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.

Structured Framework for Multidisciplinary Parent Counseling and Medical Interventions for Fetuses and Infants with Trisomy 13 or Trisomy 18.

OBJECTIVE: Trisomy 13 (T13) and 18 (T18) are aneuploidies associated with multiple structural congenital anomalies and high rates of fetal demise and neonatal mortality. Historically, patients with either one of these diagnoses have been treated similarly with exclusive comfort care rather than invasive interventions or intensive care, despite a wide phenotypic variation and substantial variations in survival length. However, surgical interventions have been on the rise in this population in recent years without clearly elucidated selection criterion. Our objective was to create a standardized approach to counseling expectant persons and parents of newborns with T13/T18 in order to provide collaborative and consistent counseling and thoughtful approach to interventions such as surgery. STUDY DESIGN: This article describes our process and presents our resulting clinical care guideline. RESULTS: We formed a multi- and interdisciplinary committee. We used published literature when available and otherwise expert opinion to develop an approach to care featuring individualized assessment of the patient to estimate qualitative mortality risk and potential to benefit from intensive care and/or surgeries centered within an ethical framework. CONCLUSION: Through multidisciplinary collaboration, we successfully created a patient-centered approach for counseling families facing a diagnosis of T13/T18. Other institutions may use our approach as a model for developing their own standardized approach. KEY POINTS: · Trisomy 13 and trisomy 18 are associated with high but variable morbidity and mortality.. · Research on which patients are most likely to benefit from surgery is lacking.. · We present our institution's framework to counsel families with fetal/neonatal T13/T18..

Prenatal Congenital Heart Disease-It Takes a Multidisciplinary Village.

Prenatal diagnosis of congenital heart disease (CHD) allows for thoughtful multidisciplinary planning about location, timing, and need for medical interventions at birth. We sought to assess the accuracy of our prenatal cardiac diagnosis, and postnatal needs for patients with CHD utilizing a multidisciplinary approach. We performed a retrospective chart review of fetal CHD patients between 1/1/18 and 4/30/19. Maternal and infant charts were reviewed for delivery planning, subspecialty care needs, genetic evaluation, prenatal and postnatal cardiac diagnoses, need for prostaglandin (PGE) and neonatal cardiac intervention. 82 maternal-fetal dyads met inclusion criteria during the study period and delivered at a median of 38w2d gestation. 32 (39%) dyads had CHD and other anomalies or genetic abnormalities. All dyads met with a genetic counselor and neonatologist. 11 patients delivered at outside hospitals as planned (all with isolated CHD not requiring neonatal intervention), and 5 chose a palliative delivery. 30 patients were counseled to expect a neonatal cardiac intervention and 25 (83%) underwent an intervention within the expected time period. No neonates required an uncounseled cardiac intervention. 29 patients planned for PGE at birth and 31 received PGE. Of the 79 postnatal echocardiograms, 60 (76%) were entirely consistent with the fetal diagnosis. A multidisciplinary approach to the prenatal diagnosis of CHD in maternal-fetal dyads is optimal and utilizing this method we were able to accurately predict postnatal physiology and ensure that patients delivered in the correct location with an appropriate supportive structure in place.

Depression and socioeconomic stressors in expectant parents with fetal congenital anomalies.

OBJECTIVE: Congenital anomalies are increasingly diagnosed before birth, which may lead to psychological distress in expectant parents. While the presence of significant symptoms of depression and stress in these parents is established, understanding their context within parents' other life stressors has not been fully investigated. We sought to characterize the socioeconomic profile and depression symptoms of expectant parents in a quaternary care academic hospital's fetal care clinic. METHODS: This prospective observational study enrolled pregnant persons and their partners in our fetal care clinic. The Edinburgh Postpartum Depression Scale (EPDS), Tool Assessing Patient Stress (TAPS), and a sociodemographic survey were utilized to assess parent psychological distress and socioeconomic stressors. Results were analyzed by the severity of the fetal anomaly. EPDS was repeated at two weeks postpartum. RESULTS: 21.7% of pregnant subjects and 25.0% of co-parents had a positive screen on the EPDS at enrollment during their pregnancy. Mothers' EPDS scores correlated with the severity of the fetal anomaly. Many parents reported socioeconomic stressors including: living remotely from the medical center, low household income, food insecurity, unemployment, or other employment concerns, and difficulty affording living expenses. Most also reported factors that can mitigate psychological distress including social support and participation in a religion or faith. CONCLUSIONS: Expectant parents with fetal anomalies should be screened for depression as well as social and economic risk factors that place them and their infants at higher risk for poor health outcomes. Further work is needed to determine the optimum interventions for addressing their depression symptoms and reducing socioeconomic stressors.

Fetal hydrops and the risk of severe preeclampsia.

