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Alpha thalassemia major (ATM) is a hemoglobinopathy that usually results in perinatal demise if in utero transfusions (IUTs) are not performed. We established an international registry (NCT04872179) to evaluate the impact of IUTs on survival to discharge (primary outcome) as well as perinatal and neurodevelopmental secondary outcomes. Forty-nine patients were diagnosed prenatally, 11 were diagnosed postnatally, and all 11 spontaneous survivor genotypes had preserved embryonic zeta-globin levels. We compared 3 groups of patients; group 1, prenatally diagnosed and alive at hospital discharge (n = 14), group 2, prenatally diagnosed and deceased perinatally (n = 5), and group 3, postnatally diagnosed and alive at hospital discharge (n = 11). Group 1 had better outcomes than groups 2 and 3 in terms of the resolution of hydrops, delivery closer to term, shorter hospitalizations, and more frequent average or greater neurodevelopmental outcomes. Earlier IUT initiation was correlated with higher neurodevelopmental (Vineland-3) scores (r = -0.72, P = .02). Preterm delivery after IUT was seen in 3/16 (19%) patients who continued their pregnancy. When we combined our data with those from 2 published series, patients who received ≥2 IUTs had better outcomes than those with 0 to 1 IUT, including resolution of hydrops, delivery at ≥34 weeks gestation, and 5-minute appearance, pulse, grimace, activity, and respiration scores ≥7. Neurodevelopmental assessments were normal in 17/18 of the ≥2 IUT vs 5/13 of the 0 to 1 IUT group (OR 2.74; P = .01). Thus, fetal transfusions enable the survival of patients with ATM and normal neurodevelopment, even in those patients presenting with hydrops. Nondirective prenatal counseling for expectant parents should include the option of IUTs.

We are living in a golden age of medicine in which the availability of prenatal diagnosis, fetal therapy, and gene therapy/editing make it theoretically possible to repair almost any defect in the genetic code. Furthermore, the ability to diagnose genetic disorders before birth and the presence of established surgical techniques enable these therapies to be delivered safely to the fetus. Prenatal therapies are generally used in the second or early third trimester for severe, life-threatening disorders for which there is a clear rationale for intervening before birth. While there has been promising work for prenatal gene therapy in preclinical models, the path to a clinical prenatal gene therapy approach is complex. We recently held a conference with the University of California, San Francisco-Stanford Center of Excellence in Regulatory Science and Innovation, researchers, patient advocates, regulatory (members of the Food and Drug Administration), and other stakeholders to review the scientific background and rationale for prenatal somatic cell gene therapy for severe monogenic diseases and initiate a dialogue toward a safe regulatory path for phase 1 clinical trials. This review represents a summary of the considerations and discussions from these conversations.

Objective: Pregnancy requires a complex physiological adaptation of the maternal cardiovascular system, which is disrupted in women with pregnancies complicated by preeclampsia, putting them at higher risk of future cardiovascular events. The measurement of body movements in response to cardiac ejection via ballistocardiogram (BCG) can be used to assess cardiovascular hemodynamics noninvasively in women with preeclampsia. Methods: Using a previously validated, modified weighing scale for assessment of cardiovascular hemodynamics through measurement of BCG and electrocardiogram (ECG) signals, we collected serial measurements throughout pregnancy and postpartum and analyzed data in 30 women with preeclampsia and 23 normotensive controls. Using BCG and ECG signals, we extracted measures of cardiac output, J-wave amplitude × heart rate (J-amp × HR). Mixed-effect models with repeated measures were used to compare J-amp × HRs between groups at different time points in pregnancy and postpartum. Results: In normotensive controls, the J-amp × HR was significantly lower early postpartum (E-PP) compared with the second trimester (T2; p = 0.016) and third trimester (T3; p = 0.001). Women with preeclampsia had a significantly lower J-amp × HR compared with normotensive controls during the first trimester (T1; p = 0.026). In the preeclampsia group, there was a trend toward an increase in J-amp × HR from T1 to T2 and then a drop in J-amp × HR at T3 and further drop at E-PP. Conclusions: We observe cardiac hemodynamic changes consistent with those reported using well-validated tools. In pregnancies complicated by preeclampsia, the maximal force of contraction is lower, suggesting lower cardiac output and a trend in hemodynamics consistent with the hyperdynamic disease model of preeclampsia.

