New developments in fetal and neonatal alloimmune thrombocytopenia.

Fetal and neonatal alloimmune thrombocytopenia, the platelet equivalent of hemolytic disease of the fetus and newborn, can have devastating effects on both the fetus and neonate. Current management of fetal and neonatal alloimmune thrombocytopenia in a subsequent affected pregnancy involves antenatal administration of intravenous immune globulin and prednisone to the pregnant woman to prevent the development of severe fetal thrombocytopenia and secondary intracranial hemorrhage in utero. That therapy has proven to be highly effective but is associated with maternal side effects and is expensive. This commentary describes 4 advances that could substantially change the current approach to detecting and managing fetal and neonatal alloimmune thrombocytopenia in the near future. The first would be an introduction of a program to screen all antepartum patients in this country for pregnancies at risk of developing fetal and neonatal alloimmune thrombocytopenia. Strategies to implement this complex process have been described. A second advance is testing of cell-free fetal DNA obtained from maternal blood to noninvasively determine the fetal human platelet antigen 1 genotype. A third, in preliminary development, is creation of a prophylactic product that would be the platelet equivalent of Rh immune globulin (RhoGAM). Finally, a fourth major potential advance is the development of neonatal Fc receptor inhibitors to replace the current medical therapy administered to pregnant women with an affected fetus. Neonatal Fc receptor recycles plasma immunoglobulin G to increase its half-life and is the means by which immunoglobulin G crosses the placenta from the maternal to the fetal circulation. Blocking the neonatal Fc receptor is an ideal way to prevent maternal immunoglobulin G antibody from causing fetal and neonatal alloimmune thrombocytopenia in a fetus at risk of developing that disorder. The pertinent pathophysiology and rationale for each of these developments will be presented in addition to our thoughts relating to steps that must be taken and difficulties that each approach would face for them to be successfully implemented.

Electronic Fetal Monitoring Credentialing Examination: The First 4000.

Objective Recognized variability in fetal heart rate interpretation led the Perinatal Quality Foundation (PQF) to develop a credentialing exam. We report an evaluation of the 1st 4000 plus PQF Fetal Monitoring Credentialing (FMC) exams. Study Design The PQF FMC exam is an online assessment for obstetric providers and nurses. The exam contains two question types: traditional multiple-choice evaluating knowledge and Script Concordance Theory (SCT) evaluating judgment. Reliability was measured through McDonald's Total Omega and Cronbach's Alpha. Pearson's correlations between knowledge and judgment were measured. Results From February 2014 through September 2018, 4,330 different individuals took the exam. A total of 4,057 records were suitable for reliability analysis: 2,105 (52%) physicians, 1,756 (43%) nurses, and 196 (5%) certified nurse midwives (CNMs). As a measure of test reliability, total Omega was 0.80 for obstetric providers and 0.77 for nurses. There was only moderate correlation between the knowledge scores and judgment scores for obstetric providers (0.38) and for nurses (0.43). Conclusion The PQF FMC exam is a reliable, valid assessment of both Electronic Fetal Monitoring (EFM) knowledge and judgment. It evaluates essential EFM skills for the establishment of practical credentialing. It also reports modest correlation between knowledge and judgment scores, suggesting that knowledge alone does not assure clinical competency.

Blood group A mothers are more likely to develop anemia during antenatal intravenous immunoglobulin treatment of fetal and neonatal alloimmune thrombocytopenia.

