Healthcare provider recognition of pregnancy related risks and management considerations in patients with tuberous sclerosis complex.

BACKGROUND: Patients with tuberous sclerosis complex (TSC) face an increased risk of maternal health complications and worsening disease manifestations during pregnancy. There are no established consensus guidelines that address the management of pregnancy in patients with TSC and healthcare providers rely on their individual experiences and preferences to derive treatment decisions. We sought to obtain provider opinion of pregnancy related maternal complications in patients with TSC, and the common evaluation and management strategies used to address these issues. METHODS: We conducted a cross-sectional survey of healthcare providers with diverse areas of expertise related to the multisystem nature of involvement in TSC. Descriptive analyses were used to analyze our three primary variables: (1) provider recognition of maternal risks/complications; (2) provider recommendations before and during pregnancy; and (3) provider/clinic protocols. RESULTS: We received responses from 87 providers from 11 countries, with 40.7% (n = 35) seeing > 30 TSC patients yearly. The majority of providers (n = 70, 88.6%) deemed that a patient with TSC needed expert care beyond the standard of care for a typical pregnancy, with over 25% of providers reporting that they have seen lymphangioleiomyomatosis (LAM) exacerbation, seizures, and preterm labor in pregnant patients with TSC. Providers who managed patients treated with mTOR inhibitors (mTORi) also agreed that mTORi use should be stopped prior to pregnancy (n = 45, 68.2%) but there was uncertainty about when to stop the mTORi (one month 28.9%, two months 11.1%, three months 42.2%, and 6-12 months 2.2%). Additionally, there were mixed opinions on restarting mTORi in response to disease progression during pregnancy. When asked about provider or clinic specific protocols, 71.6% (n = 53) of providers stated that they do not have a clear protocol for management decisions for patients with TSC before or during pregnancy. CONCLUSION: Healthcare providers recognize that patients with TSC are at an increased risk for maternal health complications during pregnancy. However, there are wide inter-individual variances in practice, especially pertaining to decisions regarding mTORi use. There is a critical need to better understand the implications of pregnancy for patients with TSC, and to draft consensus recommendations to guide management decisions.

Twin-twin transfusion syndrome recipient with arterial calcification and heterozygous variant in ABCC6: Evidence of a gene-environment interaction?

We report a case of a twin-twin transfusion syndrome (TTTS) recipient who, after successful fetoscopic surgery, developed a large pericardial effusion and calcifications of the aorta and main pulmonary artery. The donor fetus never had cardiac strain and never developed cardiac calcifications. A heterozygous likely pathogenic variant in ABCC6 (c.2018T > C, p.Leu673Pro) was identified in the recipient twin. While TTTS recipient twins are at risk of arterial calcifications and right heart failure secondary to the disease, calcifications of the great vessels are also observed in generalized arterial calcification of infancy, a Mendelian genetic disorder with associated biallelic pathogenic variations in ABCC6 or ENPP1, which can result in significant pediatric morbidity or mortality. The recipient twin in this case had some degree of cardiac strain prior to TTTS surgery; however, the progressive calcification of the aorta and pulmonary trunk occurred weeks after TTTS resolution. This case raises the possibility of a gene-environment interaction and emphasizes the need for genetic evaluation in the setting of TTTS and calcifications.

Perinatal Outcomes of Fetuses and Infants Diagnosed with Trisomy 13 or Trisomy 18.

OBJECTIVES: To identify factors associated with prenatal, perinatal, and postnatal outcomes, and determine medical care use for fetuses and infants with trisomy 13 (T13) and trisomy 18 (T18). STUDY DESIGN: This population-based retrospective cohort study included all prenatal and postnatal diagnoses of T13 or T18 in the greater Cincinnati area from January 1, 2012, to December 31, 2018. Overall survival, survival to hospital discharge, medical management, and maternal, fetal, and neonatal characteristics are analyzed. RESULTS: There were 124 pregnancies (125 fetuses) that were identified, which resulted in 72 liveborn infants. Male fetal sex and hydrops were associated with a higher rate of spontaneous loss. The median length of survival was 7 and 29 days, for infants with T13 and T18, respectively. Of the 27 infants alive at 1 month of age, 13 (48%) were alive at 1 year of age. Only trisomy type (T13), goals of care (comfort care), and extremely low birthweight were associated with a shorter length of survival. A high degree of variability existed in the use of medical services, with 28% of infants undergoing at least 1 surgical procedure and some children requiring repeated (≤29) or prolonged (>1 year) hospitalizations. CONCLUSIONS: Although many infants with T13 or T18 did not survive past the first week of life, nearly 20% lived for more than 1 year with varying degrees of medical support. The length of survival for an infant cannot be easily predicted, and surviving infants have high health care use throughout their lifespans.

Alobar holoprosencephaly: Exploring mothers' perspectives on prenatal decision-making and prognostication.

