator Perinatal outcomes by CMA result Birth outcomes varied significantly by the type of fetal CNV detected and are presented in Table 2 . Fetuses with a pathogenic CNV had a higher TOP rate compared with those with a VUS (49.3% vs. 18.2%, p < 0.05) or ‘no clinically significant’ CNV (3.3%, p < 0.05). Table 2 Birth outcome of fetuses with and without a copy number variant. Pregnancy result Pathogenic copy number variant Variant of uncertain significance No clinically significant genomic imbalance Total n (% pCNVs) n (% VUS) n (% NAD) n (% total) Livebirth 93 (42.1) 244 (76.5) 1213 (93.9) 1550 (84.6) Termination of pregnancy 109 (49.3) 58 (18.2) 42 (3.3) 209 (11.4) Spontaneous stillbirth (≥ 20 weeks) 9 (4.1) 10 (3.1) 19 (1.5) 38 (2.1) Miscarriage (< 20 weeks) 7 (3.2) 2 (0.6) 10 (0.8) 19 (1.0) Neonatal death (death within 28 days of birth) 2 (0.9) 4 (1.3) 8 (0.6) 14 (0.8) Infant death (death within 2 years of birth) 1 (0.5) 1 (0.3) 0 (0.0) 2 (0.1) Total 221 (100.0) 319 (100.0) 1292 (100.0) 1832 (100.0) Abbreviations: pCNV, pathogenic copy number variant; VUS, variant of uncertain significance; NAD, no clinically significant genomic imbalance Perinatal outcome by indication for prenatal diagnosis The perinatal outcomes of pregnancies with and without a CNV varied by indication for prenatal diagnosis (Table 3 ). For pregnancies with a pCNV or VUS the most common indication for prenatal diagnosis was an ultrasound abnormality, 54.8% (121/221) and 62.4% (199/319) respectively. A TOP occurred in 56.2% (68/121) of cases with a pCNV and an ultrasound abnormality. In comparison, when there was a VUS and an ultrasound abnormality, a TOP occurred in 30.6% (61/199) of cases. Almost two percent of pregnancies with ‘no clinically significant genomic imbalance’ and a high chance screening result resulted in a TOP (17/1067). These did not have an ultrasound abnormality. Table 3 Birth outcomes of pregnancies with and without a copy number variant by indication for prenatal diagnosis Indications for prenatal diagnosis Livebirth Termination of pregnancy Spontaneous stillbirth ( ≥ 20weeks) Miscarriage (< 20 weeks) Neonatal/ infant death Total n (% indication) n (% indication) n (% indication) n (% indication) n (% indication) n (% indication) Pathogenic copy number variant Ultrasound abnormality † 39 (32.2) 68 (56.2) 7 (5.8) 4 (3.3) 3 (2.5) 121 (100.0) Positive screening result ‡ 35 (64.8) 16 (29.6) 1 (1.9) 2 (3.7) 0 (0.0) 54 (100.0) All other testing indications § 19 (41.3) 25 (54.3) 1 (2.2) 0 (0.0) 0 (0.0) 46 (100.0) Total 93 (42.1) 109 (49.3) 9 (4.1) 7 (3.2) 3 (1.4) 221 (100.0) Variant of uncertain significance Ultrasound abnormality † 138 (68.3) 46 (23.1) 9 (4.5) 2 (1.0) 4 (2.0) 199 (100.0) Positive screening result ‡ 74 (93.7) 3 (3.8) 1 (1.3) 0 (0.0) 1 (1.3) 79 (100.0) All other testing indications § 32 (78.0) 9 (22.0) 0 (0.0) 0 (0.0) 0 (0.0) 41 (100.0 Total 244 (76.5) 58 (18.2) 10 (3.1) 2 (0.6) 5 (1.6) 319 (100.0) No clinically significant genomic imbalance Ultrasound abnormality † 53 (68.8) 18 (23.4) 4 (5.2) 1 (1.3) 1 (1.3) 77 (100.0) 1 Positive screening result ‡ 1024 (96.0) 17 (1.6) 11 (1.0) 8 (0.7) 7 (0.7) 1067 (100.0) All other testing indications § 136 (91.9) 7 (4.7) 4 (2.7) 1 (0.7) 0 (0.0) 148 (100.0) Total 1213 (93.9) 42 (3.3) 19 (1.5) 10 (0.8) 8 (0.6) 1292 (100.0) † Ultrasound abnormality included soft marker on ultrasound such as increased nuchal translucency and hypoplastic nasal bone. ‡ Positive (‘high chance’ or ‘high risk’) screening result included non-invasive prenatal testing, first trimester combined screening and second trimester serum screening. § “ All other testing indications” included family history of chromosomal abnormality, single gene condition, and advanced maternal age. 1 70/77 had a concurrent indication of a positive (‘high chance’ or ‘high risk’) screening result. Responders and non-responders A total of 3304 research letters were sent to 1364 eligible patients over the 20-month study period (1607 invitations (including repeats), 893 first reminders, 804 second reminders) (Fig. 1 ). Initially, a third of all study invitations were returned to sender due to incorrect address (31.9%, 435/1364). An updated address was found for 43.2% (188/435) of these using the AEC public electoral roll. Overall, 1047 participants were successfully contacted (1047/1364, 76.8%). The rate of informed consent to participate in the PALM study among those who were successfully contacted (‘responders’) was 19.2% (201/1047) (Fig. 1 ). Comparison of cases and controls Data collected through examination of hospital medical records were used to compare the 1832 ‘potential participants’ (with a known birth outcome) stratified by CNV status (cases vs. controls). There were no consistent patterns of difference in sociodemographic characteristics between cases and controls in their study eligibility or ability to be contacted via mail (see Supplementary Table 1 and Supplementary Table 2 for details). A slight difference in response rate was observed with 23.8% of cases responding compared with 17.8% of controls (Table 4 ). Table 4 Potential sources of participation bias. Cases Controls Variable Responders (participants) Non-responders P value Responders (participants) Non-responders P value n = 57 (%) n = 182 (%) n = 144 (%) n = 664 (%) IRSAD quintile 1 (most disadvantaged) 9 (15.8) 29 (15.9) 0.40 6 (4.2) 75 (11.3) 0.012 2 4 (7.0) 25 (13.7) 22 (15.3) 77 (11.6) 3 13 (22.8) 52 (28.6) 29 (20.1) 184 (27.7) 4 17 (29.8) 46 (25.3) 48 (33.3) 190 (28.6) 5 (most advantaged) 14 (24.6) 20 (16.5) 39 (27.1) 138 (20.8) Remoteness area Metropolitan 45 (78.9) 158 (86.8) 0.15 127 (88.2) 613 (92.3) 0.11 Regional/remote 12 (21.1) 24 (13.2) 17 (11.8) 51 (7.7) Mother’s age at recruitment < 35 years 13 (22.8) 48 (26.4) 0.31 8 (5.6) 67 (10.1) 0.24 35–39 years 20 (35.1) 45 (24.7) 35 (24.3) 155 (23.3) ≥ 40 years 24 (42.1) 89 (48.9) 101 (70.1) 442 (66.6) Parity 0 22 (38.6) 58 (31.9) 0.83 55 (38.2) 205 (30.9) 0.0042 1 21 (36.8) 68 (37.4) 50 (34.7) 251 (37.8) 2 9 (15.8) 37 (20.3) 30 (20.8) 115 (17.3) 3 3 (5.3) 14 (7.7) 7 (4.9) 43 (6.5) 4+ 2 (3.5) 5 (2.7) 0 (0.0) 34 (5.1) Missing 0 (0.0) 0 (0.0) 2 (1.4) 16 (2.4) Child’s age at recruitment ≥ 5 years 25 (43.9) 58 (31.9) 0.097 35 (24.3) 173 (26.1) 0.66 < 5 years 32 (56.1) 124 (68.1) 109 (75.7) 491 (73.9) IRSAD, Index of Relative Socioeconomic Advantage and Disadvantage Compared with non-responding controls, participating controls were significantly more likely to be of higher socioeconomic status and lower parity. There was no evidence of any differences between responders and non-responding cases (Table 4 ). Private practice referrers A substantial proportion of patients were referred for their diagnostic procedure by a private referrer rather than a public hospital (1132/3868, 29.3%, Fig. 1 ). These 1132 patients were referred by 497 private clinicians. Of these, 304 clinicians (associated with 874 patients) could be contacted by phone and/or email; 28 clinicians (9.2%; associated with 119 patients (13.6%)) agreed to pre-screen their patients for study eligibility; 14 patients were ultimately recruited through this method. Data from the 119 patients screened by private referrers were not collected and were excluded from this analysis as pre-screening of potential participants was performed at the discretion of the private referrer. Regional participants One in five patients who had a prenatal diagnostic procedure in a tertiary hospital was referred from a regional hospital (175/850, 20.6%). To assist recruitment and minimise selection bias by location, the protocol was amended to include data collection from the three largest referring regional health services (representing 156/175 regional patients). It took on average 20-months from ethics amendment approval to site governance approval. The additional burden of adding these three sites resulted in an additional 9 participants (all cases). Recruitment rate Overall, the 201 mother-child pairs were recruited into the PALM childhood outcome study, comprising 144 controls and 57 cases (10 pCNVs, 47 VUS). This cohort represented 2.5% of the initial 8184 prenatal diagnosis cases pre-screened from the Victorian Prenatal Diagnosis Data Collection. This was lower than 8.7% (719/8184) recruitment rate estimated in the original study protocol. 15 DISCUSSION CMA has been instrumental in improving the diagnostic yield of prenatal diagnosis, but published data on the perinatal and paediatric outcomes of fetal CNVs are scarce due to their rarity. We conducted a lengthy and thorough manual linkage process to retrospectively recruit 201 mother-child pairs for a prospective childhood outcome study from a starting data source of re-identifiable prenatal diagnostic test results. This complex process was necessary to overcome the challenges of maintaining patient privacy and traversing siloed medical record information across health services and research institutes. Overall, the rates of TOP for the pCNVs in our cohort were at the lower end of the range reported in the literature. We observed a 49.3% TOP rate for pCNVs overall and a 56.2% TOP rate for pCNVs with an ultrasound abnormality. This compares with TOP rates for pCNV ranging from 50–100% in other studies. 13 , 14 , 27 – 32 Higher rates have been report for pCNVs with an ultrasound abnormality (either structural or soft marker) (76.2–100%) in China, France, and Israel. 13 , 29 – 32 Similarly, for VUS we observed a 18.2% TOP rate for VUS overall and a 23.1% rate for VUS with an ultrasound abnormality. Again, this aligns with the lower end of reported TOP rates for VUS from 11.0-44.9%, 14, 29 – 31 , 33 , 34 with higher rates for de novo VUS (50.8–58.0%) 13, 34 and fetuses with an ultrasound abnormality (17.1–37.5%). 13, 29 – 31 , 34 There are many methodological factors that may contribute to the different TOP rates for pCNV and VUS that preclude meaningful direct comparisons between studies. These factors include highly variable cohort sizes, study inclusion criteria, clinical testing pathways, CNV classification systems, health system and patient factors, availability of TOP, and timing of prenatal diagnosis. Paediatrics cohorts established from prenatal genomic testing populations are rare due to logistical and ethical challenges, yet they are crucial for obtaining long-term outcome data. A previous cohort of this nature examined the childhood outcomes of children prenatally diagnosed with confined placental mosaicism in the Australian state of Victoria. 35 By utilising the same prenatal diagnosis dataset this paediatric cohort was not biased towards children with an established clinical phenotype. Despite contacting participants 5.5 years after prenatal diagnosis, the study achieved a recruitment rate of 76%. This is almost four times the response rate achieved in our study (19.1%). It is unknown what factors contributed to the higher recruitment rate but one factor could be the clinician-patient relationship as the treating doctor facilitated the contact between the participant and the research team, rather than a hospital departmental representative as in our study. Moreover, despite modifying the study protocol to minimise exposure to COVID-19 (such as offering virtual assessments), the pandemic might have negatively influenced patient attitudes towards participating in research studies. 36 There are only two other studies that have reported paediatric outcomes of children with a prenatal diagnosis of a CNV. 13 , 37 Shi et al. prospectively followed up 109 children with a prenatally diagnosed VUS up the age of 2–4 years. Five children apparently showed clinical signs or phenotypic features of disease, but the clinical assessments were not described in detail. Muys et al. retrospectively recruited 85 mother-child pairs with a pCNV or VUS (‘cases’) and 123 with no or a benign CNV (‘controls’). The response rate of 15.8% (208/1312) was lower than our results, even though their study had lower participant burden (parental questionnaire only). However, these response rates may not be comparable. Muys et al. did not perform extensive pre-screening to determine perinatal outcomes: several participants were ineligible due to a perinatal or neonatal death. Had we not performed our extensive pre-screening step, 282 women who experienced a perinatal loss would have been invited to participate in our childhood outcome study. Also, Muys et al. did not report the number of research invitation letters successfully delivered, only the total number sent. Use of registered post and manual follow up at the AEC public roll enabled us to determine the number of potential participants successfully contacted. Of note 21.3% (43/201) of our final cohort were contacted following use of the AEC to update contact addresses, demonstrating the value of this additional step. Strengths and limitations This is one of the largest studies to manually determine the perinatal outcomes of pregnancies with and without a prenatally diagnosed CNV. Through this process, we have successfully established a paediatric cohort and prospectively conducted detailed cognitive and clinical assessments on each child. Data analysis is currently underway, with public dissemination of results expected in 2024. Another one of our strengths was the attention paid to patient psychological safety through manual record review and the exclusion of patients who had experienced a perinatal loss or infant death. We thereby averted potential distress for 282 families by removing them from our study invitation list. However, the extensive pre-screening procedures at multiple maternity hospitals and the siloed nature of Australian health records pose substantial resource and administrative barriers to future research of this type. One of the limitations of our cohort is the missing birth data on one quarter of potentially eligible patients due to private and regional referral patterns. This finding highlights the challenges in tracing participants and engaging with hospitals for population-based research studies. Future directions Establishing systems that enable the routine paediatric follow up of prenatally diagnosed genetic abnormalities are essential for understanding the full phenotypic spectrum of CNVs. In particular, there are no standard recommendations regarding long term follow up of children with VUS. Our cohort will provide long term outcome data on the developmental outcomes of children with VUS that may help guide future clinical care. One of the barriers to collecting long term outcomes from genomic CNVs is the limitations of current congenital anomaly coding systems such as the International Classification of Diseases 10th Revision (ICD-10). The ICD-10 has very few specific genetic diagnostic codes as it is based on phenotypes and organ systems. More locally, our state-wide Victorian Congenital Anomalies Report reports the population prevalence and birth outcomes for common autosomal trisomies but not CNVs (pathogenic or VUS). 