BACKGROUND: Incompatibility between parental platelet (PLT) antigens may lead to sensitization of mother and development of fetal and neonatal alloimmune thrombocytopenia (FNAIT) resulting in fetal thrombocytopenia. Intravenous immunoglobulin (IVIG) with or without prednisone is the most effective, evidence-based antenatal treatment for subsequent FNAIT-affected pregnancies. IVIG infusion causes hemolysis in other settings, the degree depending upon patient blood groups (BGs). STUDY DESIGN AND METHODS: In ClinicalTrials.gov NCT00194987, 102 pregnant women received randomized antenatal treatment: Arm A received 2 g/kg/week IVIG; Arm B received 1 g/kg/week IVIG + 0.5 mg/kg/day prednisone. This post hoc analysis explored BG and anemia in 69 FNAIT mothers treated with Arm A or Arm B without salvage treatment to explore the effects of IVIG and steroid treatment on development of anemia in these women. Mothers whose treatment changed, for example, those with insufficient or unknown fetal PLT response who received salvage therapy, were excluded. RESULTS: For Arm A, 17 of 21 (hemoglobin [Hb] < 10 g/dL) mothers with anemia but only three of 15 mothers without anemia had BG-A and/or BG-B (p = 0.0005). BG was unrelated to anemia in Arm B; only nine of 33 Arm B mothers became anemic during treatment. The mean decrease in Hb level in women with BG-non-O was 1.9 g/dL and in women with BG-O was 1.1 g/dL (p = 0.004). Anemia was not caused by iron deficiency; the lowest mean corpuscular volume was 79. CONCLUSION: FNAIT women with BG-non-O more frequently develop anemia secondary to high-dose IVIG infusion (2 g/kg/week), quite possibly from isohemagglutinin-mediated hemolysis; maternal Hb requires monitoring. IVIG at 1 g/kg/week did not cause anemia in women with BG-non-O; concomitant prednisone likely alleviated the IVIG effect. Maternal BG could influence selection of antenatal treatment for FNAIT.

Proposed diagnostic criteria for the case definition of amniotic fluid embolism in research studies.

Amniotic fluid embolism is a leading cause of maternal mortality in developed countries. Our understanding of risk factors, diagnosis, treatment, and prognosis is hampered by a lack of uniform clinical case definition; neither histologic nor laboratory findings have been identified unique to this condition. Amniotic fluid embolism is often overdiagnosed in critically ill peripartum women, particularly when an element of coagulopathy is involved. Previously proposed case definitions for amniotic fluid embolism are nonspecific, and when viewed through the eyes of individuals with experience in critical care obstetrics, would include women with a number of medical conditions much more common than amniotic fluid embolism. We convened a working group under the auspices of a committee of the Society for Maternal-Fetal Medicine and the Amniotic Fluid Embolism Foundation whose task was to develop uniform diagnostic criteria for the research reporting of amniotic fluid embolism. These criteria rely on the presence of the classic triad of hemodynamic and respiratory compromise accompanied by strictly defined disseminated intravascular coagulopathy. It is anticipated that limiting research reports involving amniotic fluid embolism to women who meet these criteria will enhance the validity of published data and assist in the identification of risk factors, effective treatments, and possibly useful biomarkers for this condition. A registry has been established in conjunction with the Perinatal Research Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development to collect both clinical information and laboratory specimens of women with suspected amniotic fluid embolism in the hopes of identifying unique biomarkers of this condition.

Noninvasive prenatal screening or advanced diagnostic testing: caveat emptor.

The past few years have seen extraordinary advances in prenatal genetic practice led by 2 major technological advances; next-generation sequencing of cell-free DNA in the maternal plasma to noninvasively identify fetal chromosome abnormalities, and microarray analysis of chorionic villus sampling and amniotic fluid samples, resulting in increased cytogenetic resolution. Noninvasive prenatal screening of cell-free DNA has demonstrated sensitivity and specificity for trisomy 21 superior to all previous screening approaches with slightly lower performance for other common aneuploidies. These tests have rapidly captured an increasing market share, with substantial reductions in the number of chorionic villus sampling and amniocentesis performed suggesting that physicians and patients regard such screening approaches as an equivalent replacement for diagnostic testing. Simultaneously, many clinical programs have noted significant decreases in patient counseling. In 2012 the Eunice Kennedy Shriver National Institute of Child Health and Human Development funded a blinded comparison of karyotype with the emerging technology of array comparative genomic hybridization showing that in patients with a normal karyotype, 2.5% had a clinically relevant microdeletion or duplication identified. In pregnancies with an ultrasound-detected structural anomaly, 6% had an incremental finding, and of those with a normal scan, 1.6% had a copy number variant. For patients of any age with a normal ultrasound and karyotype, the chance of a pathogenic copy number variant is greater than 1%, similar to the age-related risk of aneuploidy in the fetus of a 38 year old. This risk is 4-fold higher than the risk of trisomy 21 in a woman younger than 30 years and 5- to 10-fold higher than the present accepted risk of a diagnostic procedure. Based on this, we contend that every patient, regardless of her age, be educated about these risks and offered the opportunity to have a diagnostic procedure with array comparative genomic hybridization performed.

Omission of fetal sampling in treatment of subsequent pregnancies in fetal-neonatal alloimmune thrombocytopenia.

