Fetal Structural Anomalies
Conditions
Brief summary
This study is evaluating the impact of prenatal sequencing on the management of fetuses with ultrasound abnormalities. The hypothesis is that a significant subset of fetal abnormalities have a genetic cause that can be identified by sequencing and that prenatal knowledge of this information will improve prenatal care, reduce unnecessary diagnostic testing, reduce the cost of care, and improve the quality of life for both the child and the family.
Detailed description
Whole exome and whole genome sequencing (WGS) have expanded the ability to determine the genetic etiology of previously undiagnosed disorders. This study is a multicenter prospective cohort study to evaluate the emerging technology of sequencing for the management of fetuses with structural anomalies. The hypothesis is that a significant subset of fetal structural anomalies has a genetic etiology identifiable by sequencing and that prenatal knowledge of this information will improve perinatal care, reduce unnecessary diagnostic testing, reduce the cost of care, and improve quality of life for both the child and the family. The aims of this study are to investigate these multiple aspects of prenatal sequencing in a single study with an innovative integrated prospective design, which will permit a robust evaluation of the benefits and risks of delivering diagnostic and prognostic genetic testing results in a prenatal setting. The study will determine, in a sequential population of pregnancies with selected fetal structural anomalies and a negative or non-causal chromosomal microarray (CMA), the frequency of pathogenic, likely pathogenic, and uncertain genomic variants identifiable by sequencing. To determine the impact of this information on clinical care, a control population of unsequenced pregnancies with similar structural anomalies will be prospectively recruited and the infants from both cohorts will be followed up to 1 year of age. This study component will evaluate differences in healthcare management and cost through discharge from hospital post-delivery, and perinatal and infant outcomes through 1 year of life. The educational, counseling and psychosocial impact of sequencing results during the prenatal period, in the nursery and through 1 year of life also will be evaluated. Since the analytical and clinical tools needed for the full translation of sequencing into care are still developing, optimization of bioinformatic tools to improve identification of pathogenic and likely pathogenic mutations associated with prenatal phenotypes of established disease genes will be investigated, as well as identification of new genes associated with presently undiagnosed fetal/neonatal phenotypes. This study will provide an in-depth evaluation of the prenatal diagnostic value of sequencing prior to its responsible introduction into practice and will provide independent data to guide its translation.
Interventions
DIAGNOSTIC_TESTPrenatal Genomic Sequencing
Whole genome sequencing (which initially will be masked and reported as exome only)
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Baylor College of Medicine
University of North Carolina
The George Washington University Biostatistics Center
Oregon Health and Science University
Children's Hospital Medical Center, Cincinnati
The University of Texas Health Science Center, Houston
Broad Institute of MIT and Harvard
The Jackson Laboratory
Columbia University
Study design
Observational model
CASE_CONTROL
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
Prenatal sequencing group 1. Fetus identified by ultrasound and/or MRI with at least one of the following: 1. One or more major structural anomalies (Appendix A) 2. A nuchal translucency measurement of ≥ 3.5 mm 3. A fetus less than 24 weeks 0 days gestation with normal anatomy and sonographically estimated fetal weight \<5th %ile without maternal hypertension, type I diabetes, or other maternal disorders known to alter fetal growth. 2. Negative prenatal CMA (or those with CMA findings not related to the ultrasound finding) 3. Singleton or twin gestation 4. Gestational age less than 36 weeks, 0 days to allow for availability of sequencing results before delivery Unsequenced Group 1. Fetus identified by ultrasound and/or MRI with at least one of the following: 1. One or more major structural anomalies (Appendix A) 2. A nuchal translucency measurement of ≥ 3.5 mm 3. A fetus less than 24 weeks 0 days gestation with normal anatomy and sonographically estimated fetal weight \<5th %ile without maternal hypertension, type I diabetes, or other maternal disorders known to alter fetal growth 2. Negative prenatal or postnatal CMA (or those with CMA findings not related to the ultrasound finding) 3. Declined prenatal sequencing 4. Singleton gestation