38 Expanding the reporting of congenital anomalies to encompass a broader spectrum of genomic variants would offer a more comprehensive understanding of the impact of prenatal diagnosis and enable us to perform better quality linkage studies for long term outcome data. CONCLUSION This study provides Australia’s first population-based data on perinatal outcomes including termination of pregnancy following prenatal diagnostic testing with CMA. Three-quarters of fetuses with a VUS and less than half of fetuses with a pCNV resulted in a livebirth. Our establishment of a mother-child cohort via prenatal ascertainment was a complex and resource-intensive process, but an important step in understanding the impact of a CNV diagnosis in pregnancy and beyond. List of abbreviations AEC: Australian Electoral Commission; CMA: Chromosomal microarray; CNV: Copy number variant; CVS: Chorionic villus sampling; HREA: Human Research Ethics Application; HREC: Human Research Ethics Committee; MCRI: Murdoch Children’s Research Institute; NHMRC: National Health and Medical Research Council; PALM: PrenatAL Microarray; pCNV: Pathogenic copy number variant; TOP: termination of pregnancy; VPDD: Victorian Prenatal Diagnosis Data collection; VUS: Variants of uncertain/unknown significance; Declarations Ethics approval and consent to participate Ethics approval was granted by the Royal Children’s Hospital Human Research Ethics Committee (reference number 60542) and Mercy Health Human Research Ethics Committee (reference number 2020-46). All participating parents provided written informed consent. Consent for publication Not applicable Availability of data and materials The data that support the findings of this study are available from the corresponding author to researchers from a recognised academic institution upon reasonable request. Competing interests The authors declare they have no competing interests. Funding This study is being funded by a NHMRC Clinical Trials and Cohort Studies grant for 2020-2022 (NHMRC APP1186862). The funding body has had no role in the study design, in the writing of the protocol or in the decision to submit the paper for publication. LH receives salary support from a Medical Research Future Fund investigator grant (APP1196010) and the University of Melbourne. The PALM study is sponsored by MCRI. The contact on behalf of the sponsor is LH. Author’s contributions LH and JH conceived the original concept for this study. LH was the lead writer for the study protocol and funding application, with intellectual input from all members of the chief investigator team (JH, DA, SL, SP). CP and JM are salaried members of the PALM study team. Data collection was performed by CP and JK; CP and LH prepared the first draft of the manuscript. All authors read, provided intellectual input and approved the final version of this manuscript. Acknowledgements We thank the associate and site investigators in the PALM study group: Ms Joanne Kennedy (Murdoch Children’s Research Institute, Royal Women’s Hospital), Ms Fiona Norris (Victorian Clinical Genetics Services), Ms Lucy Gugasyan (Monash Pathology), Ms Emma Brown (Monash Pathology), Dr Suzanne Svobodova (Monash Pathology), Dr Matt Regan (Monash Medical Centre), Ms Helen Kincaid (Monash Medical Centre), Dr Anand Vasudevan (Royal Women’s Hospital and Western Health), Ms Susan Fawcett (Royal Women’s Hospital), Ms Melissa Graetz (Mercy Hospital for Women), A/Prof Joanne Said (Western Health), Dr Lisa Begg (Box Hill Hospital, Eastern Health), Dr Nicole Yuen (Bendigo Health), Dr Natasha Frawley (Grampians Health Ballarat), and Dr Geraldine Masson (Barwon Health Geelong). References Brady PD, Vermeesch JR. Genomic microarrays: a technology overview. Prenat Diagn. 2012;32(4):336-43. Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86(5):749-64. Manning M, Hudgins L. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet Med. 2010;12(11):742-5. Battaglia A, Doccini V, Bernardini L, Novelli A, Loddo S, Capalbo A, et al. Confirmation of chromosomal microarray as a first-tier clinical diagnostic test for individuals with developmental delay, intellectual disability, autism spectrum disorders and dysmorphic features. Eur J Paediatr Neurol. 2013;17(6):589-99. Royal Australian and New Zealand College of Obstetricians and Gynaecologists. Statement C-Obs 59. Prenatal screening and diagnosis of fetal chromosomal and genetic conditions. Available from: https://www.ranzcog.edu.au. 2018. Committee Opinion No.682: Microarrays and Next-Generation Sequencing Technology: The Use of Advanced Genetic Diagnostic Tools in Obstetrics and Gynecology. Obstet Gynecol. 2016;128(6):e262-e8. Wapner RJ, Martin CL, Levy B, Ballif BC, Eng CM, Zachary JM, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012;367(23):2175-84. Pynaker C, HUI L, HALLIDAY J. The Annual Report on Prenatal Diagnostic Testing in Victoria, 2021. Murdoch Childrens Research Institute; 2022. Pynaker C, Norris F, Hui L, Halliday J. Perinatal outcomes and genomic characteristics of fetal copy number variants: An individual record linkage study of 713 pregnancies. Prenat Diagn. 2023;43(4):516-26. Westerfield L, Darilek S, van den Veyver IB. Counseling Challenges with Variants of Uncertain Significance and Incidental Findings in Prenatal Genetic Screening and Diagnosis. J Clin Med. 2014;3(3):1018-32. Libman V, Friedlander Y, Chalk M, Hochner H, Shkedi-Rafid S. Receiving uncertain results from prenatal chromosomal microarray analysis: Women's decisions on continuation or termination of pregnancy. Prenat Diagn. 2023;43(6):773-80. Lou S, Lomborg K, Lewis C, Riedijk S, Petersen OB, Vogel I. \"It's probably nothing, but…\" Couples' experiences of pregnancy following an uncertain prenatal genetic result. Acta Obstet Gynecol Scand. 2020;99(6):791-801. Shi P, Liang H, Hou Y, Chen D, Ren H, Wang C, et al. The uncertainty of copy number variants: pregnancy decisions and clinical follow-up. Am J Obstet Gynecol. 2023;229(2):170.e1-.e8. Brabbing-Goldstein D, Reches A, Svirsky R, Bar-Shira A, Yaron Y. Dilemmas in genetic counseling for low-penetrance neuro-susceptibility loci detected on prenatal chromosomal microarray analysis. Am J Obstet Gynecol. 2018;218(2):247.e1-.e12. Hui L, Pynaker C, Kennedy J, Lewis S, Amor DJ, Walker SP, et al. Study protocol: childhood outcomes of fetal genomic variants: the PrenatAL Microarray (PALM) cohort study. BMC Pediatr. 2021;21(1):447. Australian Bureau of Statistics, Births, Australia. Lindquist A, Hui L, Poulton A, Kluckow E, Hutchinson B, Pertile MD, et al. State-wide utilization and performance of traditional and cell-free DNA-based prenatal testing pathways: the Victorian Perinatal Record Linkage (PeRL) study. Ultrasound Obstet Gynecol. 2020;56(2):215-24. Victoria, Australia. Abortion Law Reform Act 2008. ACT NUMBER 58/2008, (2008). Kearney HM, Thorland EC, Brown KK, Quintero-Rivera F, South ST. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med. 2011;13(7):680-5. South ST, Lee C, Lamb AN, Higgins AW, Kearney HM. ACMG Standards and Guidelines for constitutional cytogenomic microarray analysis, including postnatal and prenatal applications: revision 2013. Genet Med. 2013;15(11):901-9. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-24. Australian Bureau of Statistics, Census of Population and Housing: Socio-Economic Indexes for Areas, Index of Relative Socioeconomic Advantage and Disadvantage [Internet]. Australian Bureau of Statistics. 2016. Harris PA, Taylor R, Minor BL, Elliott V, Fernandez M, O'Neal L, et al. The REDCap consortium: Building an international community of software platform partners. J Biomed Inform. 2019;95:103208. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377-81. StataCorp. Stata Statistical Software: Release 17. College Station, TX: StataCorp LLC. 2021. Sergeant E. Epitools Epidemiological Calculators. Ausvet. Available at: http://epitools.ausvet.com.au. 2018. Stern S, Hacohen N, Meiner V, Yagel S, Zenvirt S, Shkedi-Rafid S, et al. Universal chromosomal microarray analysis reveals high proportion of copy-number variants in low-risk pregnancies. Ultrasound Obstet Gynecol. 2021;57(5):813-20. Li Y, Yan H, Chen J, Chen F, Jian W, Wang J, et al. The application of late amniocentesis: a retrospective study in a tertiary fetal medicine center in China. BMC Pregnancy Childbirth. 2021;21(1):266. Song T, Xu Y, Li Y, Zheng J, Guo F, Jin X, et al. Clinical Experience of Prenatal Chromosomal Microarray Analysis in 6159 Ultrasonically Abnormal Fetuses. Reprod Sci. 2023. Egloff M, Hervé B, Quibel T, Jaillard S, Le Bouar G, Uguen K, et al. Diagnostic yield of chromosomal microarray analysis in fetuses with isolated increased nuchal translucency: a French multicenter study. Ultrasound Obstet Gynecol. 2018;52(6):715-21. Cai M, Lin N, Su L, Wu X, Xie X, Li Y, et al. Copy number variations in ultrasonically abnormal late pregnancy fetuses with normal karyotypes. Sci Rep. 2020;10(1):15094. Hu T, Tian T, Zhang Z, Wang J, Hu R, Xiao L, et al. Prenatal chromosomal microarray analysis in 2466 fetuses with ultrasonographic soft markers: a prospective cohort study. Am J Obstet Gynecol. 2021;224(5):516.e1-.e16. Mardy AH, Wiita AP, Wayman BV, Drexler K, Sparks TN, Norton ME. Variants of uncertain significance in prenatal microarrays: a retrospective cohort study. Bjog. 2021;128(2):431-8. Chen L, Wang L, Yin D, Zeng Y, Tang F, Wang J. Influence of the detection of parent-of-origin on the pregnancy outcomes of fetuses with copy number variation of unknown significance. Sci Rep. 2020;10(1):8864. Amor DJ, Neo WT, Waters E, Heussler H, Pertile M, Halliday J. Health and developmental outcome of children following prenatal diagnosis of confined placental mosaicism. Prenat Diagn. 2006;26(5):443-8. Abdulhussein D, Yap TE, Manzar H, Miodragovic S, Cordeiro F. Factors impacting participation in research during the COVID-19 pandemic: results from a survey of patients in the ophthalmology outpatient department. Trials. 2022;23(1):823. Muys J, Jacquemyn Y, Blaumeiser B, Bourlard L, Brison N, Bulk S, et al. Prenatally detected copy number variants in a national cohort: A postnatal follow-up study. Prenat Diagn. 2020;40(10):1272-83. Congenital anomalies in Victoria, 2015-2016. Consultative Council on Obstetric and Paediatric Mortality and Morbidity; 2018. Additional Declarations The authors declare no competing interests. Supplementary Files SupplementaryTables.docx Cite Share Download PDF Status: Published Journal Publication published 21 Aug, 2024 Read the published version in BMC Pediatrics → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-4285240\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Research Article\",\"associatedPublications\":[],\"authors\":[{\"id\":292607601,\"identity\":\"9078d697-8886-49cd-b371-382ed2846e87\",\"order_by\":0,\"name\":\"Cecilia Pynaker\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Reproductive Epidemiology group, Murdoch Children’s Research Institute, Parkville, VIC, Australia\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Cecilia\",\"middleName\":\"\",\"lastName\":\"Pynaker\",\"suffix\":\"\"},{\"id\":292607602,\"identity\":\"4159ac88-c7fa-46ae-9e4e-0b35bae87c8e\",\"order_by\":1,\"name\":\"Jacqui McCoy\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Reproductive Epidemiology group, Murdoch Children’s Research Institute, Parkville, VIC, Australia\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Jacqui\",\"middleName\":\"\",\"lastName\":\"McCoy\",\"suffix\":\"\"},{\"id\":292607603,\"identity\":\"36ba407a-7c41-49a1-931c-07621b3f65e6\",\"order_by\":2,\"name\":\"Jane Halliday\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Reproductive Epidemiology group, Murdoch Children’s Research Institute, Parkville, VIC, Australia. Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Jane\",\"middleName\":\"\",\"lastName\":\"Halliday\",\"suffix\":\"\"},{\"id\":292607604,\"identity\":\"ac8ef89d-5d9c-4445-ae93-7c2759946971\",\"order_by\":3,\"name\":\"Sharon Lewis\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Reproductive Epidemiology group, Murdoch Children’s Research Institute, Parkville, VIC, Australia. Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Sharon\",\"middleName\":\"\",\"lastName\":\"Lewis\",\"suffix\":\"\"},{\"id\":292607605,\"identity\":\"58b54c6e-fe20-445c-9fc3-1e557e32acee\",\"order_by\":4,\"name\":\"David J Amor\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Reproductive Epidemiology group, Murdoch Children’s Research Institute, Parkville, VIC, Australia. Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia. Neurodisability and Rehabilitation group, Murdoch Children’s Research Institute, Parkville, VIC, Australia\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"David\",\"middleName\":\"J\",\"lastName\":\"Amor\",\"suffix\":\"\"},{\"id\":292607606,\"identity\":\"f86086cc-b994-4508-90e8-5373fd4e5e5d\",\"order_by\":5,\"name\":\"Susan P Walker\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Department of Obstetrics, Gynaecology and Newborn Medicine, University of Melbourne, Parkville, VIC, Australia. Mercy Hospital for Women, Heidelberg, VIC, Australia\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Susan\",\"middleName\":\"P\",\"lastName\":\"Walker\",\"suffix\":\"\"},{\"id\":292607607,\"identity\":\"122956e4-b87f-44e2-a5fc-b837b6cef9c8\",\"order_by\":6,\"name\":\"Lisa Hui\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8UlEQVRIie3OMYvCMBTA8VeEZglmfYLgVwgUSsEDv0q76BK7FI4bHAoHvc3Zr3GLOKqBuvQDZBVXB+XgcBKTiIMcBt1uyH9ISODHewA+3z+s3dJHUAJl+l4CJKm+uZOEN9IpLcEnCFwJ8KV9P0MI2R6ChexGarxaqw/MgXzOESbSsRiNMGgkjVWeStFgAbR+R6idBDCoDBFcjivMShQxQugiZHcyJJoZctakt9fk7CIQ2ykcDSnNFGp/XIvFSVaNKDZ7LkWNRUiHRZJNRw8JY5udOlb9AfsS0Y+YvOWMyG91+O0/JLb0bu6fH5/P5/O93AU+dErYDv/x/QAAAABJRU5ErkJggg==\",\"orcid\":\"https://orcid.org/0000-0002-9720-3562\",\"institution\":\"Reproductive Epidemiology group, Murdoch Children’s Research Institute, Parkville, VIC, Australia. Department of Obstetrics, Gynaecology and Newborn Medicine, University of Melbourne, Parkville, VIC, Australia. Mercy Hospital for Women, Heidelberg, VIC, Australia. Northern Health, Epping, VIC, Australia\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Lisa\",\"middleName\":\"\",\"lastName\":\"Hui\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2024-04-18 05:26:57\",\"currentVersionCode\":1,\"declarations\":{\"humanSubjects\":true,\"vertebrateSubjects\":false,\"conflictsOfInterestStatement\":false,\"humanSubjectEthicalGuidelines\":true,\"humanSubjectConsent\":true,\"humanSubjectClinicalTrial\":true,\"humanSubjectCaseReport\":false,\"vertebrateSubjectEthicalGuidelines\":false},\"doi\":\"10.21203/rs.3.rs-4285240/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-4285240/v1\",\"draftVersion\":[],\"editorialEvents\":[{\"content\":\"https://doi.org/10.1186/s12887-024-05012-6\",\"type\":\"published\",\"date\":\"2024-08-22T00:00:00+00:00\"}],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":55002703,\"identity\":\"dbb2dfd9-753f-46aa-988b-02ee0b6c29fa\",\"added_by\":\"auto\",\"created_at\":\"2024-04-19 18:40:37\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":223555,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eStudy flowchart of the pre-screening and recruitment of participants.\\u003c/p\\u003e\\n\\u003cp\\u003eCNV, copy number variant; pCNV, pathogenic copy number variant; VUS, copy number variant of uncertain significance\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"PALMFig118APR2024.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4285240/v1/7a2fc309d39e1697d237a68d.png\"},{\"id\":66420300,\"identity\":\"ca1216fb-8187-4697-95a4-d590866bd8fd\",\"added_by\":\"auto\",\"created_at\":\"2024-10-11 15:33:22\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":1258326,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4285240/v1/f97e870c-f936-4c27-8d36-c05294703170.pdf\"},{\"id\":55002704,\"identity\":\"eb646249-947b-4751-8646-b6c3ba2845e8\",\"added_by\":\"auto\",\"created_at\":\"2024-04-19 18:40:37\",\"extension\":\"docx\",\"order_by\":1,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":64097,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"SupplementaryTables.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-4285240/v1/d216d61de37a2ca5c476b959.docx\"}],\"financialInterests\":\"The authors declare no competing interests.\",\"formattedTitle\":\"\\u003cp\\u003ePerinatal outcomes after a prenatal diagnosis of a fetal copy number variant: A retrospective population-based cohort study\\u003c/p\\u003e\",\"fulltext\":[{\"header\":\"BACKGROUND\",\"content\":\"\\u003cp\\u003eChromosomal microarray analysis (CMA) can interrogate the human genome to a higher resolution than G-banded karyotyping.\\u003csup\\u003e\\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e\\u003c/sup\\u003e This has enabled the detection of submicroscopic deletions and duplications, termed copy number variants (CNVs), which can be benign or pathogenic depending on their location and gene content. CMA is well-established as the gold-standard first-tier diagnostic test for paediatric patients with an unexplained developmental disability, intellectual disability or congenital anomalies, providing 15\\u0026ndash;20% higher diagnostic yield than G-banded karyotyping.\\u003csup\\u003e\\u003cspan additionalcitationids=\\\"CR3\\\" citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e\\u003c/sup\\u003e\\u003c/p\\u003e \\u003cp\\u003eAlongside paediatric care, CMA has also revolutionised prenatal care. It has been 10 years since CMA replaced G-banded karyotyping as the recommended diagnostic test for fetuses with an ultrasound abnormality because of its superior diagnostic yield.\\u003csup\\u003e\\u003cspan additionalcitationids=\\\"CR6\\\" citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e\\u003c/sup\\u003e CMAs can detect pathogenic copy number variants (pCNV) linked to established syndromes, but also CNV of uncertain clinical significance (VUS). VUS are CNVs that often involve non-disease causing genes, may not have been previously identified or described, or for which there is limited information on genotype-phenotype correlation due to incomplete penetrance and variable expressivity.\\u003c/p\\u003e \\u003cp\\u003eIn the Australian state of Victoria, there has been an increase in the proportion of prenatal diagnostic tests analysed with CMA, from 39.4% in 2013 to 93.1% in 2021, regardless of indication for testing.\\u003csup\\u003e\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e\\u003c/sup\\u003e Concurrently, the proportion of fetuses diagnosed with a pCNV has increased over the past decade, from 1.0% in 2013 to 4.4% in 2022.\\u003csup\\u003e\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e\\u003c/sup\\u003e The most frequent pCNVs in our population are 22q11.2 deletion (DiGeorge syndrome), 4p16.3 deletion (Wolf-Hischhorn syndrome), and 5p15.33 deletion (cri-du-chat syndrome).\\u003csup\\u003e\\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e\\u003c/sup\\u003e These account for 13.5%, 3.9%, 3.0% of pregnancies with a pCNV respectively. However, the vast majority of pCNVs are rare, which makes counselling on long term childhood outcomes difficult, especially when ascertained before birth when the phenotype is incomplete.\\u003c/p\\u003e \\u003cp\\u003eA VUS is diagnosed in approximately 5% of fetuses following chorionic villus sampling or amniocentesis.\\u003csup\\u003e\\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e\\u003c/sup\\u003e These VUS can be challenging as there is often no prenatal phenotype to guide CNV interpretation. The limited data available are commonly skewed towards cases diagnosed postnatally, possibly biased towards the more severe end of the phenotypic spectrum.\\u003csup\\u003e\\u003cspan additionalcitationids=\\\"CR11\\\" citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e\\u003c/sup\\u003e In Australia, there are currently no guidelines for the routine follow up and assessment of children with a prenatally diagnosed VUS. Furthermore, as genomic databases and clinical interpretation guidelines are updated some prenatal VUS are subsequently reclassified as either pathogenic or benign.\\u003csup\\u003e\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e\\u003c/sup\\u003e This highlights the challenge of providing appropriate long term care, as children may not only be lost to follow up after the newborn period, but may also carry a nonextant genetic diagnosis throughout childhood due to changes in scientific knowledge.\\u003csup\\u003e\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e\\u003c/sup\\u003e\\u003c/p\\u003e \\u003cp\\u003eThe PrenatAL Microarray (PALM) is a nationally-funded cohort study of mother-child pairs who have had a prenatal diagnosis with a chromosomal microarray (CMA) from 2013 to 2019 in the Australian state of Victoria. In brief, this cohort study of children- with and without a prenatally-ascertained CNV- aims to examine their developmental, social-emotional and health outcomes in early childhood through a range of parent completed questions, in person cognitive assessments, and clinical paediatric review.\\u003csup\\u003e\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e\\u003c/sup\\u003e The full protocol has been previously published in this journal.\\u003csup\\u003e\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e\\u003c/sup\\u003e\\u003c/p\\u003e \\u003cp\\u003eIn this paper, we report the perinatal outcomes of fetuses that had a prenatal chromosomal microarray (potential PALM participants, with and without a CNV), including rates of termination of pregnancy (TOP) and spontaneous perinatal losses following prenatal diagnosis. We also present the challenges of creating a representative paediatric cohort of children from a prenatal cohort.\\u003c/p\\u003e\"},{\"header\":\"METHODS\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eStudy population\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis was a population-based study set in the Australian state of Victoria. Victoria has approximately 78,000 births per year with a median maternal age of 31.5 years.\\u003csup\\u003e\\u003cspan class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e\\u003c/sup\\u003e All pregnant individuals are offered screening for fetal structural anomalies and chromosomal conditions, with an uptake of 83.6% state-wide.\\u003csup\\u003e17\\u003c/sup\\u003e Between 2013\\u0026ndash;2021, 80.9% of prenatal diagnostic tests were analysed by CMA.\\u003csup\\u003e\\u003cspan class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e\\u003c/sup\\u003e TOP is lawful on maternal request up to 24 weeks, and after 24 weeks if two medical practitioners deem it \\u0026ldquo;appropriate in all the circumstances\\u0026rdquo;.\\u003csup\\u003e\\u003cspan class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eEligibility criteria for paediatric cohort\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eParticipants were eligible if: the pregnancy resulted in a livebirth, they were the primary-caregiver for the child at hospital discharge, resident in the Australian state of Victoria, and able to provide informed consent in English (did not require a translator).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eData sources\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eMultiple sources were utilised to identify and pre-screen potential study participants.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eVictorian Prenatal Diagnosis Database\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe Victorian Prenatal Diagnosis Database (VPDD) is a population-based research dataset that collects all chromosome testing results from amniotic fluid and chorionic villus samples (CVS).\\u003csup\\u003e\\u003cspan class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e\\u003c/sup\\u003e The VPDD was screened for pregnant individuals who underwent prenatal diagnosis with CMA from January 2013 to December 2019. Clinical laboratories classified prenatal CNVs in accordance with established guidelines.\\u003csup\\u003e\\u003cspan class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e\\u0026ndash;\\u003cspan class=\\\"CitationRef\\\"\\u003e21\\u003c/span\\u003e\\u003c/sup\\u003e \\u0026lsquo;Cases\\u0026rsquo; included pregnancies with a pathogenic or likely pathogenic CNV (pCNV) and variant of uncertain significance (VUS). \\u0026lsquo;Controls\\u0026rsquo; were pregnancies that had a primary clinical indication other than an ultrasound abnormality and had \\u0026lsquo;no clinically significant genomic imbalance\\u0026rsquo; reported on CMA. These included positive (\\u0026lsquo;high chance) screening result (non-invasive prenatal testing, combined first trimester screening, or second trimester serum screening), and other testing indications (such as advanced maternal age, maternal request). There were also some controls where the ultrasound abnormality was a secondary indication after a primary indication of a positive screening result.\\u003c/p\\u003e\\n\\u003cp\\u003eDue to the modifier of a structural anomaly or known genetic condition on childhood outcomes, \\u0026lsquo;controls\\u0026rsquo; with a clinical indication of a fetal structural abnormality, family history of a chromosomal condition or a single gene condition were excluded. Further details will be available in the next phase of the PALM study and any controls with a major structural abnormality on antenatal ultrasound excluded from analysis.