Maternal red blood cell alloimmunization prevalence in the United States.

Hemolytic disease of fetus and newborn (HDFN) is a life-threatening disease mediated by maternal alloimmunization to red blood cell (RBC) antigens. Studies of maternal alloimmunization prevalence in the United States (U.S.) lack national data. This study describes prevalence and trends in alloimmunization in pregnancy in the U.S. RBC antibodies (abs) were identified in a large, nationwide, commercial laboratory database from 2010-2021. The cohort comprised pregnancies for which the year of lab collection and patient's state of residence were available. Data were normalized based on U.S. Centers for Disease Control and Prevention estimates of live births and weighted by year and U.S. Census Division. Cochrane-Armitage tests assessed temporal trends of alloimmunization. Of 9,876,196 pregnancies, 1.5% (147,262) screened positive for RBC abs, corresponding to an estimated prevalence of 1,518/100,000 pregnancies. Of identified RBC abs, anti-D comprised 64.1% (586/100,000 pregnancies). Prevalence of other high-risk RBC abs for HDFN included anti-K (68/100,000) and anti-c (29/100,000). Incidence of all three high-risk abs increased from 2010-21 (all p<0.001). Among almost 10 million pregnancies in the US, comprising an estimated 14.4% of all pregnancies, 1.5% screened positive for RBC abs. Almost three-quarters (74.3%; 683/100,000) of RBC abs identified were high-risk for HDFN. Though prevalence of anti-D is difficult to interpret without the ability to distinguish alloimmunization from passive immunity, it remains problematic in HDFN, ranking second only to anti-K in critical titers. Given the sequelae of HDFN, new initiatives are required to reduce the incidence of alloimmunization in patients of reproductive potential.

Receipt of RhD-positive whole blood for life-threatening bleeding in female children: A survey in alloimmunized mothers regarding minimum acceptable survival benefit relative to risk of maternal alloimmunization to anti-D.

BACKGROUND: Low-titer group O whole blood (LTOWB) for treatment of hemorrhagic shock sometimes necessitates transfusion of RhD-positive units due to short supply of RhD-negative LTOWB. Practitioners must choose between using RhD-positive LTOWB when RhD-negative is unavailable against the risk to a female of childbearing potential of becoming RhD-alloimmunized, risking hemolytic disease of the fetus and newborn (HDFN) in future children, or using component therapy with RhD-negative red cells. This survey asked females with a history of red blood cell (RBC) alloimmunization about their risk tolerance of RhD alloimmunization compared to the potential for improved survival following transfusion of RhD-positive blood for an injured RhD negative female child. STUDY DESIGN AND METHODS: A survey was administered to RBC alloimmunized mothers. Respondents were eligible if they were living in the United States with at least one red cell antibody known to cause HDFN and if they had at least one RBC alloimmunized pregnancy. RESULTS: Responses from 107 RBC alloimmmunized females were analyzed. There were 32/107 (30%) with a history of severe HDFN; 12/107 (11%) had a history of fetal or neonatal loss due to HDFN. The median (interquartile range) absolute improvement in survival at which the respondents would accept RhD-positive transfusions for a female child was 4% (1%-14%). This was not different between females with and without a history of severe or fatal HDFN (p = .08 and 0.38, respectively). CONCLUSION: Alloimmunized mothers would accept the risk of D-alloimmunization in a RhD-negative female child for improved survival in cases of life-threatening bleeding.

Erythrokinetic mechanism(s) causing the "late anemia" of hemolytic disease of the fetus and newborn.

A transfusion-requiring "late anemia" can complicate the management of neonates convalescing from hemolytic disease of the fetus and newborn (HDFN). This anemia can occur in any neonate after HDFN but is particularly prominent in those who received intrauterine transfusions and/or double-volume exchange transfusions. Various reports describe this condition as occurring based on ongoing hemolysis, either due to passive transfer of alloantibody through breast milk or persistence of antibody not removed by exchange transfusion. However, other reports describe this condition as the result of inadequate erythrocyte production. Both hypotheses might have merit, because perhaps; (1) some cases are primarily due to continued hemolysis, (2) others are primarily hypoproductive, and (3) yet others result from a mixture of these two mechanisms. We propose prospective collaborative studies that will resolve this issue by serially quantifying end-tidal carbon monoxide. Doing this will better inform the assessment and treatment of neonates recovering from HDFN.

The Special Delivery Unit: A Novel Concept for Mother-Baby Continuity for Major Fetal Abnormalities.

