Exploring inheritance, and clinical penetrance of distal Xq28 duplication syndrome: insights from 47 new unpublished cases.

BACKGROUND: Distal Xq28 duplication, or int22h1/int22h2-mediated Xq28 duplication syndrome, leads to cognitive impairment, neurobehavioral issues, and facial dysmorphisms. Existing literature has limited information on clinical traits and penetrance. METHODS: We identified cases of distal Xq28 duplication (chrX: 154,126,575-154,709,680, GRCh37/hg19) through a review of clinical records and microarray reports from five centers, encompassing both postnatal and prenatal cases, with no prior family knowledge of the duplication. RESULTS: Our search found 47 cases across 26 families, with duplications ranging from 208 to 935 Kb. In total, 8 out of 26 index cases featured a 200-300 kb partial duplication, mainly from Armenian/Caucasian Jewish backgrounds. Most prenatal cases showed no major fetal ultrasound malformations. Of cases with known inheritance mode (15 out of 26), maternal inheritance was more common (80%). The study identified seven male carriers of the duplication from six unrelated families, indicating partial penetrance in males. CONCLUSION: Our study provides key insights into distal Xq28 duplication. Most prenatal tests showed no major fetal ultrasound issues. Maternal inheritance was common, with unaffected mothers. In the postnatal group, a balanced gender distribution was observed. Among male family members, two fathers had ADHD, one was healthy, and one brother had mild symptoms, indicating partial penetrance in males.

Exploring the factors affecting classification and reporting of uncertain prenatal microarray findings, using a "virtual fetus" model-a pilot study.

OBJECTIVE: Significant discrepancy exists between laboratories in classification and reporting of copy number variants (CNVs). Studies exploring factors affecting prenatal CNV management are rare. Our "virtual fetus" pilot study examines these factors. METHOD: Ten prenatally diagnosed CNVs of uncertain significance (VUS) > 1Mb, encompassing OMIM-morbid genes, inherited from healthy parents, were classified by 15 MD geneticists from laboratory, prenatal, and preimplantation genetic testing (PGT) units. Geneticists addressed factors affecting classification, obligation to report, and recommendation for invasive testing or PGT. RESULTS: CNVs were classified likely benign (10.7%), VUS (74.7%), likely pathogenic (8.7%), or pathogenic (6.0%). Classification discrepancy was higher for losses versus gains. Classifying pathogenic/likely pathogenic was more common for losses (adjusted odds ratio [aOR] 10.9, 95% CI 1.55-76.9), and geneticists specializing in gynecology (aOR 4.9, 95% CI 1.03-23.3). 84.0% of respondents would report CNVs, depending on classification and family phenotype. Invasive testing in pregnancies was recommended for 29.3% of CNVs, depending on the classification and geneticist's specialization. PGT was recommended for 32.4%, depending on classification, experience years, and family's phenotype (38.0% for patients undergoing in vitro fertilization irrespectively, 26.7% otherwise). CONCLUSION: Factors affecting CNV classification/reporting are mainly dosage, family phenotype, geneticist specialization and experience. Understanding factors from our pilot study may facilitate developing an algorithm for clinical consensus and optimal management.

"We hear and we fear" - Insights of 1203 Women on Personnel Conversations During Cesarean Delivery.