\\u003c/p\\u003e\\n\\u003cp\\u003eClinical laboratories that submitted the cases and controls to the VPDD internally reidentified records and obtained the name of the public maternity hospital or private clinical referrer. Follow up was different for these two groups:\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003ea) Public hospital medical record review\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eHospital medical records were manually reviewed for perinatal outcome and study eligibility. Perinatal outcomes were coded as either miscarriage (spontaneous pregnancy loss\\u0026thinsp;\\u0026lt;\\u0026thinsp;20 weeks\\u0026rsquo; gestation), stillbirth (infant born with no signs of life\\u0026thinsp;\\u0026ge;\\u0026thinsp;20 weeks\\u0026rsquo; gestation), TOP, neonatal death (death within 28 days of birth), infant death (death within 2 years of birth), or live birth.\\u003c/p\\u003e\\n\\u003cp\\u003eA minimum de-identified dataset was collected for all individuals screened containing: hospital name, maternal postcode, test date, gestational age, clinical indication, CNV classification, perinatal outcome, parity, and study eligibility status. Maternal postcode was mapped to the corresponding local government area and assigned the relevant Index of Relative Socioeconomic Advantage and Disadvantage (IRSAD) allocated by the Australian Bureau of Statistics from 2016 Census data.\\u003csup\\u003e\\u003cspan class=\\\"CitationRef\\\"\\u003e22\\u003c/span\\u003e\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eb) Private clinical referrers\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003ePrivate clinicians were contacted by phone and/or email and asked to pre-screen their patients for study eligibility and send an invitation letter to eligible participants. No minimum dataset was collected for these patients as pre-screening was performed at the clinician\\u0026rsquo;s discretion.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eStudy recruitment\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eStudy invitation letters were sent by registered post between November 2021 and June 2023. Each contained a participant information and consent form, hard-copy questionnaire booklet, and replied paid envelope. Registered post enabled tracking of research letters, including proof of mailing and signature on delivery. The public roll of the Australian Electoral Commission (AEC) was used to check the details of participants whose post were returned to sender. Participants had the option to complete a hard copy or online consent form and questionnaire. Completed hard copies were returned using the provided replied paid envelope, while the online version, hosted in Research Electronic Data Capture (REDCap), were accessed via a QR code in the invitation letter.\\u003csup\\u003e\\u003cspan class=\\\"CitationRef\\\"\\u003e23\\u003c/span\\u003e, \\u003cspan class=\\\"CitationRef\\\"\\u003e24\\u003c/span\\u003e\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eProtocol amendments\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003ePandemic impacts\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eIn response to the COVID-19 pandemic in 2020, the study protocol was updated to include alternative online child assessments. Due to pandemic-related disruptions, a 12-month extension was requested due to delays in recruitment, participant assessments, and obtaining approvals for new regional sites.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eLow recruitment rate\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eIn response to a low recruitment rate, the study protocol was amended. Participants were: (i) sent two reminder letters, and (ii) offered an AUD$110 gift card in appreciation of their time. The first reminder was sent three weeks after the initial study invitation (if successfully delivered), and the second reminder three weeks after the first reminder. Ethics Committee approval for all amendments was obtained.\\u003c/p\\u003e\\n\\u003cdiv id=\\\"Sec3\\\" class=\\\"Section2\\\"\\u003e\\n\\u003ch2\\u003eStatistical analysis\\u003c/h2\\u003e\\n\\u003cp\\u003eStatistical analysis was performed in Stata17 using chi-squared test for proportions with p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05 considered significant.\\u003csup\\u003e\\u003cspan class=\\\"CitationRef\\\"\\u003e25\\u003c/span\\u003e\\u003c/sup\\u003e Wilson score method was used to calculate 95% confidence intervals using Epitools.\\u003csup\\u003e\\u003cspan class=\\\"CitationRef\\\"\\u003e26\\u003c/span\\u003e\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eEthics approval\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis study received Human Research Ethics Committee approval from the Royal Children\\u0026rsquo;s Hospital on April 8, 2020 (Reference no. 60542) and Mercy Health on September 15, 2020 (Reference no. 2020-046).\\u003c/p\\u003e\\n\\u003c/div\\u003e\"},{\"header\":\"RESULTS\",\"content\":\"\\u003cp\\u003e\\u003cem\\u003ePre-screening of potential participants\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eDuring the 7-year study period 8184 prenatal diagnostic tests were performed by CMA; a fetal CNV was reported for 1029 samples (12.6%, 95%CI: 11.9\\u0026ndash;13.3%), and \\u0026lsquo;no clinically significant CNV\\u0026rsquo; reported in 7155 samples (87.4%, 95%CI: 85.7\\u0026ndash;88.1%). Of these, 4316 with \\u0026lsquo;no clinically significant CNV\\u0026rsquo; were excluded due to an indication of an ultrasound abnormality, family history of a chromosomal condition, or a single gene condition.\\u003c/p\\u003e\\n\\u003cp\\u003eFigure \\u003cspan class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e illustrates the pre-screening and recruitment of participants with and without a copy number variant.\\u003c/p\\u003e\\n\\u003cp\\u003eThe personal identifiers of the 2458 potential cases and controls were provided to the eight relevant hospitals and were manually reviewed for eligibility criteria. Only 74.5% (n\\u0026thinsp;=\\u0026thinsp;1832) had a known birth outcome documented in the hospital records. The remaining missing birth outcome data was due to patients delivering in a different hospital to the one in which the prenatal diagnostic procedure was performed.\\u003c/p\\u003e\\n\\u003cp\\u003eOf those with a known birth outcome (n\\u0026thinsp;=\\u0026thinsp;1832), 1364 (74.5%) were eligible for recruitment (\\u0026lsquo;potential participants\\u0026rsquo;) and 468 (25.5%) were ineligible. Of the 468 ineligible, 282 (60.3%) had \\u0026lsquo;no live pregnancy outcome\\u0026rsquo; (209 terminations of pregnancy (TOP) and 73 miscarriages, stillbirths, and infant deaths), 157 (33.5%) required a translator, and 29 (6.2%) were excluded for other reasons (Table\\u0026nbsp;\\u003cspan class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e).\\u003c/p\\u003e\\n\\u003cdiv class=\\\"gridtable\\\"\\u003e\\n\\u003ctable id=\\\"Tab1\\\" border=\\\"1\\\"\\u003e\\u003ccaption\\u003e\\n\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 1\\u003c/div\\u003e\\n\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\n\\u003cp\\u003eReasons for study ineligibility.\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003c/caption\\u003e\\n\\u003cthead\\u003e\\n\\u003ctr\\u003e\\n\\u003cth rowspan=\\\"2\\\" align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eReason for study ineligibility\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ePathogenic copy number variant\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eVariant of uncertain significance\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eNo clinically significant genomic imbalance\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eTotal\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003en (% pCNVs)\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003en (% VUS)\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003en (% NAD)\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003en (% total)\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003c/tr\\u003e\\n\\u003c/thead\\u003e\\n\\u003ctbody\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ePerinatal/infant death\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e128 (90.1)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e75 (72.8)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e79 (35.4)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e282 (60.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eTranslator required\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e12 (8.5)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e22 (21.4)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e123 (55.2)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e157 (33.5)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eMother (gestational carrier) not the intended primary caregiver\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1 (0.7)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1 (1.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e7 (3.1)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e9 (1.9)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eMultifetal pregnancy\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0 (0.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0 (0.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e2 (0.9)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e2 (0.4)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eUnable to provide informed consent\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0 (0.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1 (1.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0 (0.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1 (0.2)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eOther\\u003csup\\u003e\\u0026dagger;\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1 (0.7)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e4 (3.9)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e12 (5.4)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e17 (3.6)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eTotal\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e142 (100.0)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e103 (100.0)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e223 (100.0)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e468 (100.0)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003c/tbody\\u003e\\n\\u003ctfoot\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd colspan=\\\"5\\\"\\u003eAbbreviations: pCNV, pathogenic copy number variant; VUS, variant of uncertain significance; NAD, no clinically significant genomic imbalance\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd colspan=\\\"5\\\"\\u003e\\u003csup\\u003e\\u0026dagger;\\u003c/sup\\u003e Other reasons for study ineligibility were made at the discretion of the site Principle Investigator\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003c/tfoot\\u003e\\n\\u003c/table\\u003e\\n\\u003c/div\\u003e\\n\\u003cp\\u003e\\u003cem\\u003ePerinatal outcomes by CMA result\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eBirth outcomes varied significantly by the type of fetal CNV detected and are presented in Table\\u0026nbsp;\\u003cspan class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003e. Fetuses with a pathogenic CNV had a higher TOP rate compared with those with a VUS (49.3% vs. 18.2%, p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05) or \\u0026lsquo;no clinically significant\\u0026rsquo; CNV (3.3%, p\\u0026thinsp;\\u0026lt;\\u0026thinsp;0.05).\\u003c/p\\u003e\\n\\u003cdiv class=\\\"gridtable\\\"\\u003e\\n\\u003ctable id=\\\"Tab2\\\" border=\\\"1\\\"\\u003e\\u003ccaption\\u003e\\n\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 2\\u003c/div\\u003e\\n\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\n\\u003cp\\u003eBirth outcome of fetuses with and without a copy number variant.\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003c/caption\\u003e\\n\\u003cthead\\u003e\\n\\u003ctr\\u003e\\n\\u003cth rowspan=\\\"2\\\" align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ePregnancy result\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ePathogenic copy number variant\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eVariant of uncertain significance\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eNo clinically significant genomic imbalance\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eTotal\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003en (% pCNVs)\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003en (% VUS)\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003en (% NAD)\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003en (% total)\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003c/tr\\u003e\\n\\u003c/thead\\u003e\\n\\u003ctbody\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eLivebirth\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e93 (42.1)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e244 (76.5)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1213 (93.9)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1550 (84.6)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eTermination of pregnancy\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e109 (49.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e58 (18.2)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e42 (3.