Exclusion criteria
Prenatal Sequencing Group 1. Prenatal sequencing or planned prenatal sequencing performed outside of the study, including gene panels 2. Maternal or paternal age less than 18 years old 3. Proven infectious or teratogenic cause of fetal anomaly 4. Planned termination of the pregnancy 5. Unavailable blood or saliva samples from both biologic parents prior to sequencing 6. Parental unwillingness to participate in 1 year postnatal follow-up 7. Language barrier (non-English or Spanish speaking) 8. Previous consent to the unsequenced prenatal group or enrollment in a previous pregnancy Unsequenced Group 1. Maternal or paternal age less than 18 years old 2. Proven infectious or teratogenic cause of fetal anomaly 3. Positive prenatal NIPT screening for trisomy 21,18 or 13. Positive 22q11.2 prenatal NIPT testing with consistent ultrasound findings is also an exclusion. 4. Planned termination of the pregnancy 5. Parental unwillingness to participate in 1 year postnatal follow-up 6. Language barrier (non-English or Spanish speaking)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Had Reportable Variants | At end of study, approx 4 years | Reportable variants: defined as either Pathogenic / Likely pathogenic (P/LP) or variant of uncertain significance (VUS) identified by sequencing and deemed reportable by the Variant Adjudication Committee. |
| Healthcare Costs | From time of diagnosis of anomaly to infant discharge | Healthcare costs from time of diagnosis of anomaly to infant discharge between sequenced and unsequenced groups. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Deaths | From discharge to 12 months postpartum | Neonatal/infant death at time of discharge and at 12 months of age. |
| NICU Stay Duration | From discharge to 12 months postpartum | Length of initial NICU stay and number of days spent in the hospital between initial discharge and 12 months of age. |
| Length in Centimeters | 12 months postpartum | Infant length at 12 months of age. |
| Weight in Kilograms | 12 months postpartum | Infant weight at 12 months of age. |
| Score on Development by Ages and Stages Questionnaire (ASQ-3) | 12 months postpartum | Developmental outcomes defined by the following parameters: communication, gross motor, fine motor, problem solving and personal-social, at 12 months of age using ASQ-3. Lower scores are associated with developmental delay. For each developmental area, parents may answer YES=10, SOMETIMES=5, or NOT YET=0 by filling in a bubble for each item response. The full score range for each domain is 0 to 60. Cutoffs for each domain are: Communication 15.64, Gross Motor 21.49, Fine Motor 34.5, Problem Solving 27.32, Personal-Social 21.73 |
| Anxiety by Self-report Questionnaire | 2 weeks after disclosure of study sequencing results or 4 weeks after enrollment for the unsequenced group; 1 month after discharge from the hospital or end of the pregnancy if there was a fetal demise or pregnancy termination; 12-15 months postpartum | Anxiety following result disclosure (or 8 weeks post enrollment for the unsequenced group), neonatal discharge and 12 months postpartum. The full score range is 0 to 21, where lower numbers represent lower anxiety (better outcome). |
| Depression by Self-report Questionnaire | 2 weeks after disclosure of study sequencing results or 4 weeks after enrollment for the unsequenced group; 1 month after discharge from the hospital or end of the pregnancy if there was a fetal demise or pregnancy termination; 12-15 months postpartum | Depression following result disclosure (or 8 weeks post enrollment for the unsequenced group), neonatal discharge and 12 months postpartum. The full score range is 0 to 24, where a lower score represents lower depression (better outcome). |
| Quality of Life by Self-report Questionnaire | Approximately 4.5 years | Quality of life for the patient and family at 12 months postpartum. |
| QALY, Measured in Cost Per Year | Approximately 4.5 years | Incremental cost per Quality Adjusted Life Year (QALY). |
| Gestational Age at Delivery | At time of delivery | Gestational age of newborn at delivery (in weeks) |