OBJECTIVE: This article describes the experience in the planning and development of a special delivery unit (SDU) at our free-standing children's hospital in Austin, Texas. STUDY DESIGN: Description of various aspects of the development of the SDU. In addition, telephone surveys were obtained from five other institutions regarding the planning and current status of their SDUs. RESULTS: Since the advent of the SDU at Children's Hospital of Philadelphia in 2008, several free-standing children's hospitals have opened similar units at their institutions. Developing an obstetrical unit in a children's hospital can be a daunting task on many fronts. The costs of providing 24-hour obstetrical, nursing, and anesthesiology coverage must be considered. Although most SDUs are associated with a fetal center and fetal surgery/interventions, some units function exclusively for the delivery of pregnancies complicated by major fetal conditions where the neonate will require immediate surgical care or other interventions. CONCLUSION: Research on the cost-effectiveness and the effect of SDUs on clinical outcome, teaching, and patient satisfaction is warranted. KEY POINTS: · Specialized delivery units are becoming more common at free-standing children's hospitals.. · The primary aim of the SDU is to maintain mother-baby continuity in cases of congenital anomalies.. · Developing an obstetrical unit at a pediatric hospital is a daunting task..

Live birth prevalence of hemolytic disease of the fetus and newborn in the United States from 1996 to 2010.

BACKGROUND: Hemolytic disease of the fetus and newborn (HDFN) is mediated by maternal alloantibodies, a consequence of immune sensitization during pregnancy with maternal-fetal incompatibility with ABO, Rhesus factor (Rh), and/or other red blood cell antigens. RhD, Kell, and other non-ABO alloantibodies are the primary cause of moderate to severe HDFN, whereas ABO HDFN is typically mild. HDFN live birth prevalence owing to Rh alloimmunization among newborns in the United States was last estimated to be 106 per 100,000 births in 1986. HDFN live birth prevalence owing to all alloantibodies was estimated to be 817 to 840 per 100,000 in Europe. There is a need for updated prevalence estimates in the United States and a better understanding of disease demographics, severity, and treatments. OBJECTIVE: This study aimed to estimate the live birth prevalence of HDFN and the proportion of severe cases of HDFN in the United States, to describe the associated risk factors, and to compare the clinical outcomes and treatments among healthy newborns, newborns with HDFN, and newborns who are sick without HDFN using a nationally representative hospital discharge database. STUDY DESIGN: In this retrospective, observational cohort study, we used data from the 1996 to 2010 National Hospital Discharge Survey to identify live births, defined by inpatient visits with the newborn flag, with and without a diagnosis of HDFN across 200 to 500 sampled hospitals (≥6 beds) per year. Patient and hospital characteristics, alloimmunization status, disease severity, treatment, and clinical outcomes were evaluated. Frequencies and weighted percentages were calculated for all variables. Logistic regression was used to compare the characteristics between newborns with HDFN and other newborns using odds ratios. RESULTS: Of 480,245 live births identified, 9810 HDFN cases were recorded. When weighted to the United States population, this corresponded to a live birth prevalence of 1695 per 100,000 live births. Compared with other newborns, newborns with HDFN were more likely to be female, Black, living in the South (vs the Midwest or West), and treated at larger (>100 beds) and government-owned hospitals. ABO and Rh alloimmunization accounted for 78.1% and 4.3% of newborns with HDFN, respectively, whereas HDFN caused by other antigens, such as Kell and Duffy, accounted for 17.6% of the cases. Among newborns with HDFN, 22% received phototherapy, 1% received simple transfusions, and 0.5% received exchange transfusions or intravenous immunoglobulin. Newborns affected by HDFN caused by Rh alloimmunization were more likely to require medical interventions, including simple or exchange transfusions, and more likely to be delivered by cesarean delivery. Overall, HDFN was associated with a longer hospital length of stay in the neonatal intensive care unit when compared with healthy and other sick newborns, a higher rate of cesarean delivery, and a higher rate of nonroutine discharge than healthy newborns. CONCLUSION: Overall, the live birth prevalence of HDFN was higher than those previously reported, whereas Rh-induced HDFN live birth prevalence was similar to those previously reported. HDFN live birth prevalence owing to Rh alloimmunization decreased over time, likely because of continued Rh immune globulin prophylaxis. Treatment patterns for newborns with HDFN and the comparative clinical outcomes when compared with healthy newborns confirm the continued clinical needs of this population.

Open and endoscopic fetal myelomeningocele surgeries display similar in-hospital safety profiles in a large, multi-institutional database.

