The uncertainty of copy number variants: pregnancy decisions and clinical follow-up.

BACKGROUND: Next-generation sequencing for copy number variants is often used as a follow-up investigation of unusual fetal ultrasound results and is capable of detecting copy number variations with a resolution of ∼0.1 Mb. In a prenatal setting, observation and subsequent management of pregnancies with a fetal variant of uncertain significance remains problematic for counseling. OBJECTIVE: This study aimed to follow the decision-making processes in pregnancies with a fetal variant of uncertain significance and prospectively assess copy number variation interpretations and implications under the newer 2020 American College of Medical Genetics and Genomics guidelines. STUDY DESIGN: In a single prenatal unit, prospective chromosome testing using copy number variation sequencing for 8030 fetuses with unexpected noninvasive findings identified 139 pregnancies with a copy number variation classified as a variant of uncertain significance according to the 2015 American College of Medical Genetics and Genomics guidelines current at the time. Parent-of-origin testing was subsequently performed to determine if the copy number variation was inherited or de novo. All couples were offered specialized genetic counseling to assist in pregnancy management decisions. For the continued pregnancies that reached term, newborns were clinically assessed for evidence of any disease at 0 to 10 months and/or at 2 to 4 years of age. RESULTS: Of the 139 variants of uncertain significance found, most (78%) were inherited with no evidence of disease in the carrier parent. On the basis of primary ultrasound findings combined with results from noninvasive prenatal screening tests, most inherited variant of uncertain significance pregnancies were continued, whereas most pregnancies involving de novo variants of uncertain significance were terminated. From clinical follow-up of the 113 live births, only 5 showed any evidence of a phenotype that was not apparently related to the original variant of uncertain significance. Prospective reanalysis of the 139 variants of uncertain significance using recent 2020 American College of Medical Genetics and Genomics guidelines changed the status of 24 variants of uncertain significance, with 15 reclassified as benign and 9 as pathogenic. However, the 5 children born with an inherited variant of uncertain significance reclassified as pathogenic showed no evidence of a disease phenotype on clinical follow-up. CONCLUSION: The severity of fetal ultrasound findings combined with results from parent-of-origin testing were the key drivers in pregnancy management decisions for patients. According to birth outcomes from continued pregnancies, most variants of uncertain significance proved to be apparently benign in nature and potentially of low risk of adverse disease outcome. There was a discordance rate of 17% for variant of uncertain significance scoring between the 2015 and 2020 American College of Medical Genetics and Genomics guidelines for defining a variant of uncertain significance, suggesting that difficulties remain for predicting true pathogenicity. Nonetheless, with increasing knowledge of population copy number variation polymorphisms, and a more complete assessment for alternative genetic causes, patients having prenatal assessments should feel less anxious when a fetal variant of uncertain significance is identified.

Female and male decision-making regarding whether to continue or abort an unintended pregnancy: a secondary analysis of the FECOND study.

OBJECTIVE: We aimed to explore partner agreement in unintended pregnancy decisions and to describe predictors of female and male perceived agreement with their partner regarding the decision to continue or terminate the pregnancy. METHODS: This is a secondary analysis of the FECOND study, a population-based probability telephone survey conducted in France in 2010 comprising 8645 respondents aged 15-49 years. Pregnancy data were reported by individuals (not couple-level data). For female- and male-reported unintended pregnancies, we used generalised estimation equation models to estimate the odds of a female-only (disagreement) versus a joint (agreement) decision to continue or terminate an unintended pregnancy. RESULTS: The decision to continue an unintended pregnancy was reported as joint in 82% of female- and 88% of male-reported pregnancies. Pregnancy continuation was more likely to be perceived as female-only versus a joint decision if men perceived initial pregnancy intention disagreement (adjusted odds ratio [aOR] 5.9; 95% confidence intervals [CI] 2.0, 16.9), if women indicated finances were very difficult at the time of conception (aOR 3.0; 95% CI 1.7, 5.2) and if women or men reported an unstable relationship at the time of conception (aOR 10.0; 95% CI 6.1, 16.4; aOR 55.3; 95% CI 15.8, 193.0). The decision to terminate an unintended pregnancy was reported as joint in 61% of female- and 74% of male-reported pregnancies. Pregnancy termination was more likely to be perceived as a female-only decision if women reported an unstable relationship at the time of conception (aOR 3.8; 95% CI 2.3, 6.2). CONCLUSION: Pregnancy intention disagreement and finance/relationship status at the time of conception inform partner agreement about the decision to continue or end an unintended pregnancy.