OBJECTIVES: Parents receiving a prenatal diagnosis of alobar holoprosencephaly (HPE) often experience uncertainty regarding the pregnancy prognosis. There is little known about how best to counsel and support families receiving the diagnosis. This study explored parental experiences and wishes after receiving a prenatal diagnosis of alobar HPE. METHODS: This was a retrospective qualitative study. Semi-structured interviews were conducted to determine factors impacting parents' decision-making process, experiences with healthcare providers, and expectations for their child's length and quality of life. Interviews were analyzed using qualitative content analysis. RESULTS: Eight mothers who received a prenatal diagnosis of alobar HPE between 2013 and 2019 participated in the study. Parental expectations were based on information conveyed during prenatal counseling. Religious and personal beliefs, perceived suffering, and provider prognostication contributed to parent decisions and goals of care. Participants reported pressure to terminate the pregnancy. Parents were not prepared for the possibility of survival beyond the perinatal period. Most parents reported no regret in their choices. CONCLUSION: Patients receiving a prenatal diagnosis of alobar HPE desire access to balanced prenatal counseling about prognosis, morbidity, and mortality. Providers should explore values and beliefs that contribute to parents' goals of care and offer appropriate information and referrals.

Experiences of reproductive genetic counselors with abortion regulations in Ohio.

Since 2010, Ohio legislators have passed more than 15 legislative changes related to abortion and abortion providers, and nine procedural abortion clinics have closed. We investigated reproductive genetic counselors' perceptions, attitudes and self-reported practices regarding Ohio's current and proposed abortion regulations. We conducted five focus groups and two telephone interviews in 2019-2020, with a total of 19 reproductive genetic counselors. Participants discussed difficulties keeping current on abortion legislation and clinics' and hospitals' policies, resulting in anticipatory anxiety and leading to additional work to discuss the laws with patients. Participants articulated that practices of reproductive genetic counseling-and patient advocacy-are impeded by the legislation. Genetic counselors perceive negative impacts on patients' autonomy, particularly reflective of healthcare disparities of marginalized groups, which may contribute to frustration and anger. Ultimately, the mental and emotional burden on genetic counselors created by abortion legislation contributes to compassion fatigue and burnout. Our findings show that Ohio's abortion regulations negatively impact reproductive genetic counselors and their relationships with their patients. Repealing existing abortion regulations and preventing future restrictive legislation may ameliorate the negative effects of regulations on reproductive genetic counselors and their patients. In the event that these laws remain, innovative communication tools and proactive professional society advocacy are potential means to mitigate the negative impact on reproductive genetic counselors.

Beyond diagnostic yield: prenatal exome sequencing results in maternal, neonatal, and familial clinical management changes.

PURPOSE: Previous studies have reported that prenatal exome sequencing (pES) can detect monogenic diseases in fetuses with congenital anomalies with diagnostic yields ranging from 6% to 81%, but there are few reports of its clinical utility. METHODS: We conducted a retrospective chart review of patients who had pES to determine whether results led to clinical management changes. RESULTS: Of 20 patients, 8 (40%) received a definitive diagnosis. Seven patients (35%) had medical management changes based on the pES results, including alterations to their delivery plan and neonatal management (such as use of targeted medications, subspecialty referrals, additional imaging and/or procedures). All patients who received a definitive diagnosis and one who received a likely pathogenic variant (n = 9; 45%) received specific counseling about recurrence risk and the medical/developmental prognosis for the baby. In five (25%) cases, the result facilitated a diagnosis in parents and/or siblings. CONCLUSION: pES results can have significant impacts on clinical management, some of which would not be possible if testing is deferred until after birth. To maximize the clinical utility, pES should be prioritized in cases where multiple care options are available and the imaging findings alone are not sufficient to guide parental decision-making, or where postnatal testing will not be feasible.

Prenatal diagnosis of Proteus syndrome: Diagnosis of an AKT1 mutation from amniocytes.

Proteus syndrome is a mosaic genetic overgrowth disorder caused by a postzygotic, mosaic activating mutation in AKT1. Rare prenatal presentations include segmental tissue overgrowth, and skeletal and CNS anomalies. We present the first report of prenatally diagnosed and molecularly confirmed Proteus syndrome. Prenatal imaging identified megalencephaly, brain and eye malformations, focal soft tissue enlargement, and ambiguous genitalia. Exome sequencing performed on cultured amniocytes demonstrated an AKT1 pathogenic variant consistent with Proteus syndrome, and postnatal examination confirmed the diagnosis. Postnatal Sanger sequencing could not identify the AKT1 pathogenic variant. This case underscores the importance of prenatal exome sequencing on cultured amniocytes for mosaic overgrowth disorders, as well as provides additional information on the prenatal phenotype of Proteus syndrome, and highlights the impact of prenatal diagnosis on postnatal management.

Aneuploid embryo transfer: clinical policies and provider opinions at United States fertility clinics.