OBJECTIVE: To assess the incidence and severity of preeclampsia in pregnancies complicated by fetal hydrops. METHODS: We performed a retrospective cohort study of singleton gestations from 2005 to 2008 in California. The primary predictor was fetal hydrops and the primary outcome was preeclampsia. Selected adverse maternal and neonatal events were assessed as secondary outcomes. Potential confounders examined included fetal anomalies, polyhydramnios, race/ethnicity, nulliparity, chronic hypertension, and gestational or pregestational diabetes mellitus. RESULTS: We identified 337 pregnancies complicated by fetal hydrops, 70.0% had a concomitant fetal anomaly and 39.8% had polyhydramnios. Compared to the general population, hydrops was associated with an increased risk for severe preeclampsia (5.26 versus 0.91%, p < .001) but not mild preeclampsia (2.86 versus 2.02%, p = .29). In multivariable analysis, fetal hydrops remained an independent risk factor for severe preeclampsia (as adjusted odds ratios (aOR) 3.13, 1.91-5.14). Hydrops was also associated with increased rates of eclampsia, acute renal failure, pulmonary edema, postpartum hemorrhage, blood transfusion, preterm birth, and neonatal death. CONCLUSIONS: We find that fetal hydrops is an independent risk factor for severe preeclampsia. In light of serious concerns for maternal and neonatal health, heightened surveillance for signs and symptoms of severe preeclampsia is warranted in all pregnancies complicated by fetal hydrops.

An application of data mining to identify potential risk factors for anophthalmia and microphthalmia.

BACKGROUND: We examined a large number of variables to generate new hypotheses regarding a wider range of risk factors for anophthalmia/microphthalmia using data mining. METHODS: Data were from the National Birth Defects Prevention Study, a multicentre, case-control study from 10 centres in the United States. There were 134 cases of "isolated" and 87 "nonisolated" (with other major birth defects) of anophthalmia/microphthalmia and 11 052 nonmalformed controls with delivery dates October 1997-December 2011. Using random forest, a data mining procedure, we compared the two case types with controls for 201 variables. Variables considered important ranked by random forest were included in a multivariable logistic regression model to estimate odds ratios and 95% confidence intervals. RESULTS: Predictors for isolated cases included paternal race/ethnicity, maternal intake of certain nutrients and foods, and childhood health problems in relatives. Using regression, inverse associations were observed with greater maternal education and with increasing intake of folate and potatoes. Odds were slightly higher with greater paternal education, for increased intake of carbohydrates and beans, and if relatives had a childhood health problem. For nonisolated cases, predictors included paternal race/ethnicity, maternal intake of certain nutrients, and smoking in the home the month before conception. Odds were higher for Hispanic fathers and smoking in the home and NSAID use the month before conception. CONCLUSIONS: Results appear to support previously hypothesised risk factors, socio-economic status, NSAID use, and inadequate folate intake, and potentially provide new areas such as passive smoking pre-pregnancy, and paternal education and ethnicity, to explore for further understanding of anophthalmia/microphthalmia.

What are the goals of prenatal genetic testing?

The landscape of genetic testing and screening has changed tremendously since the initial description of the molecular structure of DNA. Given this, it is critical that providers reflect on the goals of prenatal screening and diagnostic testing, and how these tests impact perinatal outcomes. The participants of this workshop were in agreement that the goal of prenatal genetic testing should be focused on improving outcomes for women and families. While prenatal testing has historically focused on the option for pregnancy termination, increasing numbers of prenatal and perinatal treatments are available. As more in utero therapies are developed, the detection of disorders that are amenable to, and would benefit from, prenatal or immediate neonatal targeted therapy will increasingly be a focus of prenatal testing. Prenatal genetic testing must also balance the ethical principles of autonomy and distributive justice. The workshop participants agreed that stakeholders such as medical professionals, professional societies, insurers, commercial laboratories, and the public should consider and come to agreement regarding the appropriate objectives for and use of these tests.

Neonatal echocardiogram in duodenal obstruction is unnecessary after normal fetal cardiac imaging.

BACKGROUND: Duodenal obstruction (DO) is associated with congenital cardiac anomalies that may complicate the delivery of anesthesia during surgical repair. As most infants undergo fetal ultrasounds that identify cardiac anomalies, our aim was to determine the utility of obtaining preoperative neonatal echocardiograms in all DO patients. METHODS: We conducted a retrospective cohort study of all DO patients treated at two tertiary care children's hospitals between January 2005 and February 2016. Prenatal ultrasounds were compared to neonatal echocardiograms to determine concordance. Binomial exact analyses were used to estimate the negative predictive value (NPV) of prenatal imaging. RESULTS: We identified 65 infants with DO. The majority of patients (93.8%) had prenatal ultrasounds, including twenty patients that underwent fetal echocardiogram. Fourteen (21.5%) were diagnosed with cardiac lesions in utero, and neonatal echocardiograms confirmed 12 lesions, without identifying any new lesions. No changes to anesthetic management were made because of cardiac lesions. The NPV of prenatal imaging was 100% (95% Confidence Interval: 91.0-100.0). CONCLUSIONS: Neonatal echocardiogram is unlikely to identify new cardiac lesions in DO patients with negative fetal imaging and delays in surgical care are unwarranted. LEVELS OF EVIDENCE: Study of Diagnostic Test-Level II.