OBJECTIVE: To assess the preferences of women undergoing cesarean delivery regarding intraoperative conversations among healthcare personnel. METHODS: This cross-sectional study was conducted by distribution of an open anonymous questionnaire on social media platforms during March 2022, targeting respondents with a history of cesarean delivery. The primary outcome was patients' experience of "being disturbed by professional and casual conversations of the personnel", rated on a 1-5 Likert scale. RESULTS: 1203 participants completed the questionnaire, with 97.6% reporting intraoperative conversations among personnel. Casual conversations were perceived as "disturbing" by more respondents vs. professional talk (33.4% vs. 27.6%, respectively, p = 0.0077). Logistic regression analysis revealed associations between feeling disturbed and higher intraoperative stress and pain - adjusted Odds Ratio (OR) 3.1, 95% confidence interval (CI) 2.1-4.5, and OR 2.7, 95%CI 1.8-4.0, respectively, for professional conversations; OR 3.0, 95%CI 2.0-4.4, and OR 1.7, 95%CI 1.1-2.7, respectively, for casual conversations. Feeling disturbed by professional conversations was also associated with urgent vs. elective operations (OR 2.0, 95%CI 1.4-3.0). Direct personnel-patient communication was associated with significantly lower stress levels (60.8% vs. 72.5% in the remaining cohort, p < 0.001). DISCUSSION: Intraoperative conversations of the personnel occur during vast majority of cesarean deliveries. Given that a substantial proportion of patients find these conversations disturbing, it is advisable to conduct a preliminary assessment of maternal preferences. This proactive step can help tailor communication strategies to individual patient comfort and preferences, ultimately enhancing the birthing experience and maternal well-being.

The association between obesity and the success of trial of labor after cesarean delivery (TOLAC) in women with past vaginal delivery.

OBJECTIVES: To evaluate the effect of overweight (body mass index; BMI 25.0-29.9 kg/m2), and obesity (BMI>30 kg/m2), on the success of trial of labor after cesarean delivery (TOLAC), with consideration of successful past vaginal birth. METHODS: This retrospective cohort study was performed using electronic database of obstetrics department at a university-affiliated tertiary medical center. All women admitted for TOLAC at 37-42 weeks of gestational age, carrying a singleton live fetus at cephalic presentation, with a single previous low segment transverse cesarean delivery between 1/2015 and 5/2021 were included. Primary outcome was the rate of cesarean delivery during labor, and subgroup analysis was performed for the presence of past vaginal birth. RESULTS: Of the 1200 TOLAC deliveries meeting the inclusion criteria, 61.9 % had BMI in the normal range, 24.6 % were overweight (BMI 25.0-29.9 kg/m2), and 13.4 % were obese (BMI of 30 kg/m2 and over). Using a multivariate analysis, BMI≥30 kg/m2 was associated with increased risk of cesarean delivery compared to normal weight. However, in the subgroup of 292 women with a history of successful vaginal birth BMI did not affect TOLAC success. CONCLUSIONS: BMI does not affect the success of TOLAC in women with previous vaginal birth. This information should be considered during patients counselling, in order to achieve a better selection of mode of delivery and higher patients' satisfaction.

Prevalence of high-penetrant copy number variants in 7734 low-risk pregnancies.

BACKGROUND: The rate of clinically significant copy number variants in chromosomal microarray analysis in low-risk pregnancies is approximately 1%. However, these results include copy number variants with low and variable penetrance, although some patients might be interested only in the detection of high-penetrant variants. OBJECTIVE: This study aimed to calculate the prevalence of high-penetrant copy number variants in a large cohort of low-risk pregnancies. STUDY DESIGN: This retrospective study was performed using microarray results of pregnancies with normal ultrasound and maternal serum screening. All clinically significant (pathogenic and likely pathogenic) copy number variants were recorded. Of these, only high-penetrant findings were selected. Findings with low and medium penetrance and copy number variants with unknown clinical penetrance, including uniparental disomy of segments not related to known imprinted syndromes, mosaic aneuploidy of <50%, and segmental mosaicism, were excluded. The calculation was performed for the overall cohort, for women aged >35 years and women aged <35 years, and after omission of noninvasive prenatal screening theoretically detectable findings (trisomies 13, 18, and 21). RESULTS: Clinically significant copy number variants were detected in 118 of 7734 cases (1.50% or 1:65), and high-penetrant copy number variants were detected in 33 of 7734 cases (0.43% or 1:234). In women aged ≥35 years, the rates of high-penetrant copy number variants were 29 of 5734 cases (0.51% or 1:198) and 4 of 2000 cases (0.20% or 1:500) in women aged <35 years (P=.0747). Following the omission of 12 theoretically noninvasive prenatal screening-detectable findings, the rates of high-penetrant copy number variants declined to 21 of 7722 cases (0.27% or 1:368) in the whole cohort-18 of 5723 cases (0.31% or 1:318) in woman aged ≥35 years and 3 of 1999 cases (0.15% or 1:666) in younger women (P=.319). CONCLUSION: The risk of high-penetrant copy number variants in low-risk pregnancies exceeds the risk of miscarriage after invasive testing, even after normal noninvasive prenatal screening results. These results are of importance to genetic counselors and obstetricians, to facilitate maternal informed decision-making when considering invasive prenatal testing in low-risk pregnancies.

