Disparities in the acceptance of chromosomal microarray at the time of prenatal genetic diagnosis.

OBJECTIVE: Chromosomal microarray (CMA) increases the diagnostic yield of prenatal genetic diagnostic testing but is not universally performed. Our objective was to identify provider and patient characteristics associated with the acceptance of CMA at the time of prenatal genetic diagnostic testing. METHODS: Retrospective cohort study of patients undergoing prenatal genetic diagnostic testing (chorionic villus sampling or amniocentesis) at a single institution between 2014 and 2020. Primary outcome was the acceptance of CMA based on the genetic counselor ,GC who saw the patient. Secondary analyses assessed patient characteristics associated with the acceptance of CMA. RESULTS: 2372 participants were included. Fifty-eight percent of participants accepted CMA. Acceptance of CMA varied significantly by GC, ranging from 31% to 90%. Patients with public insurance and those who identified as Black or Hispanic/Latina were less likely to have CMA performed (aOR 0.24, 95% CI 0.20-0.30, and 0.68, 95% CI 0.50-0.92). Even among those with a structural anomaly present, public insurance was associated with significantly lower odds of CMA being performed (aOR 0.39, 95% CI 0.25-0.61). CONCLUSIONS: Acceptance of CMA at the time of prenatal genetic diagnostic testing varied based on the GC performing the counseling. Public insurance was associated with lower frequency of accepting CMA.

Differentiating complete hydatidiform mole and coexistent fetus and placental mesenchymal dysplasia: A series of 9 cases and review of the literature.

To identify the differentiating features in clinical presentation, management, and maternal/fetal outcome in complete hydatidiform mole and coexistent fetus compared with placental mesenchymal dysplasia. Between 1997 and 2015, five women with complete hydatidiform mole and coexistent fetus and four women with placental mesenchymal dysplasia were managed at the University of California San Francisco. Clinical features were analyzed and compared with previously published data. Of the five cases of complete hydatidiform mole and coexistent fetus, two had live births. ß-hCG levels were > 200,000 IU/L in all cases. On imaging, a clear plane between the cystic component and the placenta favored a diagnosis of complete hydatidiform mole and coexistent fetus. None of the patients went on to develop gestational trophoblastic neoplasia (GTN), with a range of follow-up from 2 to 38 months. Combining this data with previously published work, the live birth rate in these cases was 38.8%, the rate of persistent GTN was 36.2%, and the rate of persistent GTN in patients with reported live births was 27%. Of the four cases of placental mesenchymal dysplasia, all four had live births. One patient developed HELLP syndrome and intrauterine growth restriction; the remaining three were asymptomatic. Maternal symptoms, fetal anomalies, ß-hCG level, and placental growth pattern on imaging may help differentiate between complete hydatidiform mole and coexistent fetus and placental mesenchymal dysplasia. There was not an increased risk of gestational trophoblastic neoplasia in patients with complete hydatidiform mole and coexistent fetus who opted to continue with pregnancy.

Bilateral Choroid Plexus Papillomas Diagnosed by Prenatal Ultrasound and MRI.

We present a rare prenatal diagnosis of bilateral choroid plexus papillomas by obstetrical ultrasound and fetal MRI at 20 weeks 6 days gestation. The fetus demonstrated bilateral enlarged, echogenic choroid plexus with increased Doppler flow suggestive of vascularized choroid tissue. Same-day fetal MRI demonstrated that the choroid plexus appeared enlarged bilaterally without definite hemorrhage. The combined features on ultrasound and MRI suggested bilateral choroid plexus papillomas with increased cerebrospinal fluid production, leading to ventriculomegaly and enlarged extra-axial spaces. The diagnosis was confirmed by postnatal pathology, which demonstrated WHO grade II atypical choroid plexus papillomas.

Gross morphologic appearance of chorionic villi and the risk of chromosomal abnormalities.