BACKGROUND: Fetal-neonatal alloimmune thrombocytopenia affects approximately 1 of 1000 live births, most of which are not severely thrombocytopenic. Despite effective treatment with intravenous gammaglobulin and/or prednisone, antenatal management of a subsequent affected pregnancy is complicated by the risks associated with fetal blood sampling. Furthermore, there are no biomarker(s) of high risk other than the occurrence of intracranial hemorrhage in a previous sibling. Management of these high-risk pregnancies requires intensive treatment initiated at 12 weeks of gestation. OBJECTIVE: The objective of the study was to evaluate whether empiric escalation of therapy at 32 weeks allows the omission of fetal blood sampling in all fetal-neonatal alloimmune thrombocytopenia-affected patients. Specifically, we sought to determine whether intensive intravenous gammaglobulin-based regimens for the treatment of a subsequent fetal-neonatal alloimmune thrombocytopenia-affected pregnancy followed by empirically escalated intravenous gammaglobulin and prednisone treatment would increase the fetal platelet count and thus safely allow omission of fetal blood sampling in the antepartum management of these patients. STUDY DESIGN: In this prospective, multicenter, randomized controlled study, 99 women with fetal-neonatal alloimmune thrombocytopenia whose prior affected child did not have an intracranial hemorrhage were randomized to receive an intensive intravenous gammaglobulin-based regimen: 2 g/kg per week or intravenous gammaglobulin 1 g/kg per week plus prednisone 0.5 mg/kg per day, starting at 20-30 weeks of gestation. Escalated therapy (intravenous gammaglobulin 2 g/kg per week plus prednisone 0.5 mg/kg per day) was recommended and usually initiated at 32 weeks when fetal counts were <50,000/mL(3) or when fetal blood sampling was not performed. The preliminary report of this study from 2007 demonstrated the efficacy of both intravenous gammaglobulin-based regimens in most patients. Most patients who underwent fetal sampling had adequate fetal counts and therefore did not have their treatment escalated. This post hoc analysis describes the 29 fetuses who had their treatment escalated either because they had low counts at 32 weeks or when sampling was not performed. This study explored whether the empiric escalation of treatment at 32 weeks was sufficiently effective in increasing fetal platelet counts in these patients. RESULTS: Mean fetal and birth counts of fetuses randomized to each of the 2 initial treatment groups were all >100,000/mL(3). Three neonates had an intracranial hemorrhage; all 3 were grade 1 and all had birth platelet counts >130,000/mL(3). In a post hoc analysis, 19 fetuses undergoing fetal blood sampling at 32 weeks had fetal platelet counts <50,000/mL(3) despite their initial treatment. Of these 19, birth platelet counts were >50,000/mL(3) in 11 of 13 fetuses who received escalated treatment compared with only 1 of 6 of those who did not (P = .01); only 3 fetuses that received initial therapy followed by escalated treatment had birth platelet counts <50,000/mL(3) and none had an intracranial hemorrhage. The platelet counts of 14 of 15 fetuses that received empirically escalated treatment without sampling were >50,000/mL(3) at birth. In addition, none of these had an intracranial hemorrhage. CONCLUSION: The 2 recommended protocols of intensive initial treatment followed by empiric escalation of therapy at 32 weeks of gestation are reasonably safe, effective in increasing fetal platelet counts, and allow omission of fetal blood sampling by increasing the fetal platelet count in almost all cases.

A Call for Change in a Changing World.

The practice of obstetrics and gynecology in the United States has changed substantially over the past 50 years, but the structure of our residency programs has not evolved at a comparable pace. The number of hours available for training during the workweek has decreased significantly, whereas the amount of essential material to learn and clinical skills to acquire has increased dramatically. The switch to minimally invasive surgical approaches has reduced the number of open abdominal cases available for training, and the aptitude required to perform difficult laparoscopic and robotic cases for benign disease is such that many programs do not have enough surgical patients to teach all of their residents how to adequately master those procedures. Obstetric patients are older and heavier than those encountered several decades ago, and the comorbidities of some of these women make their antepartum and intrapartum management extremely complex. Furthermore, the explosion of genetic knowledge has made prenatal counseling infinitely more challenging. In this commentary we review these and related issues and then address the question of whether current training programs are preparing our graduates to optimally perform in the clinical arena they will enter after finishing their residencies. Some ways in which the current system could be modified are suggested, and a plea is made for the creation of a high-level task force to address this problem on a national level.