Lessons learned from the first national population-based genetic carrier-screening program for Duchenne muscular dystrophy.

PURPOSE: To summarize the results of first year implementation of pan-ethnic screening testing for Duchenne muscular dystrophy (DMD) and present the ensuing challenges. METHODS: Data acquisition for this study was performed by retrospective search of Ministry of Health registry for reports of all laboratories performing genetic screening tests. DMD testing was performed by multiplex ligation-dependent probe amplification technology. In case of single-exon deletion, sequencing of the specific exon was performed to rule out underlying single-nucleotide variant. RESULTS: Of overall 85,737 DMD tests, 82 clinically significant findings were noted (0.095%, or 1:1,046 women). In addition, 80 findings with uncertain clinical significance were detected (0.093%, or 1:1072), as well as 373 cases (0.4%, or 1:230) of single-exon deletions subsequently identified as false positives because of underlying single-nucleotide variant, mostly variants in exon 8 in North African Jewish population, and in exon 48 in Arab Muslim population. CONCLUSION: Interpretation of population-based DMD carrier screening is complex, occasionally requiring additional genetic testing methods and ethical considerations. Multicenter data registry, including ethnic origin and familial segregation in selected cases, is crucial for optimal definition of the results during genetic counseling and informed decisions regarding prenatal testing.

[ADVANCES AND CHALLENGES IN THE FIELD OF GENETIC TESTING - AN INTRODUCTORY ARTICLE].

INTRODUCTION: In the current issue of Harefuah, we present original research articles and reviews, reflecting the tremendous development of the field of genetic testing. This progress provides extensive tools for determining genetic diagnoses, thereby enabling detailed explanation for patients and their family members regarding the specific genetic disorder, adjustment of medical evaluation and follow-up, and allowing informed decision-making during pregnancy. Furthermore, there are advances in the assessment of recurrence of risks among members of the extended family, including future pregnancies, with a possibility of prenatal diagnosis and pre-implantation genetic testing.

[CHARACTERIZATION OF THE INDICATIONS FOR PERFORMING GENE PANEL SEQUENCING TESTS IN A GENOMIC CENTER].

INTRODUCTION: Following the recent human genome revolution, novel technologies have been developed in the last decade enabling advanced sequencing tests, including genetic panel tests that focus on groups of specific genes associated with a certain medical condition (phenotype). Since the process of assembling a genetic panel may be complex and requires significant manpower and time, it is important to define the most common and requested panels, for gradual construction and introduction of panel tests starting with the most common. AIMS: Since no information was found in the literature defining the common panels, the aim of the study was to define the indications for performing a gene panel within the framework of the provided services, and to estimate their frequency. METHODS: Prospective data acquisition was performed by a party responsible for approval of panel tests within Clalit Health Services Organization. The indications for all approved panel tests were registered since the launch of Clalit's Genomic Center. The total number of indications was counted, and according to the Pareto principle, 20% of the most frequent indications were chosen. In addition, the indications were divided into main medical disciplines. RESULTS: Overall, 132 indications were recorded for approved gene panel tests; 20% of these indications, i.e. the first 26 indications in terms of frequency, covered 79.6% of the cases. The most frequent approved panels were epilepsy (10.4%, confidence interval (CI) 8.5-12.6%), Maturity-onset diabetes of the young (MODY) (9.6%, CI 7.8-11.7%), cardiomyopathy (8.3%, CI 6.6-10.3%) and hearing impairment (7.6%, CI 6.0-9.6%). The most common disciplines in descending order were neurological diseases (23.0%, CI 20.3-25.9%), endocrinology (13.1%, CI 11.1-15.6%), heart diseases (9.0%, CI 7.3-11.1%) and eye diseases (7.8%, CI 6.2-9.8%). CONCLUSIONS: A review of panel approvals at the Genomic Center of Clalit showed a number of frequent indications. DISCUSSION: We believe this information can be useful for the establishment of genomic laboratories, as well as for the improvement of the service to the patients, by enabling the referral for specific panel tests by medical experts who are not geneticists or genetic counselors, after appropriate training (such as the "Genetics First" program of Clalit).