Metformin in the first trimester and risks for specific birth defects in the National Birth Defects Prevention Study.

BACKGROUND: We assessed associations between first-trimester metformin use for pregestational diabetes and specific major birth defects. METHODS: We compared risks associated with first-trimester metformin use by diabetic women to nondiabetic women on no diabetes medication; we calculated crude odds ratios by exact logistic regression and adjusted by inverse probability weighting. Confounding by diabetes was assessed by comparing risks for metformin-exposed diabetic women to those for insulin-exposed diabetics and nondiabetics treated with metformin for subfertililty. RESULTS: Among 9,279 nonmalformed controls and 24,375 malformed cases, diabetics who used metformin (with or without insulin) had increased adjusted odds ratios (aORs) for several birth defects associated with diabetes. However, women treated with metformin for subfertility had aORs similar to or lower than those for diabetic metformin users, and many approximated the null. For atrial septal defect secundum, anorectal defects, and limb reduction defects, the estimates for metformin when used for subfertility were 2-3-fold. CONCLUSION: While metformin use for diabetes was associated with an increased risk of many birth defects, when metformin was used for subfertility most defects had aORs that approximated the null, while only three defects had modestly increased aORs, two of which had lower confidence bounds that included the null. Our study does not suggest that metformin poses an appreciable risk for major birth defects, but further studies are necessary.

Eliminating first trimester markers: will replacing PAPP-A and ßhCG miss women at risk for small for gestational age?

OBJECTIVE: Placental analytes are traditionally used for aneuploidy screening, although may be replaced by cell-free fetal DNA. Abnormal analytes also identify women at risk for small for gestational age (SGA). We sought to quantify the proportion of women at risk for SGA by low pregnancy-associated plasma protein-A (PAPP-A) or ßhCG who would not otherwise be identified by maternal risk factors. METHODS: We studied first-trimester PAPPA-A and ßhCG from 658 euploid singleton pregnancies from a prospective longitudinal cohort. Analytes were standardized for gestational age in multiples of the median (MoM). SGA was defined as birthweight z-score ≤-1.28. Maternal risk factors included chronic hypertension, pre-gestational diabetes and age ≥40. RESULTS: Mean GA was 38.8 ± 1.9 weeks; 6.8% had a SGA infant. Low PAPP-A and ßhCG were identified in 48 (7.4%) and 9 (1.4%) of pregnancies, respectively, of whom 18.9% were SGA (OR 3.0, 95% CI 1.4-6.3). 88% did not have risk factors for SGA. Among women with no risk factors, low PAPP-A was a significant predictor of SGA (OR 3.3, 95% CI 1.5-7.4). CONCLUSION: Most women with abnormal analytes did not have risk factors for SGA. Eliminating PAPP-A and ßhCG may present missed opportunities to identify women at risk for SGA.

Absent fetal nasal bone: what does it mean for the euploid fetus?

OBJECTIVES: Our purpose was to review the outcomes of singleton pregnancies in which an absent nasal bone was noted on first- or second-trimester sonography and aneuploidy was not present. METHODS: We identified singleton pregnancies from 2005 to 2011 in which an absent nasal bone was noted on sonography, aneuploidy was excluded, and newborn examinations were available for review. Sonographic reports were reviewed for anomalies, growth, and amniotic fluid volume. Newborn records were reviewed for physical examinations, complications, and radiologic or genetic tests. RESULTS: We identified 142 fetuses with a sonographic appearance of an absent nasal bone. We excluded 52 cases with aneuploidy and 33 in which newborn examination information was unavailable. Fifty-seven cases met inclusion criteria. For 3 euploid fetuses with an absent nasal bone on sonography, the presence of additional anomalies on second-trimester sonography ultimately signaled an adverse outcome: the presence of multiple congenital anomalies, a microdeletion syndrome, and a specific genetic diagnosis. CONCLUSIONS: All cases with adverse outcomes had additional prenatal sonographic findings. For the remainder, normal newborn examination findings provide some reassurance, especially in the setting of otherwise normal second-trimester sonographic findings. A microarray as a test for microdeletion and duplication syndromes in this situation could be considered.

Recurrent second trimester pregnancy loss: evaluation and management.

PURPOSE OF REVIEW: Recurrent pregnancy loss usually refers to first trimester losses. The present article describes the importance of a thorough evaluation for any patient presenting with a second trimester loss, and reviews current data regarding evidence-based evaluation and management for those families who have had recurrent episodes of second trimester losses. A management protocol is presented to guide management of a current pregnancy with a history of recurrent second trimester losses. RECENT FINDINGS: Previous literature has focused on isolated causes of second trimester loss and management. The present review incorporates all presentations of loss into a stepwise evaluative and management paradigm. SUMMARY: This comprehensive literature review and management protocol will provide the clinician with a thorough, systematic, and practical approach to the patient with recurrent pregnancy loss in order to maximize her chance of optimal pregnancy outcome.