BACKGROUND: Open intrauterine fetal myelomeningocele repair has demonstrated decreased ventriculoperitoneal shunting and improved motor outcomes despite maternal and fetal risks. Few data directly compare the safety of open vs endoscopic approaches. OBJECTIVE: This study aimed to analyze in-hospital maternal and fetal outcomes of pregnant patients undergoing open vs endoscopic fetal myelomeningocele repair using a large, multi-center database. STUDY DESIGN: This was a review of the Pediatric Health Information System database from October 1, 2015, to December 31, 2021. All patients who underwent open or endoscopic fetal myelomeningocele repair according to the International Classification of Diseases, Tenth Revision, were identified. Demographics, gestational age, and outcomes were analyzed. Descriptive and univariate statistics were used. RESULTS: A total of 378 pregnant patients underwent fetal myelomeningocele repair. The approach was endoscopic in 143 cases (37.8%) and open in 235 cases (62.2%). Overall postprocedural outcomes included no maternal in-hospital mortalities or intensive care unit admissions, a median length of stay of 4 days (interquartile range, 4-5), 14 cases (3.7%) of surgical and postoperative complications, 6 cases (1.6%) of intrauterine infections, 12 cases (3.2%) of obstetrical complications (including preterm premature rupture of membranes), 3 cases (0.8%) of intrauterine fetal demise, and 16 cases (4.2%) of preterm delivery. Compared with an open approach, the endoscopic approach occurred at a later gestational age (25 weeks [interquartile range, 24-25] vs 24 weeks [interquartile range, 24-25]; P<.001) and had an increased rate of intrauterine infection (6 [4.2%] cases vs 0 [0%] case; P=.002). There was no difference between approaches in the rates of surgical complications, obstetrical complications, intrauterine fetal demise, or preterm deliveries. CONCLUSION: Compared with an open approach, endoscopic fetal myelomeningocele repair displays a comparable rate of fetal complications, including intrauterine fetal demise and preterm delivery, and a similar in-hospital maternal safety profile despite an association with increased intrauterine infection.

Immunomodulation for early-onset haemolytic disease of the fetus/newborn: Can we delay the need for intrauterine transfusions?

When cases of severe fetal anaemia due to maternal red-cell alloimmunization present in the early second trimester, standard treatment with intrauterine transfusion often results in fetal loss. The report by Vlachodimitropoulou et al. offers new insight into the use of maternal intravenous immune globulin to delay the need for intrauterine transfusion. Performing these procedures at a later gestational age increases the likelihood of technical success and subsequent perinatal survival. Commentary on: Vlachodimitropoulou et al. Intravenous immune globulin in the management of severe early onset of red cell alloimmunization. Br J Haematol 2023; 200:97-103.

Congenital myotonic dystrophy: An overlooked diagnosis not amenable to detection by sequencing.

OBJECTIVE: To increase the clinical awareness of the need for genetic evaluation for congenital myotonic dystrophy (CDM1) in cases of fetal akinesia sequence and idiopathic polyhydramnios. METHODS: Retrospective case review. RESULTS: A 27 y.o. G1P0 with no significant family history presented for ultrasound at 25 weeks gestation. Notable findings included lack of extension of the fetal arms and legs with bilateral talipes consistent with fetal akinesia sequence. Polyhydramnios with an amniotic fluid index of 32.2 cm was also present. Amniotic fluid obtained by amniocentesis was sent for chromosomal microarray and a next generation sequencing fetal akinesia panel which both returned normal. The patient underwent serial amnioreductions for recurrent severe polyhydramnios with removal of a total of 9.3 L. Further amniotic fluid testing for CDM1 identified >200 repeats in one copy of the fetal DMPK gene, consistent with a diagnosis of CDM1. The patient was delivered at 35 weeks gestation and neonatal demise occurred on the second day of life. CONCLUSION: Congenital myotonic dystrophy should be a consideration for cases of severe polyhydramnios identified by ultrasound. Myotonic dystrophy is detected using PCR and southern blot and is not typically included on next generation sequencing (NGS) panels that test for similar conditions. Clinicians should consider more specialized genetic testing than microarray and NGS in these cases.

Predicting fetal and neonatal demise after fetoscopy for twin-twin transfusion syndrome using recursive partitioning.

