The utility of gene sequencing in identifying an underlying genetic disorder in prenatally suspected lower urinary tract obstruction.

OBJECTIVE: Fetal megacystis generally presents as suspected lower urinary tract obstruction (LUTO), which is associated with severe perinatal morbidity. Genetic etiologies underlying LUTO or a LUTO-like initial presentation are poorly understood. Our objectives are to describe single gene etiologies in fetuses initially ascertained to have suspected LUTO and to elucidate genotype-phenotype correlations. METHODS: A retrospective case series of suspected fetal LUTO positive for a molecular diagnosis was collected from five centers in the Fetal Sequencing Consortium. Demographics, sonograms, genetic testing including variant classification, and delivery outcomes were abstracted. RESULTS: Seven cases of initially prenatally suspected LUTO-positive for a molecular diagnosis were identified. In no case was the final diagnosis established as urethral obstruction that is, LUTO. All variants were classified as likely pathogenic or pathogenic. Smooth muscle deficiencies involving the bladder wall and interfering with bladder emptying were identified in five cases: MYOCD (2), ACTG2 (2), and MYH11 (1). Other genitourinary and/or non-genitourinary malformations were seen in two cases involving KMT2D (1) and BBS10 (1). CONCLUSION: Our series illustrates the value of molecular diagnostics in the workup of fetuses who present with prenatally suspected LUTO but who may have a non-LUTO explanation for their prenatal ultrasound findings.

Route of delivery does not impact postnatal surgical morbidity in pregnancies affected by fetal achondroplasia.

PURPOSE: Pregnancies affected by maternal or fetal achondroplasia present unique challenges. The optimal route of delivery in fetuses with achondroplasia has not been established. Our objective was to determine whether the route of delivery affects postnatal achondroplasia-related surgical burden. METHODS: We conducted a secondary analysis of Achondroplasia Natural History Study (CLARITY), which is a multicenter natural history cohort study of patients with achondroplasia. Achondroplasia-related surgical morbidity, which we defined as the need for one or more postnatal achondroplasia-related surgeries, was assessed in relation to the route of delivery and whether the mother also had achondroplasia. Rate of each individual surgery type (otolaryngology, brain, foramen magnum, spine, and extremity) was also assessed in relation to the route of delivery. RESULTS: Eight hundred fifty-seven patients with achondroplasia with known route of delivery and known maternal stature were included. Three hundred sixty (42%) patients were delivered vaginally, and 497 (58%) patients were delivered by a cesarean delivery. There was no difference in the odds of requiring any postnatal achondroplasia-related surgery in those with achondroplasia who were delivered vaginally compared with those delivered by cesarean birth (odds ratio 0.95, 95% CI = 0.68-1.34, P = .80). No difference was present in the odds of requiring any postnatal achondroplasia-related surgery when route of delivery was compared for fetuses born to 761 average stature mothers (odds ratio 1.05, 95% CI = 0.74-1.51, P = .78). There was also no difference in the odds of requiring each of the individual achondroplasia-related surgeries by route of delivery, including cervicomedullary decompression. CONCLUSION: Our study suggests that it is reasonable for average stature patients carrying a fetus with achondroplasia to undergo a trial of labor in the absence of routine obstetric contraindications.

Vascular aneurysms in Ehlers-Danlos syndrome subtypes: A systematic review.

Aneurysmal lesions are commonly seen in Ehlers-Danlos Syndrome (EDS). To better identify the regional and vessel-specific spectrum of aneurysms in different subtypes of EDS, we performed a systematic review. We searched Medline for relevant studies from 1963 to April 2022. Studies providing a report of any EDS subtype by genetic diagnosis, histologic analysis, or clinical criteria were included. A total of 448 patients from 220 studies were included. 720 vessel-specific aneurysms were reported: 386 in the abdominopelvic area, 165 in the intracranial region, 98 in the thorax, 2 in the extremities, and 6 in the venous system. In 27 out of the 65 patients with ruptured aneurysms, the ruptured aneurysm was the initial presentation. Multiple aneurysms were present in 163 out of 249 patients who had been systematically evaluated for other locations of aneurysms. The head and neck and abdominopelvic regions are two potential foci for aneurysm formation in patients with EDS. The aneurysm development in EDS is not confined to arteries; the venous system and cardiac septa may also be affected. Many patients develop multiple aneurysms, either at the time of the initial presentation or throughout their lifetime and aneurysm formation or rupture may be the first presentation of EDS.

Prenatal phenotyping of fetal tubulinopathies: A multicenter retrospective case series.