| Number of Participants With VUS - Sequenced Group ONLY | 12 months postpartum | Variants of uncertain significance (VUS) that have not yet been associated with this disease phenotype. This outcome was only intended to be measured in participants in the Sequenced arm, as outlined in the study protocol. Data for this outcome was not collected from any participant in the Unsequenced arm. |
| Number of Participants With Variants Classified as GUS - Sequenced Group ONLY | 12 months postpartum | VUS subclassified as compelling variants in novel genes that are not yet disease associated (genes of uncertain clinical significance; GUS). This outcome was only intended to be measured in participants in the Sequenced arm, as outlined in the study protocol. Data for this outcome was not collected from any participant in the Unsequenced arm. |
| Digital WES - Comparison of Coding and Non-coding Results - Sequenced Group ONLY | Approximately 4.5 years | Pathogenic, likely pathogenic and VUS variants identified by sequencing (coding and non-coding regions) compared with coding regions only (digital WES). |
| Proband Only Versus Trio - Comparison of Results Between Trio and Proband Only - Sequenced Group ONLY | Approximately 4.5 years | Pathogenic, likely pathogenic and VUS variants identified by analysis of a proband alone compared to a proband-parent trio. |
| Change in Management (Healthcare) as Determined by NICU Physician and Record Review - Sequenced Group ONLY | From delivery until discharge or death (neonatal) | Number of participants who had a change in management decisions attributable to genomic results, defined as changes to the patient's treatment plan or changes to the counseling of the patient/family regarding the immediate or long-term medical management. This outcome was only intended to be measured in participants in the Sequenced arm, as outlined in the study protocol. Data for this outcome was not collected from any participant in the Unsequenced arm. |
| Parental Support Needs by Self-report Questionnaire - Sequenced Group ONLY | At sequencing completion, approximately 4.5 years | Assessment of educational/counseling and social support needs of the mother and father. The full score range is 12 to 60, where a higher score represents a higher satisfaction with the experience (better outcome). |
| Parental Understanding by Self-report Questionnaire - Sequenced Group ONLY | At sequencing completion, approximately 4.5 years | Accuracy of parental understanding of genetic test results. The parental responses to the question How well do you understand your prenatal genetic test results? will be collected. All possible responses are: Not at all, A little bit, Moderately, Quite a bit, and Extremely |
| Number of Participants Who Had a Change in the Sequencing Result - Sequenced Group ONLY | From sequencing completion to data analysis period, up to 4.5 years | Reinterpretations of sequencing results that lead to a change in classification of sequencing variants. This outcome was only intended to be measured in participants in the Sequenced arm, as outlined in the study protocol. Data for this outcome was not collected from any participant in the Unsequenced arm. |
| Turnaround Time - Sequenced Group ONLY | Time from sequencing initiation until study site result, up to 38 days | Turnaround time of sequencing components and how it changes over time. This outcome was only intended to be measured in participants in the Sequenced arm, as outlined in the study protocol. Data for this outcome was not collected from any participant in the Unsequenced arm. |
| Total Number of Identified Phenotypes Associated With Disease- Sequenced Group ONLY | 12 months postpartum | Phenotypic Expansion: Apparent prenatal phenotypic expansion from currently defined pediatric phenotypes. |
| Neonatal Outcomes | Up to 28 days after birth | Neonatal outcomes will be compared and outcomes will be measured by the number of newborns who experience: need for ventilator support, sepsis, need for pressor support, need for extracorporeal membrane oxygenation (ECMO), metabolic abnormalities (e.g., acidosis, elevated uric acid, hypo-/hyperglycemia), intraventricular hemorrhage, periventricular leukomalacia, encephalopathy, and seizure. |
Countries
United States
Participant flow
Recruitment details
Signed informed consent was obtained from the mother and the genetic father of the fetus prior to any study procedures for prospective enrollment. Enrollment of participants in the retrospective unsequenced prenatal group occurred under a waiver of consent. The participants in this record refer to the fetuses from which all study data was collected.