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e209 (11.4)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eSpontaneous stillbirth\\u003c/p\\u003e\\n\\u003cp\\u003e(\\u0026ge;\\u0026thinsp;20 weeks)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e9 (4.1)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e10 (3.1)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e19 (1.5)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e38 (2.1)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eMiscarriage\\u003c/p\\u003e\\n\\u003cp\\u003e(\\u0026lt;\\u0026thinsp;20 weeks)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e7 (3.2)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e2 (0.6)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e10 (0.8)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e19 (1.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eNeonatal death\\u003c/p\\u003e\\n\\u003cp\\u003e(death within 28 days of birth)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e2 (0.9)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e4 (1.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e8 (0.6)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e14 (0.8)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eInfant death\\u003c/p\\u003e\\n\\u003cp\\u003e(death within 2 years of birth)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1 (0.5)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e1 (0.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e0 (0.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e2 (0.1)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eTotal\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e221 (100.0)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e319 (100.0)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e1292 (100.0)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"char\\\" char=\\\".\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e1832 (100.0)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003c/tbody\\u003e\\n\\u003ctfoot\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd colspan=\\\"5\\\"\\u003eAbbreviations: pCNV, pathogenic copy number variant; VUS, variant of uncertain significance; NAD, no clinically significant genomic imbalance\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003c/tfoot\\u003e\\n\\u003c/table\\u003e\\n\\u003c/div\\u003e\\n\\u003cp\\u003e\\u003cem\\u003ePerinatal outcome by indication for prenatal diagnosis\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe perinatal outcomes of pregnancies with and without a CNV varied by indication for prenatal diagnosis (Table\\u0026nbsp;\\u003cspan class=\\\"InternalRef\\\"\\u003e3\\u003c/span\\u003e). For pregnancies with a pCNV or VUS the most common indication for prenatal diagnosis was an ultrasound abnormality, 54.8% (121/221) and 62.4% (199/319) respectively. A TOP occurred in 56.2% (68/121) of cases with a pCNV and an ultrasound abnormality. In comparison, when there was a VUS and an ultrasound abnormality, a TOP occurred in 30.6% (61/199) of cases. Almost two percent of pregnancies with \\u0026lsquo;no clinically significant genomic imbalance\\u0026rsquo; and a high chance screening result resulted in a TOP (17/1067). These did not have an ultrasound abnormality.\\u003c/p\\u003e\\n\\u003cdiv class=\\\"gridtable\\\"\\u003e\\n\\u003ctable id=\\\"Tab3\\\" border=\\\"1\\\"\\u003e\\u003ccaption\\u003e\\n\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 3\\u003c/div\\u003e\\n\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\n\\u003cp\\u003eBirth outcomes of pregnancies with and without a copy number variant by indication for prenatal diagnosis\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003c/caption\\u003e\\n\\u003cthead\\u003e\\n\\u003ctr\\u003e\\n\\u003cth rowspan=\\\"2\\\" align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eIndications for prenatal diagnosis\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eLivebirth\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eTermination of pregnancy\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eSpontaneous stillbirth\\u003c/p\\u003e\\n\\u003cp\\u003e(\\u003cspan class=\\\"Underline\\\"\\u003e\\u0026ge;\\u003c/span\\u003e\\u0026thinsp;20weeks)\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eMiscarriage\\u003c/p\\u003e\\n\\u003cp\\u003e(\\u0026lt;\\u0026thinsp;20 weeks)\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eNeonatal/\\u003c/p\\u003e\\n\\u003cp\\u003einfant death\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eTotal\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003en (% indication)\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003en (% indication)\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003en (% indication)\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003en (% indication)\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003en (% indication)\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003en (% indication)\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003c/tr\\u003e\\n\\u003c/thead\\u003e\\n\\u003ctbody\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd colspan=\\\"7\\\" align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003ePathogenic copy number variant\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eUltrasound abnormality\\u003csup\\u003e\\u0026dagger;\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e39 (32.2)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e68 (56.2)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e7 (5.8)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e4 (3.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e3 (2.5)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e121 (100.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ePositive screening result\\u003csup\\u003e\\u0026Dagger;\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e35 (64.8)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e16 (29.6)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e1 (1.9)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e2 (3.7)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0 (0.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e54 (100.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eAll other testing indications\\u003csup\\u003e\\u0026sect;\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e19 (41.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e25 (54.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e1 (2.2)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0 (0.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0 (0.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e46 (100.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eTotal\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e93 (42.1)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e109 (49.3)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e9 (4.1)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e7 (3.2)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e3 (1.4)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e221 (100.0)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd colspan=\\\"7\\\" align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eVariant of uncertain significance\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eUltrasound abnormality\\u003csup\\u003e\\u0026dagger;\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e138 (68.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e46 (23.1)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e9 (4.5)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e2 (1.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e4 (2.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e199 (100.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ePositive screening result\\u003csup\\u003e\\u0026Dagger;\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e74 (93.7)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e3 (3.8)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e1 (1.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0 (0.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e1 (1.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e79 (100.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eAll other testing indications\\u003csup\\u003e\\u0026sect;\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e32 (78.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e9 (22.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0 (0.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0 (0.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0 (0.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e41 (100.0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eTotal\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e244 (76.5)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e58 (18.2)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e10 (3.1)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e2 (0.6)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e5 (1.6)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e319 (100.0)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd colspan=\\\"7\\\" align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eNo clinically significant genomic imbalance\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eUltrasound abnormality\\u003csup\\u003e\\u0026dagger;\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e53 (68.8)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e18 (23.4)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e4 (5.2)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e1 (1.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e1 (1.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e77 (100.0)\\u003csup\\u003e\\u003cspan class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003ePositive screening result\\u003csup\\u003e\\u0026Dagger;\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e1024 (96.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e17 (1.6)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e11 (1.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e8 (0.7)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e7 (0.7)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e1067 (100.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eAll other testing indications\\u003csup\\u003e\\u0026sect;\\u003c/sup\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e136 (91.9)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e7 (4.7)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e4 (2.7)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e1 (0.7)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0 (0.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e148 (100.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eTotal\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e1213 (93.9)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e42 (3.3)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e19 (1.5)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e10 (0.8)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e8 (0.6)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003e1292 (100.0)\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003c/tbody\\u003e\\n\\u003ctfoot\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd colspan=\\\"7\\\"\\u003e\\u003csup\\u003e\\u0026dagger;\\u003c/sup\\u003eUltrasound abnormality included soft marker on ultrasound such as increased nuchal translucency and hypoplastic nasal bone.\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd colspan=\\\"7\\\"\\u003e\\u003csup\\u003e\\u0026Dagger;\\u003c/sup\\u003ePositive (\\u0026lsquo;high chance\\u0026rsquo; or \\u0026lsquo;high risk\\u0026rsquo;) screening result included non-invasive prenatal testing, first trimester combined screening and second trimester serum screening.\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd colspan=\\\"7\\\"\\u003e\\u003csup\\u003e\\u0026sect; \\u0026ldquo;\\u003c/sup\\u003eAll other testing indications\\u0026rdquo; included family history of chromosomal abnormality, single gene condition, and advanced maternal age.\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd colspan=\\\"7\\\"\\u003e\\u003csup\\u003e1\\u003c/sup\\u003e 70/77 had a concurrent indication of a positive (\\u0026lsquo;high chance\\u0026rsquo; or \\u0026lsquo;high risk\\u0026rsquo;) screening result.\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003c/tfoot\\u003e\\n\\u003c/table\\u003e\\n\\u003c/div\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eResponders and non-responders\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eA total of 3304 research letters were sent to 1364 eligible patients over the 20-month study period (1607 invitations (including repeats), 893 first reminders, 804 second reminders) (Fig.\\u0026nbsp;\\u003cspan class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). Initially, a third of all study invitations were returned to sender due to incorrect address (31.9%, 435/1364). An updated address was found for 43.2% (188/435) of these using the AEC public electoral roll. Overall, 1047 participants were successfully contacted (1047/1364, 76.8%).\\u003c/p\\u003e\\n\\u003cp\\u003eThe rate of informed consent to participate in the PALM study among those who were successfully contacted (\\u0026lsquo;responders\\u0026rsquo;) was 19.2% (201/1047) (Fig.