OBJECTIVE: Donor demise after laser surgery for twin-twin transfusion syndrome (TTTS) is well-characterized, but recipient demise is not, nor is neonatal death. This study aims to characterize factors associated with recipient death, donor death, and dual twin death after laser, both before and after birth. METHODS: This is a prospective cohort study of monochorionic twin pairs who underwent laser ablation for TTTS. Risk factors for fetal and neonatal death of both twins were identified using univariable analysis and recursive partitioning, a novel statistical method to quantify contributions of each factor to outcomes. RESULTS: In 413 twin pairs, death of both twins occurred in 9.2% (38/413), donor death in 12.1% (50/413), and recipient death in 2.4% (10/413). Recursive partitioning showed that gestational age at delivery predicts dual twin death (below 23.7 weeks, likely [p < 0.001], above 28.3 weeks, unlikely [p = 0.004]). Abnormal umbilical artery Doppler and weight discordance predict donor demise (p < 0.001 and p = 0.033, respectively). Cervical length under 16 mm predicts neonatal death of both twins (p < 0.001). CONCLUSIONS: Parents can gain individualized information about the survival of each fetus based on variables available from preoperative and delivery variables. Short cervix and premature delivery cause significant mortality in TTTS.

Low Transverse versus Midline Abdominal Skin Incisions for in utero Spina Bifida Repair.

OBJECTIVE: The 2 types of maternal skin incisions for in utero spina bifida repair are low transverse (LT) incision perceived to be cosmetic benefit and midline longitudinal (ML) incision, typically associated with a reduction in surgical time and lower blood loss. Our objective was to compare short- and long-term outcomes associated with these 2 types of skin incisions following in utero spina bifida repair. METHODS: Prospective observational cohort of 72 patients undergoing fetal spina bifida repair at a single institution between September 2011 and August 2018. The decision for the type of incision was at the discretion of the surgeons. The primary outcome was total operative time. Secondary outcomes included an analog scale of wound pain score on postoperative day 3, duration of postoperative stay, and postoperative wound complications within the first 4 weeks. The Patient Scar Assessment Questionnaire, a validated questionnaire, was obtained for all patients (≥6 months from delivery) using 4 categories (appearance, consciousness, satisfaction with appearance and with symptoms), with higher scores reflecting a poorer perception of the scar. RESULTS: There were 43 women (59.7%) in the LT group and 29 (40.3%) in the ML group. In all patients, the same incision was used during cesarean delivery. The total operative time was higher in the LT group by 33 min (p < 0.001), primarily due to abdominal wall incision time (open and closure). No significant differences were found between the groups in pain score, length of postoperative stay, or the rate of wound complications. Fifty-three patients (73.6%) responded to the questionnaire, 36/43 from the LT group and 17/29 from the ML group. There was no difference in the scores of appearance, consciousness, and satisfaction with appearance and symptoms between the groups. CONCLUSION: ML incisions shorten operative times without altering long-term incision-related satisfaction when compared to LT incisions.

Medical therapy to attenuate fetal anaemia in severe maternal red cell alloimmunisation.

Haemolytic disease of the fetus and newborn (HDFN) remains an important cause of fetal mortality with potential neonatal and longer-term morbidity. HDFN is caused by maternal red cell alloimmunisation, with IgG antibodies crossing the placenta to destroy fetal erythroid cells expressing the involved antigen. Intrauterine fetal blood transfusion is the therapy of choice for severe fetal anaemia. Despite a strong evidence base and technical advances, invasive fetal therapy carries risk of miscarriage and preterm birth. Procedure-related risks are increased when invasive, in utero transfusion is instituted prior to 22 weeks to treat severe early-onset fetal anaemia. This review focuses upon this cohort of HDFN and discusses intravenous immunoglobin (IVIg) and novel monoclonal antibody (M281, nipocalimab) treatments which, if started at the end of the first trimester, may attenuate the transplacental passage and fetal effects of IgG antibodies. Such therapy has the ability to improve fetal survival in this severe presentation of HDFN when early in utero transfusion may be required and may have wider implications for the perinatal management in general.

Outcomes after In Utero Myelomeningocele Repair Based on Delivery Location.