Participants by arm
| Arm | Count |
|---|---|
| Prenatally Sequenced Group Pregnancies with fetal structural anomalies will undergo prenatal genomic sequencing. | 751 |
| No Prenatal Sequencing (Unsequenced) Group Pregnancies will not have any prenatal genomic sequencing. | 346 |
| Total | 1,097 |
Baseline characteristics
| Characteristic | Total | Prenatally Sequenced Group | No Prenatal Sequencing (Unsequenced) Group |
|---|---|---|---|
| Age, Continuous | 21.0 weeks | 20.4 weeks | 22.1 weeks |
| Anomaly systems involved Multiple anomaly systems | 389 Participants | 277 Participants | 112 Participants |
| Anomaly systems involved Single anomaly system | 708 Participants | 474 Participants | 234 Participants |
| Race/Ethnicity, Customized Maternal race/ethnicity Black | 121 Participants | 66 Participants | 55 Participants |
| Race/Ethnicity, Customized Maternal race/ethnicity Hispanic | 252 Participants | 156 Participants | 96 Participants |
| Race/Ethnicity, Customized Maternal race/ethnicity Other | 103 Participants | 81 Participants | 22 Participants |
| Race/Ethnicity, Customized Maternal race/ethnicity White | 621 Participants | 448 Participants | 173 Participants |
| Race/Ethnicity, Customized Paternal race/ethnicity Black | 88 Participants | 68 Participants | 20 Participants |
| Race/Ethnicity, Customized Paternal race/ethnicity Hispanic | 183 Participants | 151 Participants | 32 Participants |
| Race/Ethnicity, Customized Paternal race/ethnicity Other | 82 Participants | 75 Participants | 7 Participants |
| Race/Ethnicity, Customized Paternal race/ethnicity White | 547 Participants | 456 Participants | 91 Participants |
| Region of Enrollment United States | 1097 participants | 751 participants | 346 participants |
| Sex: Female, Male Female | 0 Participants | — | — |
| Sex: Female, Male Male | 0 Participants | — | — |
| Type of anomaly Cardiovascular | 343 Participants | 193 Participants | 150 Participants |
| Type of anomaly central nervous system | 282 Participants | 203 Participants | 79 Participants |
| Type of anomaly Craniofacial | 130 Participants | 96 Participants | 34 Participants |
| Type of anomaly Cystic hygroma (nuchal translucency (NT) ≥ 4.5 mm) | 78 Participants | 74 Participants | 4 Participants |
| Type of anomaly Effusion | 118 Participants | 88 Participants | 30 Participants |
| Type of anomaly Fetal growth restriction < 5th percentile | 91 Participants | 65 Participants | 26 Participants |
| Type of anomaly Gastro-intestinal tract | 136 Participants | 90 Participants | 46 Participants |
| Type of anomaly Genitourinary | 217 Participants | 152 Participants | 65 Participants |
| Type of anomaly Intrathoracic | 110 Participants | 66 Participants | 44 Participants |
| Type of anomaly NT ≥ 3.5 mm to < 4.5 mm without evidence of cystic hygroma | 34 Participants | 31 Participants | 3 Participants |
| Type of anomaly Osteoarticular | 233 Participants | 164 Participants | 69 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 75 / 751 | 37 / 346 |
| other Total, other adverse events | 0 / 751 | 0 / 346 |
| serious Total, serious adverse events | 0 / 751 | 0 / 346 |
Outcome results
Primary
Healthcare Costs
Healthcare costs from time of diagnosis of anomaly to infant discharge between sequenced and unsequenced groups.
Time frame: From time of diagnosis of anomaly to infant discharge
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Prenatally Sequenced Group | Healthcare Costs | 149985 US dollars | Standard Deviation 375687 |
| No Prenatal Sequencing (Unsequenced) Group | Healthcare Costs | 165192 US dollars | Standard Deviation 350000 |
Primary
Number of Participants Who Had Reportable Variants
Reportable variants: defined as either Pathogenic / Likely pathogenic (P/LP) or variant of uncertain significance (VUS) identified by sequencing and deemed reportable by the Variant Adjudication Committee.
Time frame: At end of study, approx 4 years
Population: Only participants in the sequenced group were analyzed for this outcome.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Prenatally Sequenced Group | Number of Participants Who Had Reportable Variants | P/LP | 114 Participants |
| Prenatally Sequenced Group | Number of Participants Who Had Reportable Variants | VUS | 22 Participants |
Secondary
Anxiety by Self-report Questionnaire
Anxiety following result disclosure (or 8 weeks post enrollment for the unsequenced group), neonatal discharge and 12 months postpartum. The full score range is 0 to 21, where lower numbers represent lower anxiety (better outcome).