\\u0026nbsp;\\u003cspan class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cem\\u003eComparison of cases and controls\\u003c/em\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eData collected through examination of hospital medical records were used to compare the 1832 \\u0026lsquo;potential participants\\u0026rsquo; (with a known birth outcome) stratified by CNV status (cases vs. controls).\\u003c/p\\u003e\\n\\u003cp\\u003eThere were no consistent patterns of difference in sociodemographic characteristics between cases and controls in their study eligibility or ability to be contacted via mail (see Supplementary Table\\u0026nbsp;1 and Supplementary Table\\u0026nbsp;2 for details). A slight difference in response rate was observed with 23.8% of cases responding compared with 17.8% of controls (Table\\u0026nbsp;\\u003cspan class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003e).\\u003c/p\\u003e\\n\\u003cdiv class=\\\"gridtable\\\"\\u003e\\n\\u003ctable id=\\\"Tab4\\\" border=\\\"1\\\"\\u003e\\u003ccaption\\u003e\\n\\u003cdiv class=\\\"CaptionNumber\\\"\\u003eTable 4\\u003c/div\\u003e\\n\\u003cdiv class=\\\"CaptionContent\\\"\\u003e\\n\\u003cp\\u003ePotential sources of participation bias.\\u003c/p\\u003e\\n\\u003c/div\\u003e\\n\\u003c/caption\\u003e\\n\\u003cthead\\u003e\\n\\u003ctr\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\n\\u003cth colspan=\\\"3\\\" align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eCases\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth colspan=\\\"3\\\" align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eControls\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003cth rowspan=\\\"2\\\" align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eVariable\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eResponders (participants)\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eNon-responders\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eP value\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eResponders (participants)\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eNon-responders\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eP value\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003en\\u0026thinsp;=\\u0026thinsp;57 (%)\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003en\\u0026thinsp;=\\u0026thinsp;182 (%)\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003en\\u0026thinsp;=\\u0026thinsp;144 (%)\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\n\\u003cp\\u003en\\u0026thinsp;=\\u0026thinsp;664 (%)\\u003c/p\\u003e\\n\\u003c/th\\u003e\\n\\u003cth align=\\\"left\\\"\\u003e\\u0026nbsp;\\u003c/th\\u003e\\n\\u003c/tr\\u003e\\n\\u003c/thead\\u003e\\n\\u003ctbody\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd colspan=\\\"7\\\" align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eIRSAD quintile\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e1 (most disadvantaged)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e9 (15.8)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e29 (15.9)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd rowspan=\\\"5\\\" align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0.40\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e6 (4.2)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e75 (11.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd rowspan=\\\"5\\\" align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0.012\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e2\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e4 (7.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e25 (13.7)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e22 (15.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e77 (11.6)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e3\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e13 (22.8)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e52 (28.6)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e29 (20.1)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e184 (27.7)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e4\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e17 (29.8)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e46 (25.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e48 (33.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e190 (28.6)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e5 (most advantaged)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e14 (24.6)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e20 (16.5)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e39 (27.1)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e138 (20.8)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd colspan=\\\"7\\\" align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eRemoteness area\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eMetropolitan\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e45 (78.9)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e158 (86.8)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd rowspan=\\\"2\\\" align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0.15\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e127 (88.2)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e613 (92.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd rowspan=\\\"2\\\" align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0.11\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eRegional/remote\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e12 (21.1)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e24 (13.2)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e17 (11.8)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e51 (7.7)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd colspan=\\\"7\\\" align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eMother\\u0026rsquo;s age at recruitment\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u0026lt;\\u0026thinsp;35 years\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e13 (22.8)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e48 (26.4)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd rowspan=\\\"3\\\" align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0.31\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e8 (5.6)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e67 (10.1)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd rowspan=\\\"3\\\" align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0.24\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e35\\u0026ndash;39 years\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e20 (35.1)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e45 (24.7)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e35 (24.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e155 (23.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u0026ge;\\u0026thinsp;40 years\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e24 (42.1)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e89 (48.9)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e101 (70.1)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e442 (66.6)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd colspan=\\\"7\\\" align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eParity\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e22 (38.6)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e58 (31.9)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd rowspan=\\\"6\\\" align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0.83\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e55 (38.2)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e205 (30.9)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd rowspan=\\\"6\\\" align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0.0042\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e1\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e21 (36.8)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e68 (37.4)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e50 (34.7)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e251 (37.8)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e2\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e9 (15.8)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e37 (20.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e30 (20.8)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e115 (17.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e3\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e3 (5.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e14 (7.7)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e7 (4.9)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e43 (6.5)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e4+\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e2 (3.5)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e5 (2.7)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0 (0.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e34 (5.1)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003eMissing\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0 (0.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0 (0.0)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e2 (1.4)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e16 (2.4)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd colspan=\\\"7\\\" align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eChild\\u0026rsquo;s age at recruitment\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u0026ge;\\u0026thinsp;5 years\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e25 (43.9)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e58 (31.9)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd rowspan=\\\"2\\\" align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0.097\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e35 (24.3)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e173 (26.1)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd rowspan=\\\"2\\\" align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e0.66\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e\\u0026lt;\\u0026thinsp;5 years\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e32 (56.1)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e124 (68.1)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e109 (75.7)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003ctd align=\\\"left\\\"\\u003e\\n\\u003cp\\u003e491 (73.9)\\u003c/p\\u003e\\n\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003c/tbody\\u003e\\n\\u003ctfoot\\u003e\\n\\u003ctr\\u003e\\n\\u003ctd colspan=\\\"7\\\"\\u003eIRSAD, Index of Relative Socioeconomic Advantage and Disadvantage\\u003c/td\\u003e\\n\\u003c/tr\\u003e\\n\\u003c/tfoot\\u003e\\n\\u003c/table\\u003e\\n\\u003c/div\\u003e\\n\\u003cp\\u003eCompared with non-responding controls, participating controls were significantly more likely to be of higher socioeconomic status and lower parity. There was no evidence of any differences between responders and non-responding cases (Table\\u0026nbsp;\\u003cspan class=\\\"InternalRef\\\"\\u003e4\\u003c/span\\u003e).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003ePrivate practice referrers\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eA substantial proportion of patients were referred for their diagnostic procedure by a private referrer rather than a public hospital (1132/3868, 29.3%, Fig.\\u0026nbsp;\\u003cspan class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003e). These 1132 patients were referred by 497 private clinicians. Of these, 304 clinicians (associated with 874 patients) could be contacted by phone and/or email; 28 clinicians (9.2%; associated with 119 patients (13.6%)) agreed to pre-screen their patients for study eligibility; 14 patients were ultimately recruited through this method. Data from the 119 patients screened by private referrers were not collected and were excluded from this analysis as pre-screening of potential participants was performed at the discretion of the private referrer.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eRegional participants\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eOne in five patients who had a prenatal diagnostic procedure in a tertiary hospital was referred from a regional hospital (175/850, 20.6%). To assist recruitment and minimise selection bias by location, the protocol was amended to include data collection from the three largest referring regional health services (representing 156/175 regional patients). It took on average 20-months from ethics amendment approval to site governance approval. The additional burden of adding these three sites resulted in an additional 9 participants (all cases).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eRecruitment rate\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eOverall, the 201 mother-child pairs were recruited into the PALM childhood outcome study, comprising 144 controls and 57 cases (10 pCNVs, 47 VUS). This cohort represented 2.5% of the initial 8184 prenatal diagnosis cases pre-screened from the Victorian Prenatal Diagnosis Data Collection. This was lower than 8.7% (719/8184) recruitment rate estimated in the original study protocol.