[HOW SIMPLE IS "SIMPLE" GENETIC COUNSELING?]

INTRODUCTION: Genetic counselors are often compared with other medical professionals in terms of productivity, based on the number of patients seen and the time required for each patient. Prenatal genetic counseling before amniocentesis in uneventful pregnancies is considered to be a "simple" counseling, with potentially less time required for each patient. Thus, in some medical centers the duration of such consultations is limited to provide only the basic explanation without detailed collection of personal and family history, while in others the explanation is given to several patients together. AIMS: To assess the need for extended genetic counseling during supposedly "simple" genetic consultations before amniocentesis. METHODS: Data was collected from January 2018 until August 2020 of all patients undergoing genetic counseling before amniocentesis due to advanced maternal age, abnormal biochemical screening, or without medical indication. The consultations were given by four genetic counselors and two medical geneticists. The need for extended genetic counseling was evaluated based on pedigree and the discussion summaries and recommendations noted in genetic counseling summaries. RESULTS: Of the 1085 relevant counseling appointments, 657 (60.5%) required additional explanation beyond the basic consultation. The reasons for extended counseling included medical disorders of the woman or spouse (21.2%), carrier state for autosomal recessive diseases (18.6%), diagnosed or suspected genetic conditions of a child or previous pregnancy (9.6%), or medical disorders in the extended family (79.1%). In 31.0% of patients, recommended carrier screening tests were recommended or added. In 32.3% of cases, only one extra subject was counseled, in 16.3% two subjects, and in 5%, three subjects or more. The additional explanations were estimated as short (up to 5 minutes) in 36.9% of the cases, intermediate (5 to 15 minutes) in 59.9%, and long (over 15 minutes) in 2.6% of cases. The consultation's duration was not affected from it being a first meeting or a recurrent consultation. CONCLUSIONS: The need for further explanation was demonstrated in over 60% of genetic consultations, performed prior to amniocentesis due to supposedly "simple" indication. DISCUSSION: This fact reflects the importance of formal genetic counseling even in cases of seemingly simple indications, with an emphasis on detailed personal and family history, dedicating sufficient time to the counseling itself. Alternatively, it is important to exercise extra caution when conducting a short explanatory conversation prior to amniocentesis, including detailed questionnaires and the patient's signature on the possible limitations of such explanations.

[SUMMARY AND UPDATES IN THE FIELD OF GENETIC TESTING IN ISRAEL - AS OF 2022].

INTRODUCTION: Considerable progress has been observed in the field of genetic counseling and testing in Israel, including the availability and funding of services. The purpose of the article is to summarize the management and present the updates in the field of genetic testing in Israel, as of 2022. The progress in the field of pregnancy-related genetic testing includes an ancestry-based annually updated genetic screening, which has significantly reduced the incidence of several severe and common hereditary diseases. A comprehensive and uniform genetic screening test was submitted for approval by the next basket committee.

A call for public funding of invasive and non-invasive prenatal testing.