Time frame: 2 weeks after disclosure of study sequencing results or 4 weeks after enrollment for the unsequenced group; 1 month after discharge from the hospital or end of the pregnancy if there was a fetal demise or pregnancy termination; 12-15 months postpartum
Population: Only includes participants who completed the questionnaire
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Prenatally Sequenced Group | Anxiety by Self-report Questionnaire | 2 weeks after disclosure of sequencing results or 4 weeks after enrollment for the unsequenced group | 2.0 score on a scale |
| Prenatally Sequenced Group | Anxiety by Self-report Questionnaire | 1 month after discharge from the hospital or end of the pregnancy | 2.0 score on a scale |
| Prenatally Sequenced Group | Anxiety by Self-report Questionnaire | 12-15 months postpartum | 2.0 score on a scale |
| No Prenatal Sequencing (Unsequenced) Group | Anxiety by Self-report Questionnaire | 2 weeks after disclosure of sequencing results or 4 weeks after enrollment for the unsequenced group | 3.0 score on a scale |
| No Prenatal Sequencing (Unsequenced) Group | Anxiety by Self-report Questionnaire | 1 month after discharge from the hospital or end of the pregnancy | 3.0 score on a scale |
| No Prenatal Sequencing (Unsequenced) Group | Anxiety by Self-report Questionnaire | 12-15 months postpartum | 2.0 score on a scale |
Secondary
Change in Management (Healthcare) as Determined by NICU Physician and Record Review - Sequenced Group ONLY
Number of participants who had a change in management decisions attributable to genomic results, defined as changes to the patient's treatment plan or changes to the counseling of the patient/family regarding the immediate or long-term medical management. This outcome was only intended to be measured in participants in the Sequenced arm, as outlined in the study protocol. Data for this outcome was not collected from any participant in the Unsequenced arm.
Time frame: From delivery until discharge or death (neonatal)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prenatally Sequenced Group | Change in Management (Healthcare) as Determined by NICU Physician and Record Review - Sequenced Group ONLY | 72 Participants |
Secondary
Depression by Self-report Questionnaire
Depression following result disclosure (or 8 weeks post enrollment for the unsequenced group), neonatal discharge and 12 months postpartum. The full score range is 0 to 24, where a lower score represents lower depression (better outcome).
Time frame: 2 weeks after disclosure of study sequencing results or 4 weeks after enrollment for the unsequenced group; 1 month after discharge from the hospital or end of the pregnancy if there was a fetal demise or pregnancy termination; 12-15 months postpartum
Population: Only includes participants who completed the questionnaire
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Prenatally Sequenced Group | Depression by Self-report Questionnaire | 2 weeks after disclosure of sequencing results or 4 weeks after enrollment for the unsequenced group | 4.0 score on a scale |
| Prenatally Sequenced Group | Depression by Self-report Questionnaire | 1 month after discharge from the hospital or end of the pregnancy | 4.0 score on a scale |
| Prenatally Sequenced Group | Depression by Self-report Questionnaire | 12-15 months postpartum | 3.0 score on a scale |
| No Prenatal Sequencing (Unsequenced) Group | Depression by Self-report Questionnaire | 2 weeks after disclosure of sequencing results or 4 weeks after enrollment for the unsequenced group | 5.0 score on a scale |
| No Prenatal Sequencing (Unsequenced) Group | Depression by Self-report Questionnaire | 1 month after discharge from the hospital or end of the pregnancy | 4.0 score on a scale |
| No Prenatal Sequencing (Unsequenced) Group | Depression by Self-report Questionnaire | 12-15 months postpartum | 3.5 score on a scale |
Secondary
Digital WES - Comparison of Coding and Non-coding Results - Sequenced Group ONLY
Pathogenic, likely pathogenic and VUS variants identified by sequencing (coding and non-coding regions) compared with coding regions only (digital WES).