Chromosomal abnormalities are associated with changes in complex aspects of chorionic villi histomorphology. This study used a simple scoring system to evaluate the association between atypical gross morphology and abnormal chromosomal testing on chorionic villus sampling (CVS). This retrospective cohort study included singleton pregnancies that underwent CVS at a single institution from 2006-2017. The degree of budding, branching, and vascularity (BBV) was scored from 0 to 3 for each CVS specimen, and individual scores were summed to calculate a composite BBV score. Scores were categorized into typical or atypical based on the cohort's distribution. The primary predictor was atypical BBV score, and the primary outcome was chromosomal abnormality. Fisher's exact test compared proportions, and logistic regression generated odds ratios. Among 1171 CVS specimens, 28% had chromosomal abnormalities. The chromosomally abnormal group had a higher rate of atypical BBV score than the normal group (7.3% vs 3.7%, P=0.009), a finding that remained statistically significant after controlling for maternal age, gestational age, and mode of CVS (aOR 2.2, 95% CI 1.24-3.82). Atypical chorionic villus morphology is associated with chromosomal abnormalities. This scoring system is simple, rapid, and easy to perform at the time of routine diagnosis.

Maternal genetic disorders and fetal development.

With improvements in early diagnosis and management of genetic diseases, more women with genetic disorders are reaching reproductive age and becoming pregnant. While pregnancy can have a significant impact on a woman's health when there is an underlying genetic disorder, there can also be fetal effects, including embryopathy, fetal growth restriction, and brain injury. Some maternal genetic disorders are associated with adverse perinatal outcomes, including a high risk of perinatal loss and preterm birth. In this article, we review several maternal genetic disorders associated with fetal risk that are important for clinicians and patients to understand and manage appropriately. These include phenylalanine hydroxylase (PAH) deficiency and other inborn errors of metabolism, tuberous sclerosis complex, myotonic dystrophy, cystic fibrosis, Turner syndrome, sickle cell disease, and connective tissue disorders.

A system-based approach to the genetic etiologies of non-immune hydrops fetalis.

A wide spectrum of genetic causes may lead to nonimmune hydrops fetalis (NIHF), and a thorough phenotypic and genetic evaluation are essential to determine the underlying etiology, optimally manage these pregnancies, and inform discussions about anticipated prognosis. In this review, we outline the known genetic etiologies of NIHF by fetal organ system affected, and provide a systematic approach to the evaluation of NIHF. Some of the underlying genetic disorders are associated with characteristic phenotypic features that may be seen on prenatal ultrasound, such as hepatomegaly with lysosomal storage disorders, hyperechoic kidneys with congenital nephrosis, or pulmonary valve stenosis with RASopathies. However, this is not always the case, and the approach to evaluation must include prenatal ultrasound findings as well as genetic testing and many other factors. Genetic testing that has been utilized for NIHF ranges from standard chromosomal microarray or karyotype to gene panels and broad approaches such as whole exome sequencing. Family and obstetric history, as well as pathology examination, can yield additional clues that are helpful in establishing a diagnosis. A systematic approach to evaluation can guide a more targeted approach to genetic evaluation, diagnosis, and management of NIHF.

Investigating human placentation and pregnancy using first trimester chorionic villi.

Chorionic villus sampling (CVS), routinely used for prenatal diagnosis of cytogenetic disorders, also possesses great potential for the study of placentation. To better understand villus biology, human placentation, and how these relate to pregnancy outcomes, we examined the morphology and transcriptomes of villi obtained via CVS from 10 to 14 weeks of pregnancy and correlated these with pregnancy attributes and clinical outcomes. First, we established a morphological scoring system based on three main villus features: branching, budding and vascularization. We then tested whether morphology scores were predictive of pregnancy attributes and clinical outcomes. Finally, we used RNA sequencing to assess the transcriptional basis of villus morphology and tested the hypothesis that gene expression may predict pregnancy outcomes. We demonstrate that villus morphology varies tremendously between patients, irrespective of gestational age, and that transcriptional differences are highly predictive of villus morphology. We show that pre-eclampsia markers are associated with villi with low morphology scores. Additionally, we identify SVEP1 as a possible biomarker for defining gestational age. Overall, chorionic villi in the first trimester remain one of the few means to correlate placental function with pregnancy outcome and these samples are a valuable and increasingly rare resource.