\\u003csup\\u003e\\u003cspan class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e\\u003c/sup\\u003e\\u003c/p\\u003e\"},{\"header\":\"DISCUSSION\",\"content\":\"\\u003cp\\u003eCMA has been instrumental in improving the diagnostic yield of prenatal diagnosis, but published data on the perinatal and paediatric outcomes of fetal CNVs are scarce due to their rarity. We conducted a lengthy and thorough manual linkage process to retrospectively recruit 201 mother-child pairs for a prospective childhood outcome study from a starting data source of re-identifiable prenatal diagnostic test results. This complex process was necessary to overcome the challenges of maintaining patient privacy and traversing siloed medical record information across health services and research institutes.\\u003c/p\\u003e \\u003cp\\u003eOverall, the rates of TOP for the pCNVs in our cohort were at the lower end of the range reported in the literature. We observed a 49.3% TOP rate for pCNVs overall and a 56.2% TOP rate for pCNVs with an ultrasound abnormality. This compares with TOP rates for pCNV ranging from 50\\u0026ndash;100% in other studies.\\u003csup\\u003e\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e, \\u003cspan additionalcitationids=\\\"CR28 CR29 CR30 CR31\\\" citationid=\\\"CR27\\\" class=\\\"CitationRef\\\"\\u003e27\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR32\\\" class=\\\"CitationRef\\\"\\u003e32\\u003c/span\\u003e\\u003c/sup\\u003e Higher rates have been report for pCNVs with an ultrasound abnormality (either structural or soft marker) (76.2\\u0026ndash;100%) in China, France, and Israel.\\u003csup\\u003e\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e, \\u003cspan additionalcitationids=\\\"CR30 CR31\\\" citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR32\\\" class=\\\"CitationRef\\\"\\u003e32\\u003c/span\\u003e\\u003c/sup\\u003e\\u003c/p\\u003e \\u003cp\\u003eSimilarly, for VUS we observed a 18.2% TOP rate for VUS overall and a 23.1% rate for VUS with an ultrasound abnormality. Again, this aligns with the lower end of reported TOP rates for VUS from 11.0-44.9%,\\u003csup\\u003e14, \\u003cspan additionalcitationids=\\\"CR30\\\" citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR33\\\" class=\\\"CitationRef\\\"\\u003e33\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR34\\\" class=\\\"CitationRef\\\"\\u003e34\\u003c/span\\u003e\\u003c/sup\\u003e with higher rates for de novo VUS (50.8\\u0026ndash;58.0%)\\u003csup\\u003e13, \\u003cspan citationid=\\\"CR34\\\" class=\\\"CitationRef\\\"\\u003e34\\u003c/span\\u003e\\u003c/sup\\u003e and fetuses with an ultrasound abnormality (17.1\\u0026ndash;37.5%).\\u003csup\\u003e13, \\u003cspan additionalcitationids=\\\"CR30\\\" citationid=\\\"CR29\\\" class=\\\"CitationRef\\\"\\u003e29\\u003c/span\\u003e\\u0026ndash;\\u003cspan citationid=\\\"CR31\\\" class=\\\"CitationRef\\\"\\u003e31\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR34\\\" class=\\\"CitationRef\\\"\\u003e34\\u003c/span\\u003e\\u003c/sup\\u003e There are many methodological factors that may contribute to the different TOP rates for pCNV and VUS that preclude meaningful direct comparisons between studies. These factors include highly variable cohort sizes, study inclusion criteria, clinical testing pathways, CNV classification systems, health system and patient factors, availability of TOP, and timing of prenatal diagnosis.\\u003c/p\\u003e \\u003cp\\u003ePaediatrics cohorts established from prenatal genomic testing populations are rare due to logistical and ethical challenges, yet they are crucial for obtaining long-term outcome data. A previous cohort of this nature examined the childhood outcomes of children prenatally diagnosed with confined placental mosaicism in the Australian state of Victoria.\\u003csup\\u003e\\u003cspan citationid=\\\"CR35\\\" class=\\\"CitationRef\\\"\\u003e35\\u003c/span\\u003e\\u003c/sup\\u003e By utilising the same prenatal diagnosis dataset this paediatric cohort was not biased towards children with an established clinical phenotype. Despite contacting participants 5.5 years after prenatal diagnosis, the study achieved a recruitment rate of 76%. This is almost four times the response rate achieved in our study (19.1%). It is unknown what factors contributed to the higher recruitment rate but one factor could be the clinician-patient relationship as the treating doctor facilitated the contact between the participant and the research team, rather than a hospital departmental representative as in our study. Moreover, despite modifying the study protocol to minimise exposure to COVID-19 (such as offering virtual assessments), the pandemic might have negatively influenced patient attitudes towards participating in research studies.\\u003csup\\u003e\\u003cspan citationid=\\\"CR36\\\" class=\\\"CitationRef\\\"\\u003e36\\u003c/span\\u003e\\u003c/sup\\u003e\\u003c/p\\u003e \\u003cp\\u003eThere are only two other studies that have reported paediatric outcomes of children with a prenatal diagnosis of a CNV.\\u003csup\\u003e\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e, \\u003cspan citationid=\\\"CR37\\\" class=\\\"CitationRef\\\"\\u003e37\\u003c/span\\u003e\\u003c/sup\\u003e Shi et al. prospectively followed up 109 children with a prenatally diagnosed VUS up the age of 2\\u0026ndash;4 years. Five children apparently showed clinical signs or phenotypic features of disease, but the clinical assessments were not described in detail. Muys et al. retrospectively recruited 85 mother-child pairs with a pCNV or VUS (\\u0026lsquo;cases\\u0026rsquo;) and 123 with no or a benign CNV (\\u0026lsquo;controls\\u0026rsquo;). The response rate of 15.8% (208/1312) was lower than our results, even though their study had lower participant burden (parental questionnaire only). However, these response rates may not be comparable. Muys et al. did not perform extensive pre-screening to determine perinatal outcomes: several participants were ineligible due to a perinatal or neonatal death. Had we not performed our extensive pre-screening step, 282 women who experienced a perinatal loss would have been invited to participate in our childhood outcome study. Also, Muys et al. did not report the number of research invitation letters successfully delivered, only the total number sent. Use of registered post and manual follow up at the AEC public roll enabled us to determine the number of potential participants successfully contacted. Of note 21.3% (43/201) of our final cohort were contacted following use of the AEC to update contact addresses, demonstrating the value of this additional step.\\u003c/p\\u003e \\u003cp\\u003eStrengths and limitations\\u003c/p\\u003e \\u003cp\\u003eThis is one of the largest studies to manually determine the perinatal outcomes of pregnancies with and without a prenatally diagnosed CNV. Through this process, we have successfully established a paediatric cohort and prospectively conducted detailed cognitive and clinical assessments on each child. Data analysis is currently underway, with public dissemination of results expected in 2024.\\u003c/p\\u003e \\u003cp\\u003eAnother one of our strengths was the attention paid to patient psychological safety through manual record review and the exclusion of patients who had experienced a perinatal loss or infant death. We thereby averted potential distress for 282 families by removing them from our study invitation list. However, the extensive pre-screening procedures at multiple maternity hospitals and the siloed nature of Australian health records pose substantial resource and administrative barriers to future research of this type.\\u003c/p\\u003e \\u003cp\\u003eOne of the limitations of our cohort is the missing birth data on one quarter of potentially eligible patients due to private and regional referral patterns. This finding highlights the challenges in tracing participants and engaging with hospitals for population-based research studies.\\u003c/p\\u003e \\u003cp\\u003e \\u003cb\\u003eFuture directions\\u003c/b\\u003e \\u003c/p\\u003e \\u003cp\\u003eEstablishing systems that enable the routine paediatric follow up of prenatally diagnosed genetic abnormalities are essential for understanding the full phenotypic spectrum of CNVs. In particular, there are no standard recommendations regarding long term follow up of children with VUS. Our cohort will provide long term outcome data on the developmental outcomes of children with VUS that may help guide future clinical care.\\u003c/p\\u003e \\u003cp\\u003eOne of the barriers to collecting long term outcomes from genomic CNVs is the limitations of current congenital anomaly coding systems such as the International Classification of Diseases 10th Revision (ICD-10). The ICD-10 has very few specific genetic diagnostic codes as it is based on phenotypes and organ systems. More locally, our state-wide Victorian Congenital Anomalies Report reports the population prevalence and birth outcomes for common autosomal trisomies but not CNVs (pathogenic or VUS).\\u003csup\\u003e\\u003cspan citationid=\\\"CR38\\\" class=\\\"CitationRef\\\"\\u003e38\\u003c/span\\u003e\\u003c/sup\\u003e Expanding the reporting of congenital anomalies to encompass a broader spectrum of genomic variants would offer a more comprehensive understanding of the impact of prenatal diagnosis and enable us to perform better quality linkage studies for long term outcome data.\\u003c/p\\u003e\"},{\"header\":\"CONCLUSION\",\"content\":\"\\u003cp\\u003eThis study provides Australia\\u0026rsquo;s first population-based data on perinatal outcomes including termination of pregnancy following prenatal diagnostic testing with CMA. Three-quarters of fetuses with a VUS and less than half of fetuses with a pCNV resulted in a livebirth. Our establishment of a mother-child cohort via prenatal ascertainment was a complex and resource-intensive process, but an important step in understanding the impact of a CNV diagnosis in pregnancy and beyond.\\u003c/p\\u003e\"},{\"header\":\"List of abbreviations\",\"content\":\"\\u003cp\\u003eAEC: Australian Electoral Commission; CMA: Chromosomal microarray; CNV: Copy number variant; CVS: Chorionic villus sampling; HREA: Human Research Ethics Application; HREC: Human Research Ethics Committee; MCRI: Murdoch Children\\u0026rsquo;s Research Institute; NHMRC: National Health and Medical Research Council; PALM: PrenatAL Microarray; pCNV: Pathogenic copy number variant; TOP: termination of pregnancy; VPDD: Victorian Prenatal Diagnosis Data collection; VUS: Variants of uncertain/unknown significance;\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eEthics approval and consent to participate\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eEthics approval was granted by the Royal Children\\u0026rsquo;s Hospital Human Research Ethics Committee (reference number 60542) and Mercy Health Human Research Ethics Committee (reference number 2020-46). All participating parents provided written informed consent.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConsent for publication\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNot applicable\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAvailability of data and materials\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe data that support the findings of this study are available from the corresponding author to researchers from a recognised academic institution upon reasonable request.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCompeting interests\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe authors declare they have no competing interests.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFunding\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis study is being funded by a NHMRC Clinical Trials and Cohort Studies grant for 2020-2022 (NHMRC APP1186862). The funding body has had no role in the study design, in the writing of the protocol or in the decision to submit the paper for publication.\\u003c/p\\u003e\\n\\u003cp\\u003eLH receives salary support from a Medical Research Future Fund investigator grant (APP1196010) and the University of Melbourne.\\u003c/p\\u003e\\n\\u003cp\\u003eThe PALM study is sponsored by MCRI. The contact on behalf of the sponsor is LH.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthor\\u0026rsquo;s contributions\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eLH and JH conceived the original concept for this study. LH was the lead writer for the study protocol and funding application, with intellectual input from all members of the chief investigator team (JH, DA, SL, SP). CP and JM are salaried members of the PALM study team. Data collection was performed by CP and JK; CP and LH prepared the first draft of the manuscript. All authors read, provided intellectual input and approved the final version of this manuscript.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgements\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eWe thank the associate and site investigators in the PALM study group: Ms Joanne Kennedy (Murdoch Children\\u0026rsquo;s Research Institute, Royal Women\\u0026rsquo;s Hospital), Ms Fiona Norris (Victorian Clinical Genetics Services), Ms Lucy Gugasyan (Monash Pathology), Ms Emma Brown (Monash Pathology), Dr Suzanne Svobodova (Monash Pathology), Dr Matt Regan (Monash Medical Centre), Ms Helen Kincaid (Monash Medical Centre), Dr Anand Vasudevan (Royal Women\\u0026rsquo;s Hospital and Western Health), Ms Susan Fawcett (Royal Women\\u0026rsquo;s Hospital), Ms Melissa Graetz (Mercy Hospital for Women), A/Prof Joanne Said (Western Health), Dr Lisa Begg (Box Hill Hospital, Eastern Health), Dr Nicole Yuen (Bendigo Health), Dr Natasha Frawley (Grampians Health Ballarat), and Dr Geraldine Masson (Barwon Health Geelong).