Time frame: Approximately 4.5 years
Secondary
Gestational Age at Delivery
Gestational age of newborn at delivery (in weeks)
Time frame: At time of delivery
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Prenatally Sequenced Group | Gestational Age at Delivery | 37.4 weeks |
| No Prenatal Sequencing (Unsequenced) Group | Gestational Age at Delivery | 38.0 weeks |
Secondary
Length in Centimeters
Infant length at 12 months of age.
Time frame: 12 months postpartum
Population: Data was collected from participants who had a follow-up visit at 12 months postpartum.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Prenatally Sequenced Group | Length in Centimeters | 73.7 cm | Standard Deviation 6.3 |
| No Prenatal Sequencing (Unsequenced) Group | Length in Centimeters | 73.6 cm | Standard Deviation 6.1 |
Secondary
Neonatal Outcomes
Neonatal outcomes will be compared and outcomes will be measured by the number of newborns who experience: need for ventilator support, sepsis, need for pressor support, need for extracorporeal membrane oxygenation (ECMO), metabolic abnormalities (e.g., acidosis, elevated uric acid, hypo-/hyperglycemia), intraventricular hemorrhage, periventricular leukomalacia, encephalopathy, and seizure.
Time frame: Up to 28 days after birth
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Prenatally Sequenced Group | Neonatal Outcomes | Pressor support | 89 Participants |
| Prenatally Sequenced Group | Neonatal Outcomes | Intraventricular hemorrhage | 42 Participants |
| Prenatally Sequenced Group | Neonatal Outcomes | ECMO | 24 Participants |
| Prenatally Sequenced Group | Neonatal Outcomes | Periventricular leukomalacia | 5 Participants |
| Prenatally Sequenced Group | Neonatal Outcomes | Mechanical ventilation | 222 Participants |
| Prenatally Sequenced Group | Neonatal Outcomes | Encephalopathy | 24 Participants |
| Prenatally Sequenced Group | Neonatal Outcomes | Metabolic abnormalities | 192 Participants |
| Prenatally Sequenced Group | Neonatal Outcomes | Seizure | 20 Participants |
| Prenatally Sequenced Group | Neonatal Outcomes | Sepsis | 92 Participants |
| No Prenatal Sequencing (Unsequenced) Group | Neonatal Outcomes | Seizure | 16 Participants |
| No Prenatal Sequencing (Unsequenced) Group | Neonatal Outcomes | Mechanical ventilation | 151 Participants |
| No Prenatal Sequencing (Unsequenced) Group | Neonatal Outcomes | ECMO | 19 Participants |
| No Prenatal Sequencing (Unsequenced) Group | Neonatal Outcomes | Pressor support | 69 Participants |
| No Prenatal Sequencing (Unsequenced) Group | Neonatal Outcomes | Sepsis | 66 Participants |
| No Prenatal Sequencing (Unsequenced) Group | Neonatal Outcomes | Metabolic abnormalities | 91 Participants |
| No Prenatal Sequencing (Unsequenced) Group | Neonatal Outcomes | Intraventricular hemorrhage | 33 Participants |
| No Prenatal Sequencing (Unsequenced) Group | Neonatal Outcomes | Periventricular leukomalacia | 4 Participants |
| No Prenatal Sequencing (Unsequenced) Group | Neonatal Outcomes | Encephalopathy | 8 Participants |
Secondary
NICU Stay Duration
Length of initial NICU stay and number of days spent in the hospital between initial discharge and 12 months of age.
Time frame: From discharge to 12 months postpartum
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Prenatally Sequenced Group | NICU Stay Duration | 6.0 days |
| No Prenatal Sequencing (Unsequenced) Group | NICU Stay Duration | 11.0 days |
Secondary
Number of Deaths
Neonatal/infant death at time of discharge and at 12 months of age.
Time frame: From discharge to 12 months postpartum
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Prenatally Sequenced Group | Number of Deaths | 75 deaths |
| No Prenatal Sequencing (Unsequenced) Group | Number of Deaths | 37 deaths |
Secondary
Number of Participants Who Had a Change in the Sequencing Result - Sequenced Group ONLY
Reinterpretations of sequencing results that lead to a change in classification of sequencing variants. This outcome was only intended to be measured in participants in the Sequenced arm, as outlined in the study protocol. Data for this outcome was not collected from any participant in the Unsequenced arm.