Obstetric care in women with genetic disorders.

The management of pregnant women who are themselves affected with genetic diseases is an increasingly relevant and important issue. Improvements in early diagnosis and management of genetic disease, as well as advances in assisted reproductive technology have impacted pregnancy rates in a cohort of women who may not have otherwise been able to conceive. A multidisciplinary approach is key to the management of pregnant women with complex health conditions, including genetic diseases. Pertinent issues should be addressed in the preconception, antepartum, intrapartum and postpartum periods to optimize maternal and fetal health. Additionally, counseling regarding risk of inheritance in offspring and options for prenatal diagnosis should be reviewed if available. This reviews aims to help provide background and insight into the management strategies for various commonly encountered and complex genetic conditions in the setting of pregnancy.

Feasibility of neonatal pulse wave velocity and association with maternal hemoglobin A1c.

BACKGROUND: Use of non-invasive peripheral arterial tonometry to assess arterial stiffness has not been studied in neonates. Perinatal factors impact childhood vascular health, but the effect in neonates remains to be examined. OBJECTIVES: To examine the feasibility of pulse wave velocity (PWV) among healthy term neonates, and to evaluate the effects of perinatal factors on neonatal PWV. METHODS: Pregnant women with singleton gestation presenting for routine care were enrolled. Postnatally, PWV measurements of their neonates were obtained using an arterial tonometer. A variability index was calculated for each PWV measurement. Intra- and inter-observer reproducibility were illustrated with Bland-Altman plots. Medical records were reviewed. Relationships between neonatal PWV and perinatal factors were examined. RESULTS: PWV measurements were attempted in 76 neonates and successfully obtained in 67 (88%). Using PWV measurements with a variability index ≤ 0.25 (48 neonates), the intra-class coefficient was 0.69. The mean differences (limits of agreement) for intra- and inter-rater reproducibility were 0.02 (-3.64 to 3.60) and 0.34 (-2.23 to 2.39), respectively. Median neonatal PWV was 2.80 m/s (range 0.60-8.40). Neonates of mothers with HgbA1c ≥6% had significantly higher PWV than neonates of mothers with HgbA1c <6% (4.12 m/s, 95% CI 3.22-5.02, vs. 2.78 m/s, 95% CI 2.28-3.28, p = 0.02). CONCLUSIONS: Neonatal PWV using peripheral arterial tonometry is feasible and reproducible when using measurements with a variability index ≤ 0.25. Neonates of mothers with increased HgbA1c had higher PWV, suggesting an effect of maternal hyperglycemia on neonatal vasculature. The long-term implications of this finding warrant further investigation.

Uterine rupture after uterine artery embolization for symptomatic leiomyomas.

BACKGROUND: There are few data regarding safety of pregnancy after uterine artery embolization. However, numerous women desire future fertility after this procedure. Uterine rupture without a history of cesarean delivery or uterine scarring is an exceedingly rare complication in pregnancy. CASE: We report a case of uterine rupture in a primigravid woman after uterine artery embolization. Her pregnancy was also complicated by placenta previa with placenta increta, resulting in a favorable neonatal outcome in an otherwise life-threatening situation for mother and fetus. CONCLUSION: Uterine artery embolization is a risk factor for abnormal placentation and uterine rupture in subsequent pregnancies.

Uptake of noninvasive prenatal testing (NIPT) in women following positive aneuploidy screening.