The case for an electronic fetal heart rate monitoring credentialing examination.

The Perinatal Quality Foundation has created an examination containing both knowledge-based and judgment questions relating to the interpretation of electronic fetal heart rate monitoring for credentialing all medical and nursing personnel working on a labor and delivery floor. A description of the examination and the rationale for its use throughout the United States is presented.

Intrapartum management of category II fetal heart rate tracings: towards standardization of care.

There is currently no standard national approach to the management of category II fetal heart rate (FHR) patterns, yet such patterns occur in the majority of fetuses in labor. Under such circumstances, it would be difficult to demonstrate the clinical efficacy of FHR monitoring even if this technique had immense intrinsic value, since there has never been a standard hypothesis to test dealing with interpretation and management of these abnormal patterns. We present an algorithm for the management of category II FHR patterns that reflects a synthesis of available evidence and current scientific thought. Use of this algorithm represents one way for the clinician to comply with the standard of care, and may enhance our overall ability to define the benefits of intrapartum FHR monitoring.

Putting the "M" back in maternal-fetal medicine.

Although maternal death remains rare in the United States, the rate has not decreased for 3 decades. The rate of severe maternal morbidity, a more prevalent problem, is also rising. Rise in maternal age, in rates of obesity, and in cesarean deliveries as well as more pregnant women with chronic medical conditions all contribute to maternal mortality and morbidity in the United States. We believe it is the responsibility of maternal-fetal medicine (MFM) subspecialists to lead a national effort to decrease maternal mortality and morbidity. In doing so, we hope to reestablish the vital role of MFM subspecialists to take the lead in the performance and coordination of care in complicated obstetrical cases. This article will summarize our initial recommendations to enhance MFM education and training, to establish national standards to improve maternal care and management, and to address critical research gaps in maternal medicine.

Fetal and neonatal alloimmune thrombocytopenia: a management algorithm based on risk stratification.

Fetal and neonatal alloimmune thrombocytopenia constitutes the most common cause of severe thrombocytopenia in fetuses and neonates and of intracranial hemorrhage among term newborns. The cornerstone of therapy involves the use of steroids and intravenous immunoglobulins. Despite the risk of potentially devastating consequences to the fetus, fetal blood sampling has typically been used to document response to therapy. We propose a therapeutic algorithm based on risk stratification with individualized treatment optimization without the use of fetal blood sampling.

Of parachutes and patient care: a call to action.

Obstetric caregivers are plagued with lawsuits alleging negligence for suboptimal outcomes. Some of those claims are unjustified, but many have merit. We are obligated to create systems designed to minimize the potential for errors that harm our patients. A variety of safety initiatives have been shown to improve patient outcomes in several centers in the United States, but it has been difficult to document the expected association between those results and reduced liability premiums. Furthermore, some individuals and institutions have been reluctant to adopt safety tools such as electronic fetal monitoring certification for all staff working on their Labor and Delivery floor, protocols for managing common clinical scenarios, simulation drills for dealing with uncommon dangerous events, and pre-procedure checklists because of the paucity of evidence based data documenting the effectiveness of those approaches. It is time to move forward with these and other safety initiatives in a serious national attempt to eliminate all preventable adverse patient outcomes in our specialty.

Intracranial hemorrhage in alloimmune thrombocytopenia: stratified management to prevent recurrence in the subsequent affected fetus.

OBJECTIVE: We sought to prevent intracranial hemorrhage (ICH) through antenatal management of alloimmune thrombocytopenia. STUDY DESIGN: A total of 33 women (37 pregnancies) with alloimmune thrombocytopenia and ICH in a previous child were stratified according to the timing of the previous child's ICH: extremely high risk (HR) (n = 8) had ICH <28 weeks, very HR (n = 17) between 28-36 weeks, and HR (n = 12) in the perinatal period. Treatment was initiated at 12 weeks with intravenous immunoglobulin 1 or 2 g/kg/wk, and if the fetal platelet count by cordocentesis was <30,000/mL despite treatment, prednisone and/or more intravenous immunoglobulin were added. RESULTS: Five of 37 fetuses suffered ICHs. Two ICHs had platelet counts >100,000/mL, and 1 was grade I. The other 2 ICHs were unequivocal treatment failures; both were grade III-IV and resulted in fetal demise. CONCLUSION: These findings demonstrate the success of stratified treatment in these HR patients, which tailored interventions according to the timing of the sibling's ICH.