Time frame: From sequencing completion to data analysis period, up to 4.5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prenatally Sequenced Group | Number of Participants Who Had a Change in the Sequencing Result - Sequenced Group ONLY | 7 Participants |
Secondary
Number of Participants With Variants Classified as GUS - Sequenced Group ONLY
VUS subclassified as compelling variants in novel genes that are not yet disease associated (genes of uncertain clinical significance; GUS). This outcome was only intended to be measured in participants in the Sequenced arm, as outlined in the study protocol. Data for this outcome was not collected from any participant in the Unsequenced arm.
Time frame: 12 months postpartum
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prenatally Sequenced Group | Number of Participants With Variants Classified as GUS - Sequenced Group ONLY | 0 Participants |
Secondary
Number of Participants With VUS - Sequenced Group ONLY
Variants of uncertain significance (VUS) that have not yet been associated with this disease phenotype. This outcome was only intended to be measured in participants in the Sequenced arm, as outlined in the study protocol. Data for this outcome was not collected from any participant in the Unsequenced arm.
Time frame: 12 months postpartum
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Prenatally Sequenced Group | Number of Participants With VUS - Sequenced Group ONLY | 7 Participants |
Secondary
Parental Support Needs by Self-report Questionnaire - Sequenced Group ONLY
Assessment of educational/counseling and social support needs of the mother and father. The full score range is 12 to 60, where a higher score represents a higher satisfaction with the experience (better outcome).
Time frame: At sequencing completion, approximately 4.5 years
Population: Only includes participants in the sequenced group who completed the questionnaire
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Prenatally Sequenced Group | Parental Support Needs by Self-report Questionnaire - Sequenced Group ONLY | 56 score on a scale |
| No Prenatal Sequencing (Unsequenced) Group | Parental Support Needs by Self-report Questionnaire - Sequenced Group ONLY | 56 score on a scale |
Secondary
Parental Understanding by Self-report Questionnaire - Sequenced Group ONLY
Accuracy of parental understanding of genetic test results. The parental responses to the question How well do you understand your prenatal genetic test results? will be collected. All possible responses are: Not at all, A little bit, Moderately, Quite a bit, and Extremely
Time frame: At sequencing completion, approximately 4.5 years
Population: Only includes participants in the sequenced group who completed the questionnaire
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Prenatally Sequenced Group | Parental Understanding by Self-report Questionnaire - Sequenced Group ONLY | Not at all | 0 parental responses |
| Prenatally Sequenced Group | Parental Understanding by Self-report Questionnaire - Sequenced Group ONLY | Moderately | 5 parental responses |
| Prenatally Sequenced Group | Parental Understanding by Self-report Questionnaire - Sequenced Group ONLY | Extremely | 18 parental responses |
| Prenatally Sequenced Group | Parental Understanding by Self-report Questionnaire - Sequenced Group ONLY | Quite a bit | 43 parental responses |
| Prenatally Sequenced Group | Parental Understanding by Self-report Questionnaire - Sequenced Group ONLY | A little bit | 1 parental responses |
| No Prenatal Sequencing (Unsequenced) Group | Parental Understanding by Self-report Questionnaire - Sequenced Group ONLY | Extremely | 145 parental responses |
| No Prenatal Sequencing (Unsequenced) Group | Parental Understanding by Self-report Questionnaire - Sequenced Group ONLY | Not at all | 3 parental responses |
| No Prenatal Sequencing (Unsequenced) Group | Parental Understanding by Self-report Questionnaire - Sequenced Group ONLY | A little bit | 22 parental responses |
| No Prenatal Sequencing (Unsequenced) Group | Parental Understanding by Self-report Questionnaire - Sequenced Group ONLY | Moderately | 83 parental responses |
| No Prenatal Sequencing (Unsequenced) Group | Parental Understanding by Self-report Questionnaire - Sequenced Group ONLY | Quite a bit | 205 parental responses |
Secondary
Proband Only Versus Trio - Comparison of Results Between Trio and Proband Only - Sequenced Group ONLY
Pathogenic, likely pathogenic and VUS variants identified by analysis of a proband alone compared to a proband-parent trio.