Maternal and pediatric delivery outcomes may vary in patients who underwent open fetal myelomeningocele repair and elected to deliver at the fetal center where their fetal intervention was performed versus at the referring physician's hospital. A prospective cohort study of 88 patients were evaluated following in utero open fetal myelomeningocele repair at a single fetal center between the years 2011-2019. Exclusion criteria included patients that delivered within two weeks of the procedure (n = 6), or if a patient was lost to follow-up (n = 1). Of 82 patients meeting inclusion criteria, 36 (44%) patients were delivered at the fetal center that performed fetal intervention, and 46 (56%) were delivered locally. Comparative statistics found that with the exception of parity, baseline characteristics and pre-operative variables did not differ between the groups. No differences in oligohydramnios incidence, preterm rupture of membranes, gestational age at delivery or delivery indications were found. Patients who delivered with a referring physician were more likely to be multiparous (p = 0.015). With the exception of a longer neonatal intensive care unit (NICU) stay in the fetal center group (median 30.0 vs. 11.0 days, p = 0.004), there were no differences in neonatal outcomes, including wound dehiscence, cerebrospinal fluid leakage, patch management, ventricular diversion, or prematurity complications. Therefore, we conclude that it is safe to allow patients to travel home for obstetric and neonatal management after open fetal myelomeningocele repair.

Prenatal and Postnatal Imaging Findings After Fetal Repair of Spinal Dysraphisms Using Cryopreserved Human Umbilical Cord Patch: A Case Series of 4 Patients.

We describe a case series of imaging findings of 4 patients who underwent spinal dysraphisms repair in utero with novel patch material, cryopreserved human umbilical cord, in our institution. In our study, the prenatal and postnatal magnetic resonance imaging and ultrasound are reviewed and showed cord tethering and syrinx progression in all cases. Our report is the first description of magnetic resonance imaging and ultrasound findings in the context of using this novel patch in severe cases of spinal dysraphisms.

Fortnightly surveillance of monochorionic diamniotic twins for twin to twin transfusion syndrome: Compliance and effectiveness.

OBJECTIVES: To determine the compliance and effectiveness of fortnightly ultrasound surveillance for detection of twin-twin transfusion syndrome (TTTS) in monochorionic diamniotic (MCDA) twin gestations. METHODS: This is a retrospective study of ultrasound surveillance of MCDA twins for TTTS. Our surveillance protocol requires fortnightly ultrasounds starting at 16 weeks of gestational age (GA) continuing until delivery. Compliance was assessed by determining the GA of surveillance initiation and time between ultrasounds. GA and Quintero Stage at diagnosis were evaluated to determine whether TTTS was detected prior to advanced disease (Quintero Stage III +) or fetal demise. RESULTS: Of 442 women, 264 (59.7%) initiated surveillance after 16 weeks; follow-up ultrasounds were late in 17.4% of cases. TTTS was diagnosed in 43 (9.7%) women at a median GA of 19.7 [17.4, 23.9] weeks. Of 25/43 (58.1%) cases diagnosed during protocol compliance, 12 had advanced disease and two had fetal demise. A similar proportion of diagnoses (n = 18), made while non-compliant, exhibited advanced disease (11/18, 61.1%, P = .40). Thirteen diagnoses occurred during periods of increased ultrasound frequency due to abnormalities (ie, fluid/estimated fetal weight discrepancies or Doppler abnormalities). CONCLUSIONS: In this population, fortnightly ultrasound compliance was suboptimal. Advanced disease and fetal demise occurred during protocol compliance.

Middle Cerebral Artery Doppler Velocimetry for the Diagnosis of Twin Anemia Polycythemia Sequence: A Systematic Review.

Twin anemia polycythemia sequence (TAPS) is a rare complication of monochorionic diamniotic (MCDA) twins. Middle cerebral artery peak systolic velocity (MCA-PSV) measurements are used to screen for TAPS while fetal or neonatal hemoglobin levels are required for definitive diagnosis. We sought to perform a systematic review of the efficacy of MCA-PSV in diagnosing TAPS. Search criteria were developed using relevant terms to query the Pubmed, Embase, and SCOPUS electronic databases. Publications reporting diagnostic characteristics of MCA-PSV measurements (i.e., sensitivity, specificity or receiver operator curves) were included. Each article was assessed for bias using the Quality Assessment of Diagnostic Accuracy Studies II (QUADAS II) tool. Results were assessed for uniformity to determine whether meta-analysis was feasible. Data were presented in tabular form. Among publications, five met the inclusion criteria. QUADAS II analysis revealed that four of the publications were highly likely to have bias in multiple areas. Meta-analysis was precluded by non-uniformity between definitions of TAPS by MCA-PSV and neonatal or fetal hemoglobin levels. High-quality prospective studies with consistent definitions and ultrasound surveillance protocols are still required to determine the efficacy of MCA-PSV in diagnosing TAPS. Other ultrasound findings (e.g., placenta echogenicity discordance) may augment Doppler studies.