For decades, prenatal screening and genetic testing strategies were limited, requiring less complex decisions. Recently, however, several new advanced technologies were introduced, including chromosomal microarray analysis (CMA) and non-invasive prenatal screening (NIPS), bringing about the need to choose the most appropriate testing for each pregnancy. A worrisome issue is that opposed to the wide implementation and debates over public funding of NIPS, currently invasive testing is still recommended only in selected pregnancies with increased risk for chromosomal aberrations (according to screening tests or sonographic anomalies). This current decision-making regarding public funding for invasive and screening testing might compromise informed consent and patient's autonomy. In this manuscript, we compare several characteristics of CMA vs. NIPS, namely: the accuracy and the diagnostic scope, the risks for miscarriage and for clinically uncertain findings, the timing for testing, and pretest counselling. We argue that it must be recognized that one size might not fit all, and suggest that both options should be presented to all couples through early genetic counseling, with public funding for the specific selected test.

Comparison between the modified French AmbUlatory Cesarean Section and standard cesarean technique-a randomized double-blind controlled trial.

BACKGROUND: The French AmbUlatory Cesarean Section is a cesarean delivery technique, which includes a vertical fascial incision to the left of the linea alba and an extraperitoneal approach to the uterus. The presumed benefits of this technique are decreased postoperative pain and accelerated recovery. However, evidence supporting these impressions is scarce. OBJECTIVE: This study aimed to compare maternal recovery after French AmbUlatory Cesarean Section vs standard cesarean delivery technique. STUDY DESIGN: In this double-blind randomized controlled trial, women undergoing elective cesarean delivery at term were allocated into French AmbUlatory Cesarean Section vs standard cesarean delivery technique. A modified French AmbUlatory Cesarean Section technique was used, adhering to all French AmbUlatory Cesarean Section operative steps except for the extraperitoneal approach. In both groups, the use of intravenous hydration, intrathecal morphine, and bladder catheter was avoided, and all women were encouraged to stand and walk 3 to 4 hours after the operation. The primary adverse composite outcome included either of the following: a visual analog scale score of >6 at 3 to 4 hours after the operation, an inability to stand up and walk to the restroom 3 to 4 hours after the operation, and a 15-Item Quality of Recovery (QoR) questionnaire score of <90 at 24 hours after the operation. The women were followed up for 6 weeks. RESULTS: Overall, 116 women were included in the trial (58 in each group). The adverse composite outcome did not differ between the 2 groups (38.9% for the French AmbUlatory Cesarean Section group vs 53.8% for the regular cesarean delivery group; P=.172). In both groups, more than 90% of the women were able to get up and walk 3 to 4 hours after the operation. Compared with the standard cesarean delivery group, the French AmbUlatory Cesarean Section group had a longer duration of the operation (43.7±11.2 vs 54.4±11.3 minutes; P<.001), a higher rate of intraoperative complications (0.0% vs 13.8%; P=.006), and a higher rate of umbilical cord pH level of <7.2 (3.4% vs 17.2%; P=.029) were noted. Evaluation via phone call 1 week after the operation showed better quality of recovery scores in the French AmbUlatory Cesarean Section group than in the standard cesarean delivery group (27.1±8.4 vs 24.6±8.0; P=.043). Other secondary outcomes did not differ between the 2 groups. CONCLUSION: As excellent maternal recovery was noted in both groups, we believe that the main factor affecting this recovery is the perioperative management (including avoidance of the use of intraoperative intravenous hydration, intrathecal morphine, and bladder catheter, with early postoperative mobilization). The maternal and neonatal safety outcomes of the French AmbUlatory Cesarean Section technique remain to be proven by larger-scale high-quality randomized controlled trials.

Risk factors associated with accidental fetal skin lacerations during cesarean delivery.