OBJECTIVE: The aim of this study was to investigate how the introduction of noninvasive prenatal testing (NIPT) impacted women's testing choices following a positive prenatal screening (PNS) result. METHODS: Beginning in March 2012, women referred to our Prenatal Diagnosis Center following a positive PNS result were offered NIPT or invasive prenatal diagnosis. Rates of invasive testing and declining follow-up were compared with testing decisions the prior year. Differences were compared using t-test and chi-square. Multivariable logistic regression was performed to identify predictors of test choice. RESULTS: Between March 2012 and February 2013, 398 screen positive women were seen: 156 (39.2%) underwent invasive testing, 157 (39.4%) had NIPT and 84 (21.1%) declined further testing. In the prior year, 638 screen positive patients were seen: 301 (47.2%) had invasive testing and 337 (52.8%) declined. The rate of invasive testing declined significantly (p = 0.012). Moreover, fewer women declined follow-up testing after introduction of NIPT, 21.2% versus 52.8%, p ≤ 0.001. Race/ethnicity and timing of results (first versus second trimester) were predictors of testing choices; payer and maternal age were not. CONCLUSION: The introduction of NIPT resulted in a significant decrease in invasive diagnostic testing. Additionally, fewer women declined further testing when NIPT was available.

Management of pregnancy in women with genetic disorders: Part 2: Inborn errors of metabolism, cystic fibrosis, neurofibromatosis type 1, and Turner syndrome in pregnancy.

UNLABELLED: With early diagnosis and increasingly effective medical care, more women with genetic syndromes are undergoing pregnancy, often presenting challenges for providers. Each year more women with genetic disease reach childbearing age. Advances in assisted reproductive technology have enabled pregnancy in a cohort of woman who experience impaired fertility because of their underlying diagnosis. Management of these women requires health care providers from multiple specialties to provide coordinated care to optimize outcomes. Potentially, serious medical issues specific to each diagnosis may exist in the preconception, antepartum, intrapartum, and postpartum periods, all of which must be understood to allow timely diagnosis and treatment. The fetus may also face issues, both related to risk for inheritance of the genetic disorder observed in the mother as well as risks related to her chronic disease status. In this article, the second of a 2-part series, we will review the key issues for managing women with various inborn errors of metabolism during pregnancy. Additionally, we will discuss the care of women with Turner syndrome, neurofibromatosis type 1, and cystic fibrosis. TARGET AUDIENCE: Obstetricians & Gynecologists and Family Physicians. LEARNING OBJECTIVES: After the completing the CME activity, physicians should be better able to classify the pulmonary and nutritional issues facing women with cystic fibrosis in pregnancy, assess the baseline evaluation that should take place in women with Turner syndrome, NF1 and cystic fibrosis before attempting pregnancy and evaluate the fetal risks that can be observed in women with untreated inborn errors of metabolism.

Management of pregnancy in women with genetic disorders, Part 1: Disorders of the connective tissue, muscle, vascular, and skeletal systems.

UNLABELLED: Due to early diagnosis and increasingly effective medical advances, the number of women with various genetic syndromes who are undergoing pregnancy is increasing, and this represents an important issue for providers of obstetric care. Each year more women with genetic disease reach childbearing age. Advances in assisted reproductive technology have enabled pregnancy in a cohort of woman who may experience impaired fertility due to their underlying diagnosis. Management of these women requires coordination of care by healthcare providers from multiple specialties to optimize outcomes. Potentially serious medical issues specific to each diagnosis often exist in the preconception, antepartum, intrapartum, and postpartum periods, all of which must be recognized to allow timely diagnosis and treatment. The fetus may also face issues related to risk for inheritance of the genetic disorder itself, as well as risks related to the chronic disease status of the mother. This article will explore the issues faced by women with various genetic disorders that may affect connective tissue, muscular, vascular, and skeletal systems. TARGET AUDIENCE: Obstetricians & Gynecologists and Family Physicians. LEARNING OBJECTIVES: After the completing the CME activity, physicians should be better able to classify the cardiovascular manifestations observed in Marfan syndrome and Ehlers-Danlos, evaluate prenatal diagnostic options and limitations for various genetic syndromes, assess the risks to the fetus in women with various genetic syndromes. Determine whether there is a preferred mode of delivery for pregnant patients with various genetic syndromes described in this paper.