\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n\\u003cli\\u003eBrady PD, Vermeesch JR. Genomic microarrays: a technology overview. Prenat Diagn. 2012;32(4):336-43.\\u003c/li\\u003e\\n\\u003cli\\u003eMiller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86(5):749-64.\\u003c/li\\u003e\\n\\u003cli\\u003eManning M, Hudgins L. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet Med. 2010;12(11):742-5.\\u003c/li\\u003e\\n\\u003cli\\u003eBattaglia A, Doccini V, Bernardini L, Novelli A, Loddo S, Capalbo A, et al. Confirmation of chromosomal microarray as a first-tier clinical diagnostic test for individuals with developmental delay, intellectual disability, autism spectrum disorders and dysmorphic features. Eur J Paediatr Neurol. 2013;17(6):589-99.\\u003c/li\\u003e\\n\\u003cli\\u003eRoyal Australian and New Zealand College of Obstetricians and Gynaecologists. Statement C-Obs 59. Prenatal screening and diagnosis of fetal chromosomal and genetic conditions. Available from: https://www.ranzcog.edu.au. 2018.\\u003c/li\\u003e\\n\\u003cli\\u003eCommittee Opinion No.682: Microarrays and Next-Generation Sequencing Technology: The Use of Advanced Genetic Diagnostic Tools in Obstetrics and Gynecology. Obstet Gynecol. 2016;128(6):e262-e8.\\u003c/li\\u003e\\n\\u003cli\\u003eWapner RJ, Martin CL, Levy B, Ballif BC, Eng CM, Zachary JM, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012;367(23):2175-84.\\u003c/li\\u003e\\n\\u003cli\\u003ePynaker C, HUI L, HALLIDAY J. The Annual Report on Prenatal Diagnostic Testing in Victoria, 2021. Murdoch Childrens Research Institute; 2022.\\u003c/li\\u003e\\n\\u003cli\\u003ePynaker C, Norris F, Hui L, Halliday J. Perinatal outcomes and genomic characteristics of fetal copy number variants: An individual record linkage study of 713 pregnancies. Prenat Diagn. 2023;43(4):516-26.\\u003c/li\\u003e\\n\\u003cli\\u003eWesterfield L, Darilek S, van den Veyver IB. Counseling Challenges with Variants of Uncertain Significance and Incidental Findings in Prenatal Genetic Screening and Diagnosis. J Clin Med. 2014;3(3):1018-32.\\u003c/li\\u003e\\n\\u003cli\\u003eLibman V, Friedlander Y, Chalk M, Hochner H, Shkedi-Rafid S. Receiving uncertain results from prenatal chromosomal microarray analysis: Women\\u0026apos;s decisions on continuation or termination of pregnancy. Prenat Diagn. 2023;43(6):773-80.\\u003c/li\\u003e\\n\\u003cli\\u003eLou S, Lomborg K, Lewis C, Riedijk S, Petersen OB, Vogel I. \\u0026quot;It\\u0026apos;s probably nothing, but\\u0026hellip;\\u0026quot; Couples\\u0026apos; experiences of pregnancy following an uncertain prenatal genetic result. Acta Obstet Gynecol Scand. 2020;99(6):791-801.\\u003c/li\\u003e\\n\\u003cli\\u003eShi P, Liang H, Hou Y, Chen D, Ren H, Wang C, et al. The uncertainty of copy number variants: pregnancy decisions and clinical follow-up. Am J Obstet Gynecol. 2023;229(2):170.e1-.e8.\\u003c/li\\u003e\\n\\u003cli\\u003eBrabbing-Goldstein D, Reches A, Svirsky R, Bar-Shira A, Yaron Y. Dilemmas in genetic counseling for low-penetrance neuro-susceptibility loci detected on prenatal chromosomal microarray analysis. Am J Obstet Gynecol. 2018;218(2):247.e1-.e12.\\u003c/li\\u003e\\n\\u003cli\\u003eHui L, Pynaker C, Kennedy J, Lewis S, Amor DJ, Walker SP, et al. Study protocol: childhood outcomes of fetal genomic variants: the PrenatAL Microarray (PALM) cohort study. BMC Pediatr. 2021;21(1):447.\\u003c/li\\u003e\\n\\u003cli\\u003eAustralian Bureau of Statistics, Births, Australia.\\u003c/li\\u003e\\n\\u003cli\\u003eLindquist A, Hui L, Poulton A, Kluckow E, Hutchinson B, Pertile MD, et al. State-wide utilization and performance of traditional and cell-free DNA-based prenatal testing pathways: the Victorian Perinatal Record Linkage (PeRL) study. Ultrasound Obstet Gynecol. 2020;56(2):215-24.\\u003c/li\\u003e\\n\\u003cli\\u003eVictoria, Australia. Abortion Law Reform Act 2008. ACT NUMBER 58/2008, (2008).\\u003c/li\\u003e\\n\\u003cli\\u003eKearney HM, Thorland EC, Brown KK, Quintero-Rivera F, South ST. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med. 2011;13(7):680-5.\\u003c/li\\u003e\\n\\u003cli\\u003eSouth ST, Lee C, Lamb AN, Higgins AW, Kearney HM. ACMG Standards and Guidelines for constitutional cytogenomic microarray analysis, including postnatal and prenatal applications: revision 2013. Genet Med. 2013;15(11):901-9.\\u003c/li\\u003e\\n\\u003cli\\u003eRichards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-24.\\u003c/li\\u003e\\n\\u003cli\\u003eAustralian Bureau of Statistics, Census of Population and Housing: Socio-Economic Indexes for Areas, Index of Relative Socioeconomic Advantage and Disadvantage [Internet]. Australian Bureau of Statistics. 2016.\\u003c/li\\u003e\\n\\u003cli\\u003eHarris PA, Taylor R, Minor BL, Elliott V, Fernandez M, O\\u0026apos;Neal L, et al. The REDCap consortium: Building an international community of software platform partners. J Biomed Inform. 2019;95:103208.\\u003c/li\\u003e\\n\\u003cli\\u003eHarris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377-81.\\u003c/li\\u003e\\n\\u003cli\\u003eStataCorp. Stata Statistical Software: Release 17. College Station, TX: StataCorp LLC. 2021.\\u003c/li\\u003e\\n\\u003cli\\u003eSergeant E. Epitools Epidemiological Calculators. Ausvet. Available at: http://epitools.ausvet.com.au. 2018.\\u003c/li\\u003e\\n\\u003cli\\u003eStern S, Hacohen N, Meiner V, Yagel S, Zenvirt S, Shkedi-Rafid S, et al. Universal chromosomal microarray analysis reveals high proportion of copy-number variants in low-risk pregnancies. Ultrasound Obstet Gynecol. 2021;57(5):813-20.\\u003c/li\\u003e\\n\\u003cli\\u003eLi Y, Yan H, Chen J, Chen F, Jian W, Wang J, et al. The application of late amniocentesis: a retrospective study in a tertiary fetal medicine center in China. BMC Pregnancy Childbirth. 2021;21(1):266.\\u003c/li\\u003e\\n\\u003cli\\u003eSong T, Xu Y, Li Y, Zheng J, Guo F, Jin X, et al. Clinical Experience of Prenatal Chromosomal Microarray Analysis in 6159 Ultrasonically Abnormal Fetuses. Reprod Sci. 2023.\\u003c/li\\u003e\\n\\u003cli\\u003eEgloff M, Herv\\u0026eacute; B, Quibel T, Jaillard S, Le Bouar G, Uguen K, et al. Diagnostic yield of chromosomal microarray analysis in fetuses with isolated increased nuchal translucency: a French multicenter study. Ultrasound Obstet Gynecol. 2018;52(6):715-21.\\u003c/li\\u003e\\n\\u003cli\\u003eCai M, Lin N, Su L, Wu X, Xie X, Li Y, et al. Copy number variations in ultrasonically abnormal late pregnancy fetuses with normal karyotypes. Sci Rep. 2020;10(1):15094.\\u003c/li\\u003e\\n\\u003cli\\u003eHu T, Tian T, Zhang Z, Wang J, Hu R, Xiao L, et al. Prenatal chromosomal microarray analysis in 2466 fetuses with ultrasonographic soft markers: a prospective cohort study. Am J Obstet Gynecol. 2021;224(5):516.e1-.e16.\\u003c/li\\u003e\\n\\u003cli\\u003eMardy AH, Wiita AP, Wayman BV, Drexler K, Sparks TN, Norton ME. Variants of uncertain significance in prenatal microarrays: a retrospective cohort study. Bjog. 2021;128(2):431-8.\\u003c/li\\u003e\\n\\u003cli\\u003eChen L, Wang L, Yin D, Zeng Y, Tang F, Wang J. Influence of the detection of parent-of-origin on the pregnancy outcomes of fetuses with copy number variation of unknown significance. Sci Rep. 2020;10(1):8864.\\u003c/li\\u003e\\n\\u003cli\\u003eAmor DJ, Neo WT, Waters E, Heussler H, Pertile M, Halliday J. Health and developmental outcome of children following prenatal diagnosis of confined placental mosaicism. Prenat Diagn. 2006;26(5):443-8.\\u003c/li\\u003e\\n\\u003cli\\u003eAbdulhussein D, Yap TE, Manzar H, Miodragovic S, Cordeiro F. Factors impacting participation in research during the COVID-19 pandemic: results from a survey of patients in the ophthalmology outpatient department. Trials. 2022;23(1):823.\\u003c/li\\u003e\\n\\u003cli\\u003eMuys J, Jacquemyn Y, Blaumeiser B, Bourlard L, Brison N, Bulk S, et al. Prenatally detected copy number variants in a national cohort: A postnatal follow-up study. Prenat Diagn. 2020;40(10):1272-83.\\u003c/li\\u003e\\n\\u003cli\\u003eCongenital anomalies in Victoria, 2015-2016. Consultative Council on Obstetric and Paediatric Mortality and Morbidity; 2018.\\u003c/li\\u003e\\n\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":true,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"Murdoch Children's Research Institute\",\"isAcceptedByJournal\":true,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true},\"keywords\":\"prenatal diagnosis, chromosomal microarray analysis, copy number variants, variant of uncertain significance, perinatal outcomes, cohort studies, paediatric population, feasibility studies\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-4285240/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-4285240/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003ch2\\u003eBackground\\u003c/h2\\u003e \\u003cp\\u003e There are no established guidelines for the follow up of infants born after a prenatal diagnosis of a genomic copy number variant (CNV), despite their increased risk of developmental issues. The aims of this study were (i) to determine the perinatal outcomes of fetuses diagnosed with and without a CNV, and (ii) to establish a population-based paediatric cohort for long term developmental follow up.\\u003c/p\\u003e\\u003ch2\\u003eMethods\\u003c/h2\\u003e \\u003cp\\u003eAn Australian state-wide research database was screened for pregnant individuals who had a prenatal chromosomal microarray (CMA) between 2013\\u0026ndash;2019 inclusive. Following linkage to laboratory records and clinical referrer details, hospital records were manually reviewed for study eligibility. Eligible participants were mother-child pairs where the pregnancy resulted in a livebirth, the mother was able to provide informed consent in English (did not require a translator) and the mother was the primary caregiver for the child at hospital discharge after birth. Research invitations were sent by registered post at an average of six years after the prenatal diagnostic test. Statistical analysis was performed in Stata17.\\u003c/p\\u003e\\u003ch2\\u003eResults\\u003c/h2\\u003e \\u003cp\\u003eOf 1832 prenatal records examined, 1364 (74.5%) mother-child pairs were eligible for recruitment into the follow up cohort. Of the 468 ineligible, 282 (60.3%) had \\u0026lsquo;no live pregnancy outcome\\u0026rsquo; (209 terminations of pregnancy (TOP) and 73 miscarriages, stillbirths, and infant deaths), 157 (33.5%) required a translator, and 29 (6.2%) were excluded for other reasons. TOP rates varied by the type of fetal CNV detected: 49.3% (109/221) for pathogenic CNVs, 18.2% (58/319) for variants of uncertain significance and 3.3% (42/1292) where no clinically significant CNV was reported on CMA. Almost 77% of invitation letters were successfully delivered (1047/1364), and the subsequent participation rate in the follow up cohort was 19.2% (201/1047).\\u003c/p\\u003e\\u003ch2\\u003eConclusions\\u003c/h2\\u003e \\u003cp\\u003eThis study provides Australia\\u0026rsquo;s first population-based data on perinatal outcomes following prenatal diagnostic testing with CMA. The relatively high rates of pregnancy loss for those with a prenatal diagnosis of a CNV presented a challenge for establishing a paediatric cohort to examine long term outcomes. Recruiting a mother-child cohort via prenatal ascertainment is a complex and resource-intensive process, but an important step in understanding the impact of a CNV diagnosis in pregnancy and beyond.\\u003c/p\\u003e\\u003ch2\\u003eTrial registration:\\u003c/h2\\u003e \\u003cp\\u003eACTRN12620000446965p; Registered on April 6, 2020.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Perinatal outcomes after a prenatal diagnosis of a fetal copy number variant: A retrospective population-based cohort study\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2024-04-19 18:40:23\",\"doi\":\"10.21203/rs.3.rs-4285240/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"researchsquare\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":true,\"externalIdentity\":\"\",\"sideBox\":\"\",\"snPcode\":\"\",\"submissionUrl\":\"/submission\",\"title\":\"Research Square\",\"twitterHandle\":\"researchsquare\",\"acdcEnabled\":true,\"dfaEnabled\":false,\"editorialSystem\":\"\",\"reportingPortfolio\":\"\",\"inReviewEnabled\":false,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"da3fc75b-cc83-49d4-807a-08dcf6e401e1\",\"owner\":[],\"postedDate\":\"April 19th, 2024\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"published-in-journal\",\"subjectAreas\":[{\"id\":30829961,\"name\":\"Obstetrics \\u0026 Gynecology\"},{\"id\":30829962,\"name\":\"Pediatrics\"},{\"id\":30829963,\"name\":\"Medical Genetics\"}],\"tags\":[],\"updatedAt\":\"2024-10-11T15:33:17+00:00\",\"versionOfRecord\":{\"articleIdentity\":\"rs-4285240\",\"link\":\"https://doi.org/10.1186/s12887-024-05012-6\",\"journal\":{\"identity\":\"bmc-pediatrics\",\"isVorOnly\":false,\"title\":\"BMC Pediatrics\"},\"publishedOn\":\"2024-08-22 00:00:00\",\"publishedOnDateReadable\":\"August 22nd, 2024\"},\"versionCreatedAt\":\"2024-04-19 18:40:23\",\"video\":\"\",\"vorDoi\":\"10.1186/s12887-024-05012-6\",\"vorDoiUrl\":\"https://doi.org/10.1186/s12887-024-05012-6\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-4285240\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-4285240\",\"identity\":\"rs-4285240\",\"version\":[\"v1\"]},\"buildId\":\"qtupq5eGEP_6zYnWcrvyt\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}