Time frame: Approximately 4.5 years
Secondary
QALY, Measured in Cost Per Year
Incremental cost per Quality Adjusted Life Year (QALY).
Time frame: Approximately 4.5 years
Secondary
Quality of Life by Self-report Questionnaire
Quality of life for the patient and family at 12 months postpartum.
Time frame: Approximately 4.5 years
Secondary
Score on Development by Ages and Stages Questionnaire (ASQ-3)
Developmental outcomes defined by the following parameters: communication, gross motor, fine motor, problem solving and personal-social, at 12 months of age using ASQ-3. Lower scores are associated with developmental delay. For each developmental area, parents may answer YES=10, SOMETIMES=5, or NOT YET=0 by filling in a bubble for each item response. The full score range for each domain is 0 to 60. Cutoffs for each domain are: Communication 15.64, Gross Motor 21.49, Fine Motor 34.5, Problem Solving 27.32, Personal-Social 21.73
Time frame: 12 months postpartum
Population: Only includes participants who completed the follow-up questionnaire
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Prenatally Sequenced Group | Score on Development by Ages and Stages Questionnaire (ASQ-3) | Gross motor | 40 score on a scale |
| Prenatally Sequenced Group | Score on Development by Ages and Stages Questionnaire (ASQ-3) | Problem solving | 50 score on a scale |
| Prenatally Sequenced Group | Score on Development by Ages and Stages Questionnaire (ASQ-3) | Fine motor | 50 score on a scale |
| Prenatally Sequenced Group | Score on Development by Ages and Stages Questionnaire (ASQ-3) | Personal-social | 45 score on a scale |
| Prenatally Sequenced Group | Score on Development by Ages and Stages Questionnaire (ASQ-3) | Communication | 45 score on a scale |
| No Prenatal Sequencing (Unsequenced) Group | Score on Development by Ages and Stages Questionnaire (ASQ-3) | Personal-social | 50 score on a scale |
| No Prenatal Sequencing (Unsequenced) Group | Score on Development by Ages and Stages Questionnaire (ASQ-3) | Communication | 45 score on a scale |
| No Prenatal Sequencing (Unsequenced) Group | Score on Development by Ages and Stages Questionnaire (ASQ-3) | Gross motor | 43 score on a scale |
| No Prenatal Sequencing (Unsequenced) Group | Score on Development by Ages and Stages Questionnaire (ASQ-3) | Fine motor | 48 score on a scale |
| No Prenatal Sequencing (Unsequenced) Group | Score on Development by Ages and Stages Questionnaire (ASQ-3) | Problem solving | 45 score on a scale |
Secondary
Total Number of Identified Phenotypes Associated With Disease- Sequenced Group ONLY
Phenotypic Expansion: Apparent prenatal phenotypic expansion from currently defined pediatric phenotypes.
Time frame: 12 months postpartum
Population: This outcome was only intended to be measured in participants in the Sequenced arm, as outlined in the study protocol. Data for this outcome was not collected from any participant in the Unsequenced arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Prenatally Sequenced Group | Total Number of Identified Phenotypes Associated With Disease- Sequenced Group ONLY | 22 phenotypes |
Secondary
Turnaround Time - Sequenced Group ONLY
Turnaround time of sequencing components and how it changes over time. This outcome was only intended to be measured in participants in the Sequenced arm, as outlined in the study protocol. Data for this outcome was not collected from any participant in the Unsequenced arm.
Time frame: Time from sequencing initiation until study site result, up to 38 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Prenatally Sequenced Group | Turnaround Time - Sequenced Group ONLY | 11.5 days | Standard Deviation 5.4 |
Secondary
Weight in Kilograms
Infant weight at 12 months of age.
Time frame: 12 months postpartum
Population: Data was collected from participants who had a follow-up visit at 12 months postpartum.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Prenatally Sequenced Group | Weight in Kilograms | 9.3 kg | Standard Deviation 1.5 |
| No Prenatal Sequencing (Unsequenced) Group | Weight in Kilograms | 9.6 kg | Standard Deviation 1.3 |