OBJECTIVE: To describe institutional clinical policies and individual provider opinions regarding aneuploid embryo transfer (aET). DESIGN: A survey about clinical policies was electronically sent to Society for Assisted Reproductive Technology (SART) member laboratory directors, and a separate survey about personal opinions was electronically sent to all SART members. SETTING: Not applicable. PATIENTS: Patients pursuing preimplantation genetic testing for aneuploidy (PGT-A). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Current clinical policies about aET were described. Individual provider opinions about aET in the context of specific aneuploidies and mosaicism were also described. RESULTS: A total of 48 laboratory directors and 212 individual providers responded to their respective surveys. Twelve (25%) clinics report that they do not have a policy regarding aET, but clinics performing PGT-A in >100 cycles per year were more likely to have a policy. Half of the individual providers agree that an embryo with trisomy 21 should be available for aET, but most disagreed with aET of embryos with other aneuploidies and most were either unsure about or unwilling to transfer embryos with mosaicism. Those who worked in primarily patient-facing roles held more agreeable opinions regarding aET. CONCLUSION: There is no consensus regarding ideal clinical policies for aET. The wide range of current clinical practices and individual provider opinions regarding under what circumstances, if any, aET should be available to patients indicates that this is a divisive issue among ART providers, and there is a clear need for specific professional guidelines to address this issue.

Making a Genetic Diagnosis in a Level IV Neonatal Intensive Care Unit Population: Who, When, How, and at What Cost?

OBJECTIVE: To investigate the prevalence of genetic disease and its economic impact in a level IV neonatal intensive care unit (NICU) by identifying and describing diseases diagnosed, genetic testing methodologies used, timing of diagnosis, length of NICU stay, and charges for NICU care. STUDY DESIGN: A retrospective chart review of patients admitted to a level IV NICU from 2013 to 2014 (n = 1327) was undertaken and data collected up to 2 years of age from the electronic medical record. RESULTS: In total, 117 patients (9%) received 120 genetic diagnoses using a variety of methodologies. A significant minority of diagnoses, 36%, were made after NICU discharge and 41% were made after 28 days of age. Patients receiving a genetic diagnosis had significantly longer mean lengths of stay (46 days vs 29.1 days; P < .01) and costlier mean charges ($598 712 vs $352 102; P < .01) for their NICU care. The NICU stay charge difference to care for a newborn with a genetic condition was on average $246 610 in excess of that for a patient without a genetic diagnosis, resulting in more than $28 000 000 in excess charges to care for all patients with genetic conditions in a single NICU over a 2-year period. CONCLUSIONS: Given the high prevalence of genetic disease in this population and the documented higher cost of care, shortening the time to diagnosis and targeting therapeutic interventions for this population could make a significant impact on neonatal care in level IV NICUs.

Pediatric Whole Exome Sequencing: an Assessment of Parents' Perceived and Actual Understanding.

Whole exome sequencing (WES) is an integral tool in the diagnosis of genetic conditions in pediatric patients, but concerns have been expressed about the complexity of the information and the possibility for secondary findings that need to be conveyed to those deciding about WES. Currently, there is no validated tool to assess parental understanding of WES. We developed and implemented a survey to assess perceived and actual understanding of WES in parents who consented to clinical WES for their child between July 2013 and May 2015. Fifty-three eligible surveys were returned (57% response rate). Areas with both low perceived and actual understanding about WES included how genes are analyzed and lack of protection against life insurance discrimination. Parents also had low actual understanding for two questions related to secondary findings - reporting of secondary findings in a parent (if tested) and whether secondary findings can be related to traits such as height and hair color. Further work to develop a validated tool to assess understanding of WES would be beneficial as WES is integrated more frequently into clinical care.

Uterine natural killer cells: supervisors of vasculature construction in early decidua basalis.

Mammalian pregnancy involves tremendous de novo maternal vascular construction to adequately support conceptus development. In early mouse decidua basalis (DB), maternal uterine natural killer (uNK) cells oversee this process directing various aspects during the formation of supportive vascular networks. The uNK cells recruited to early implantation site DB secrete numerous factors that act in the construction of early decidual vessels (neoangiogenesis) as well as in the alteration of the structural components of newly developing and existing vessels (pruning and remodeling). Although decidual and placental development sufficient to support live births occur in the absence of normally functioning uNK cells, development and structure of implantation site are optimized through the presence of normally activated uNK cells. Human NK cells are also recruited to early decidua. Gestational complications including recurrent spontaneous abortion, fetal growth restriction, preeclampsia, and preterm labor are linked with the absence of human NK cell activation via paternally inherited conceptus transplantation antigens. This review summarizes the roles that mouse uNK cells normally play in decidual neoangiogenesis and spiral artery remodeling in mouse pregnancy and briefly discusses changes in early developmental angiogenesis due to placental growth factor deficiency.