OBJECTIVE: To identify risk factors associated with accidental fetal skin lacerations (AFL) during cesarean section (CS). METHODS: This retrospective cohort study was obtained from the registry of two large medical centers between 2014 and 2019. The study group comprised all newborns identified with AFL. The rates of various potential risk factors were compared between the study group and a group of CS at which no AFL had occurred (the control group). RESULTS: Of the 14 666 CS deliveries, 48 cases of AFL (0.33%) were documented, 52% of these following urgent CS. Compared with the control group (n = 14 618), the only risk factors associated with AFL were premature rupture of membranes (PROM) (odds ratio [OR] 5.38, 95% convidence interval [CI] 2.97-9.74) and meconium-stained amniotic fluid (OR 6.50, 95% CI 2.55-16.54). In subgroup analysis by CS urgency, no significance for these factors was noted in elective CS group; but higher rates of both PROM and meconium-stained amniotic fluid were noted in the AFL during urgent CS (OR 14.23, 95% CI 6.30-32.16 and OR 15.36, (95% CI 5.65-41.75, respectively). CONCLUSIONS: During urgent CS, the surgeon should bear in mind that the presence of PROM or meconium-stained amniotic fluid should prompt extra care and application of preventive measures to decrease the rates of AFL.

Absence of oral nutritional support in low food intake inpatients is associated with an increased risk of hospital-acquired pressure injury.

BACKGROUND & AIMS: Hospital-acquired pressure injury (HAPI) incidence is a common burden in hospitals. Decreased food intake leading to malnutrition compromises body tissues involved in pressure injury occurrence. However, most tools for predicting pressure injuries do not include daily food intake monitoring nor consider further nutritional interventions. This study aimed to investigate clinical practices for food intake monitoring and its association with predicting HAPI risk, together with Norton Scale use, and whether the initiation or absence of oral nutritional supplements (ONS), separately from other nutritional interventions, was associated with HAPI incidence in low food intake inpatients, who consumed less than 50% of requirements. METHODS: This observational cohort study covered a one-year period (08/2018-07/2019). Demographic and clinical data were extracted from computerized files of patients hospitalized ≥7 days, aged ≥60 years, and who ate orally. Patients receiving enteral or parenteral nutrition were excluded. Differences were studied between groups without and with HAPI grade ≥2. Subgroups divided by Norton Scale and intake, Norton Scale and albumin levels, food intake and initiation (or not) of any nutritional intervention versus ONS only, were examined for the consistency of association with HAPI. RESULTS: Of the 5155 admissions during the study period, 895 patients fulfilled the inclusion criteria: 48% female, mean age 77.6 ± 9.1 years, 11% with MUST score ≥2. Nutritional intake was reported in 76% of patients, of them 22% had low food intake, and 9% of the study group developed HAPI grade ≥2. Regarding HAPI incidence, no differences were found between groups divided by MUST scores. Independent risk factors significantly associated with HAPI were Norton <14, albumin levels <3 g/dl, and low food intake. Not providing ONS in low food intake patients had an adjusted 3.49-fold (95%CI 1.57-7.75) increase in HAPI risk (6-fold for non-adjusted relative risk). CONCLUSION: Failure to initiate ONS as part of nutritional support in low food intake patients is associated with high HAPI risk in these patients. Consequently, monitoring of daily food intake for identifying low intake patients should be integrated into routinely used tools such as the Norton Scale, and adherence to nutritional protocols should be addressed.

Factors Affecting the Success of Repeated Misoprostol Course for the Treatment of Missed Abortion.

OBJECTIVE: To assess the rates of success of the second dose of Misoprostol administration and to evaluate the parameters that affect the success of this approach. STUDY DESIGN: This retrospective cohort study was performed using institutional database of Carmel Medical Center between the dates of 1/11/2012-1/11/2017. Patients with ultrasound proven intrauterine abnormal pregnancy, treated for missed abortion or blighted ovum by two doses of intravaginal Misoprostol were included. The primary outcome was the treatment success rate of repeated Misoprostol treatment, and factors affecting this outcome. RESULTS: Overall, 97 patients were included in the study. The success of repeated dose of Misoprostol was noted in 46 cases (47.4%). A higher success rate was noted in symptomatic women - 64.3% vs. 35.7% in asymptomatic patients (Odds Ratio 2.6, 95% Confidence Interval 1.1-6.5). In addition, marginal significance was noted for pregnancies with an embryonic pulse previously observed (66.7% in the success group vs. 33.3% in failed treatment, p=0.051). DISCUSSION: Efficacy of a repeated Misoprostol course was shown to have a success rate of 47%%. This success rate is slightly increased in women presenting symptoms of bleeding before first administration. This information is highly important in the clinical discussion with each patient prior choosing a possible treatment.