ObjectiveTo examine the relationship between cardiomediastinal shift angle (CMSA) and adverse perinatal outcomes and hydrops in cases of congenital pulmonary airway malformation (CPAM).Study designThis retrospective study evaluated CPAM cases referred to our institution from 2008 to 2015. The primary outcome was a composite score for adverse perinatal outcome. CMSA was measured for each case and evaluated for its association with the primary outcome. The prediction accuracy of CMSA for adverse perinatal outcome was assessed using receiver operator characteristic (ROC) curves.ResultsEighteen (21.2%) of the 85 cases experienced an adverse perinatal outcome. Increases in CMSA were associated with adverse perinatal outcomes and hydrops in bivariate analyses. Adjusted analyses found each 10-degree increase in CMSA to be associated with increased odds of an adverse perinatal outcome (adjusted odds ratio [aOR] 2.2, 95% confidence interval [CI]: 1.4-3.3) and hydrops (aOR 3.0, 95% CI: 1.5-6.1). CMSA performed well and was comparable to CPAM volume ratio in predicting adverse perinatal outcomes (area under the curve 0.81 and 0.84, respectively).ConclusionWe describe a novel measurement of mediastinal shift in cases of CPAM and its relationship with adverse perinatal outcomes and hydrops. These findings may shape the evaluation and management of CPAMs, improve our understanding of their prognosis, and influence patient counseling.

Background: Intrauterine transfusion (IUT) is an invasive but critical and potentially life‐saving intervention for severe fetal anemia with demonstrated improvement in outcomes. The fetus is vulnerable to hemodynamic alterations and transfusion‐related adverse events; therefore, special consideration must be given to blood component selection and modification. There is widespread IUT practice variability, and existing guidance primarily relies on expert opinion and single center experiences. Study Design and Methods: Experts in Maternal Fetal Medicine, Pediatric Hematology, and Transfusion Medicine from centers across the United States, collectively performing about 120 IUT annually, offer a multidisciplinary perspective on the performance of IUT and preparation of blood components. This perspective includes strategies for identifying an at‐risk fetus, communicating between disciplines, determining the necessary blood volume, selecting and processing blood components, documenting the procedure in medical record, and managing the neonate. Results: Identifying an at‐risk fetus relies on review of the clinical history, non‐invasive monitoring, and laboratory evaluation. We recommend the use of relatively fresh, group O, cytomegalovirus‐safe, freshly irradiated, red blood cells (RBC) that are Hemoglobin S negative and antigen‐negative for any maternal antibody, if indicated. These RBC units should be concentrated to remove additives and increase the hematocrit thus minimizing fluctuations in fetal volume status. The units intended for IUT should be labeled clearly and the documentation of transfusion differentiated in the maternal medical record. Discussion: An awareness of the technical, logistical, and regulatory considerations for IUT performance will facilitate improved communication and patient care, especially when rare units of RBC are required. [ABSTRACT FROM AUTHOR]

Objective: This article evaluates gender differences in academic rank and National Institutes of Health (NIH) funding among academic maternal-fetal medicine (MFM) physicians., Study Design: This was a cross-sectional study of board-certified academic MFM physicians. Physicians were identified in July 2017 from the MFM fellowship Web sites. Academic rank and receipt of any NIH funding were compared by gender. Data on potential confounders were collected, including years since board certification, region of practice, additional degrees, number of publications, and h-index., Results: We identified 659 MFM physicians at 72 institutions, 312 (47.3%) male and 347 (52.7%) female. There were 246 (37.3%) full, 163 (24.7%) associate, and 250 (37.9%) assistant professors. Among the 154 (23.4%) MFM physicians with NIH funding, 89 (57.8%) were male and 65 (42.2%) were female ( p  = 0.003). Adjusting for potential confounders, male MFM physicians were twice as likely to hold a higher academic rank than female MFM physicians (adjusted odds ratio [aOR], 2.04 [95% confidence interval, 1.39-2.94], p  < 0.001). There was no difference in NIH funding between male and female MFM physicians (aOR, 1.23 [0.79-1.92], p  = 0.36)., Conclusion: Compared with female academic MFM physicians, male academic MFM physicians were twice as likely to hold a higher academic rank but were no more likely to receive NIH funding., Competing Interests: None., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)