Nonimmune hydrops fetalis (NIHF) is a rare disorder with a high perinatal mortality of at least 50%. One cause of NIHF is generalized lymphatic dysplasia (GLD), a rare form of primary lymphedema of the extremities and systemic involvement including chylothoraces and pericardial effusions. An autosomal recessive form of GLD has been described, caused by variants in the PIEZO1 gene. It has been reported clinically to cause NIHF and childhood onset of facial and limb lymphedema, most of which were diagnosed postnatally. We present a case of a woman with recurrent pregnancies affected by NIHF because of novel compound heterozygous variants in the PIEZO1 gene diagnosed prenatally using exome sequencing (ES). Two variants in PIEZO1 (c.3206G>A and c.6208A>C) were identified that were inherited from the father and mother, and are predicted to cause a nonsense and missense change, respectively, in the PIEZO1 subunits. Ultrasound demonstrated severe bilateral pleural effusions, whole body edema and polyhydramnios. Histopathology revealed an increased number of lymphatic channels, many of which showed failure of luminal canalization. Sanger sequencing confirmed the same variants in a prior fetal demise. We provide phenotypic correlation with ultrasound and autopsy finding, review PIEZO1 variants as a cause of GLD and discuss the uses of prenatal ES to date.

Background Since its commercial release in 2011 cell-free DNA screening has been rapidly adopted as a routine prenatal genetic test. However, little is known about its performance in actual clinical practice. Objective To investigate factors associated with the accuracy of abnormal autosomal cell- free DNA results. Study Design Retrospective cohort study of 121 patients with abnormal cell-free DNA results from a referral maternal-fetal medicine practice from March 2013 to July 2015. Patients were included if cell-free DNA results for trisomy 21, trisomy 18, trisomy 13, or microdeletions (if reported by the laboratory) were positive or non-reportable. The primary outcome was confirmed aneuploidy or microarray abnormality on either prenatal or postnatal karyotype or microarray. Secondary outcomes were identifiable associations with in vitro fertilization, twins, ultrasound findings, testing platform, and testing laboratory. Kruskal-Wallis or Fisher’s exact tests were used as appropriate. Results 121 patients had abnormal cell-free DNA results for for trisomy 21, trisomy 18, trisomy 13, and/or microdeletions. 105 patients had abnormal cell-free DNA results for for trisomy 21, trisomy 18, trisomy 13. Of these, 92 (87.6%) were positive and 13 (12.4%) were non-reportable. The results of the 92 positive cell-free DNA were for trisomy 21 (48, 52.2%), trisomy 18 (22, 23.9%), trisomy 13 (17, 18.5%), triploidy (2, 2.2%), and positive for >1 parameter (3, 3.3%). Overall, the positive predictive value of cell-free DNA was 73.5% (61/83, 95% confidence interval (CI) 63% to 82%) for all trisomies (by chromosome: trisomy 21, 83.0% (39/47, CI 69% to 92%, trisomy 18, 65.0% (13/20, CI 41% to 84%), and trisomy 13, 43.8% (7/16, CI 21% to 70%). Abnormal cell-free DNA results were associated with positive serum screening (by group: trisomy 21 17/48, 70.8%; trisomy 18 7/22, 77.8%; trisomy 13 3/17, 37.5%; non-reportable 2/13, 16.7%; p=0.004), and abnormal first trimester ultrasound (trisomy 21 25/45, 55.6%; trisomy 18 13/20, 65%; trisomy 13 6/14, 42.9%; non-reportable 1/13, 7.7%; p=0.003). There was no association between false positive rates and testing platform, but there was a difference between the four laboratories (p=0.018). Twenty-six patients had positive (n=9) or non-reportable (n=17) microdeletion results. Seven of nine screens positive for microdeletions underwent confirmatory testing; all were false positives. Conclusions The positive predictive value of 73.5% for cell-free DNA screening for autosomal aneuploidy is lower than reported. The positive predictive value for microdeletion testing was 0%. Diagnostic testing is needed to confirm abnormal cell-free DNA results for aneuploidy and microdeletions.

In our cohort, abnormal SC cfDNA results were associated with in vitro fertilization and twins. Our results indicate cfDNA for sex prediction in twins of limited utility. Positive predictive value and sensitivity for SC determination were lower than previously reported.

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Objective This study aims to evaluate the utility of social media to distribute a patient survey on differences in management and outcomes of monochorionic–diamniotic (MCDA) pregnancies. Study Design A cross-sectional survey was posted to an English-language MCDA twins patient-centered support group within the social media site, Facebook from April 2, 2018 to June 26, 2018. Subjects were recruited through a technique called “snowballing,” whereby individuals shared the survey to assist with recruiting. Patient reported data were analyzed using Chi-square and Kruskal–Wallis's tests to explore characteristics associated with surveillance and outcomes as related to region and provider type. Results Over 3 months, the post “reached” 14,288 Facebook users, among which 5,653 (40%) clicked on the post. A total of 2,357 respondents with MCDA pregnancies completed the survey. Total 1,928 (82%) were from the United States (US) and 419 (18%) from other countries. Total 85% of patients had co-management with maternal–fetal medicine (MFM), more in the US compared with the rest of the world (87 vs. 74%, p < 0.01). MFM involvement led to increased adherence to biweekly ultrasounds (91 vs. 65%, p < 0.01), diagnosis of monochorionicity by 12 weeks (74 vs. 69%, p < 0.01) and better education about twin–twin transfusion syndrome (90 vs. 66%, p < 0.01). Pregnancies with MFM involvement had a higher take-home baby rate for both babies (92 vs. 89%, p < 0.01) or for at least one baby (98 vs. 93%, p < 0.01) compared with those without MFM involvement. Conclusion A survey distributed via social media can be effective in evaluating real-life management and outcomes of an uncommon obstetrical diagnosis. This survey elucidates wide international variation in adherence to guidelines, management, and outcomes.