The anxiety caused by abnormal results of Down syndrome screening tests.

The objective of our survey was to evaluate the anxiety experienced by women receiving abnormal results of prenatal Down syndrome screening by an electronic anonymous survey. Anxiety level was evaluated by a six-item Spielberger State-Trait Anxiety Inventory. Of 559 respondents, high anxiety scores were reported in the majority (86.0%). Higher anxiety scores were noted in women informed of the abnormal result by the caregiver vs. written answer. 59.1% of the respondents preferred the risk reported as percentage, while only 4.4% gave precedence to the current form (e.g. 1 in 100). The participants noted several factors which could relieve their anxiety, including an explanatory booklet (72.4%) or a website (77.9%). In conclusion, women receiving abnormal results of Down syndrome screening experience significant anxiety. Efforts should be made to relieve this distress, including changing the historical ratio risk format to percentage, adding a non-directive verbal annotation, an explanatory website and improving health professionals' understanding of the exact statistical meaning of the risk.Impact statementWhat is already known on this subject? Abnormal results of prenatal screening for Down syndrome might cause the women significant anxiety. Several simple methods are able to relieve this distress; however, they are frequently not implemented in the routine practice.What the results of this study add? We show that abnormal results of the screening tests are associated with high anxiety scores in the majority of women (86.0%). The majority of the respondents preferred the risk reported as percentage (vs. historical representation as a ratio). The participants noted several factors which could relieve their anxiety, including an explanatory booklet or a website.What the implications are of these findings for clinical practice and/or further research? Based on the results, we discuss the numerous ways able to available alleviate the distress.

Chromosomal Microarray Analysis Compared With Noninvasive Prenatal Testing in Pregnancies With Abnormal Maternal Serum Screening.

OBJECTIVE: To examine the effect of maternal age on the rate of clinically significant chromosomal microarray analysis results in pregnancies with abnormal maternal serum screening and to establish the residual risk for abnormal microarray findings after omitting noninvasive prenatal testing (NIPT)-detectable aberrations in pregnancies with abnormal maternal serum screening. METHODS: This retrospective study included all chromosomal microarray analysis tests performed in pregnancies with abnormal maternal serum screening and normal ultrasonogram results over the years 2013-2021. The rate of clinically significant (pathogenic and likely pathogenic) chromosomal microarray analysis findings was compared with a local control cohort of 7,235 pregnancies with normal maternal serum screening and ultrasonogram results, stratified by maternal age. Calculation of residual risk for clinically significant chromosomal microarray analysis results after normal NIPT was performed by omission of common NIPT-detectable anomalies. Systematic review for studies examining the yield of chromosomal microarray analysis in pregnancies with abnormal maternal serum screening was performed from inception to October 2021, with no time or language restrictions. RESULTS: Of the 559 amniocenteses performed due to abnormal maternal serum screening, 21 (3.8%; 95% CI 2.4-5.7%) clinically significant chromosomal microarray analysis results were found. The residual risk for chromosomal microarray analysis aberrations after theoretically normal NIPT was estimated to be 2.0% (95% CI 1.1-3.6%) (1/50) and was significantly higher for women younger than age 35 years with abnormal maternal serum screening, compared with women with low-risk pregnancies. Systematic review yielded six articles encompassing 4,890 chromosomal microarray analysis results in pregnancies with abnormal maternal serum screening, demonstrating 2.3% residual risk for chromosomal microarray analysis anomalies after theoretically normal NIPT. DISCUSSION: Clinically significant chromosomal microarray analysis findings can be found in 1 of every 50 pregnancies with high-risk maternal serum screening after theoretically normal NIPT, implying that invasive testing and not NIPT should be recommended in such pregnancies. In addition, NIPT use as a first-tier screening modality instead of maternal serum screening would miss pregnancies at increased risk not only for common autosomal trisomies but for additional chromosomal microarray analysis-detectable disorders.