OBJECTIVE: Tubulinopathies refer to conditions caused by genetic variants in isotypes of tubulin resulting in defective neuronal migration. Historically, diagnosis was primarily via postnatal imaging. Our objective was to establish the prenatal phenotype/genotype correlations of tubulinopathies identified by fetal imaging. METHODS: A large, multicenter retrospective case series was performed across nine institutions in the Fetal Sequencing Consortium. Demographics, fetal imaging reports, genetic screening and diagnostic testing results, delivery reports, and neonatal imaging reports were extracted for pregnancies with a confirmed molecular diagnosis of a tubulinopathy. RESULTS: Nineteen pregnancies with a fetal tubulinopathy were identified. The most common prenatal imaging findings were cerebral ventriculomegaly (15/19), cerebellar hypoplasia (13/19), absence of the cavum septum pellucidum (6/19), abnormalities of the corpus callosum (6/19), and microcephaly (3/19). Fetal MRI identified additional central nervous system features that were not appreciated on neurosonogram in eight cases. Single gene variants were reported in TUBA1A (13), TUBB (1), TUBB2A (1), TUBB2B (2), and TUBB3 (2). CONCLUSION: The presence of ventriculomegaly with cerebellar abnormalities in conjunction with additional prenatal neurosonographic findings warrants additional evaluation for a tubulinopathy. Conclusive diagnosis can be achieved by molecular sequencing, which may assist in coordination, prognostication, and reproductive planning.

Utility of the cerebroplacental ratio (CPR) in marijuana exposed growth restricted fetuses.

OBJECTIVE: Fetal growth restriction (FGR) is associated with an increased risk of adverse perinatal outcomes. The cerebroplacental ratio (CPR) represents the interaction of alterations in blood flow to the fetal brain and placenta. CPR has been utilized as a superior reflection of fetal hypoxia/acidemia and therefore a better predictor of fetal morbidity. We sought to determine the role of the CPR as an adjunctive tool to identify fetuses at increased risk of adverse perinatal outcomes in a study population of marijuana (MJ) exposed FGR fetuses. METHODS: This was a retrospective cohort study of high-risk singleton pregnancies over a 4-year period. Self-identified daily MJ users with FGR fetuses in the 3rd trimester were isolated. Fetal biometry, amniotic fluid indices, and CPRs were calculated. A CPR <1 was considered abnormal. FGR fetuses with normal and abnormal CPRs were then compared. RESULTS: 26/192 (13.5%) of MJ exposed fetuses were diagnosed with FGR in the 3rd trimester. 12/26 (46%) had an abnormal CPR and 14 had a normal CPR (mean CPR 0.60 vs 1.57, p = .0001). The mean EFW percentile was lower in the abnormal CPR group in comparison to the group with normal CPR (3.33 vs 7.64, p = .0001). Both groups showed evidence of brain sparing with an overall mean head circumference of 17.55 in comparison to a mean abdominal circumference of 5.63. A CPR <1 was associated with more severe FGR, oligohydramnios, and abnormal UA Doppler studies. CONCLUSIONS: Approximately half of the MJ exposed FGR fetuses had an abnormal CPR. In this subset of patients, >90% had severe FGR, a higher proportion had absence/reversal of end diastolic flow in the UA, and a higher proportion had oligohydramnios. This demonstrates that an abnormal CPR identifies a group of FGR fetuses at a greater risk of adverse perinatal outcomes.

Effect of intrauterine marijuana exposure on fetal growth patterns and placental vascular resistance.

OBJECTIVE: The recent legalization of marijuana has increased overall use, including in pregnancy. Studies have previously associated marijuana use with adverse fetal neurodevelopmental outcomes. We sought to compare fetal sonographic growth parameters and placental perfusion, as measured by umbilical artery Dopplers, in women using daily marijuana versus nonusers. METHODS: A retrospective cohort study capturing self - identified pregnant daily marijuana users with gestational aged matched controls was performed. We compared maternal demographics, fetal biometry, nuchal translucency, and umbilical artery Dopplers in marijuana users versus controls. Intrauterine growth restriction was defined as an estimated fetal weight <10th %. RESULTS: In 55 first trimester ultrasounds, there were no differences in crown rump lengths or nuchal translucencies between the groups. Likewise, in 195-second trimester ultrasounds, no differences were noted in biometry. Second trimester umbilical artery systolic to diastolic ratios were higher in marijuana users compared to nonusers (4.02 versus 3.92, p = .024). In the third trimester, 26 of 192 marijuana exposed fetuses were growth restricted compared to 6 of 192 controls (p = .002), and umbilical artery systolic to diastolic ratios were higher (3.52 versus 3.12, p = .0001). Four cases of absent and reversed end diastolic flow were observed in marijuana users, while no cases were observed in controls. CONCLUSIONS: Our data shows that daily marijuana use is associated with impaired fetal growth and increased placental vascular resistance. Marijuana consumption in pregnancy should be avoided until further studies delineate its exact potential for fetotoxicity.