Maternal and fetal outcomes of intraplacental choriocarcinoma complicated by fetomaternal hemorrhage: a systematic review.

INTRODUCTION: Intraplacental choriocarcinoma is a gestational trophoblastic neoplasia located within the placenta. Due to the usual silent presentation, more than half of the cases are diagnosed incidentally. It has been demonstrated that this pathology is linked to feto-maternal hemorrhage (FMH), stillbirth, and intrauterine growth restriction. The aim of our review was to establish if there are recurrent signs that might lead to an early diagnosis and better management in cases complicated by FMH. MATERIALS AND METHODS: We performed a systematic review of the literature from 2000 up to March 2023. The adopted research strategy included the following terms: (gestational choriocarcinoma obstetrics outcome) AND (intraplacental choriocarcinoma) AND (gestational choriocarcinoma). The MEDLINE (PubMed), Google Scholar, and Scopus databases were searched. RESULTS: The research strategy identified 19 cases of FMH coexisting with intraplacental choriocarcinoma (IC), as described in 17 studies. The perinatal mortality rate was 36.8%. In eight cases, histological diagnosis of IC was made post-delivery. Metastatic lesions were found in 75% (6/8) of described cases. One case of maternal death has been described. Chemotherapy was necessary in seven cases. Sporadical prenatal ultrasound signs were described. DISCUSSION: The diagnosis of IC is usually delayed, mostly due to aspecific symptoms and signs. Histological analysis of the placenta, when not routinely performed, should be performed when warning symptoms are encountered. The maternal prognosis was good, with a mortality rate of 5.5%. A fertility-sparing approach is always possible even in the presence of metastasis. Chemotherapy seems to be useful in cases of maternal and neonatal metastasis.

Fetomaternal hemorrhage: a clue to intraplacental choriocarcinoma and neonatal malignancy.

Fetomaternal hemorrhage (FMH) is a known cause of neonatal anemia due to fetal blood loss to the maternal circulation, occurring when the maternal-fetal barrier is disrupted. Several causes must be considered, although in most cases the etiology remains unknown. Intraplacental choriocarcinoma (ICC) is a rare entity and has been related with massive FMH, intrauterine fetal demise, severe neonatal anemia and metastatic choriocarcinoma in both mother and infant. There are 25 cases of histopathologically confirmed ICC complicated with FMH described in the literature. Because FMH occurs unexpectedly and the majority of patients with ICC are asymptomatic, this diagnosis may be missed. Once FMH is confirmed, underlying malignancy should be kept in mind. The authors present a case report of severe neonatal anemia following FMH related to ICC and highlight the importance of serum ß-hCG monitoring in cases of massive FMH.

Clinical practices and outcomes of RhD immunoglobulin prophylaxis following large-volume fetomaternal haemorrhage in Queensland, Australia.

BACKGROUND: Guidelines for laboratory assessment of fetomaternal haemorrhage (FMH) was published by the Australian and New Zealand Society of Blood Transfusion (ANZSBT) in 2002. However, data on adherence by practitioners and clinical outcomes are lacking. AIMS: The primary objective is to examine the follow-up testing and dosing of additional RhD immunoglobulin in RhD negative women who experienced large-volume FMH for whom additional intravenous RhD immunoglobulin was requested in Queensland, Australia. The secondary objectives are to examine the rate and risk factors of RhD alloimmunisation in these women. MATERIALS AND METHODS: RhD negative women with FMH >6 mL for whom additional dose(s) of intravenous RhD immunoglobulin was requested through Australian Red Cross Lifeblood from February 2007 to February 2018 were identified. For each patient, the volume of FMH, methods and timing of FMH quantitation, dose of RhD immunoglobulin, maternal and cord blood groups were analysed against the corresponding antibody screen and identification. RESULTS: Following FMH >6 mL, only 15% and 11.5% of cases adhered to current ANZSBT guideline on follow-up testing and supplemental RhD immunoglobulin dosing respectively. Despite the provision of single supplemental RhD immunoglobulin at a ratio of 100 IU to 1 mL fetal red cells, the rate of RhD alloimmunisation in RhD negative women with RhD positive fetus or fetus of unknown RhD status following FMH >6 mL is at least 4%. CONCLUSIONS: Poor compliance with guidelines for follow-up and management of large-volume FMH may contribute to increased risk of RhD alloimmunisation. Further analysis of data is warranted.

The prevalence of an elevated F cell population in a maternal and gynaecology cohort.

OBJECTIVES: This study aimed to determine F cell prevalence in a cohort of maternal and gynaecology specimens using QuikQuant anti-HbF flow cytometry (FC) kit and to investigate if the presence of maternal F cells can lead to fetomaternal haemorrhage (FMH) overestimation. BACKGROUND: The gold standard to estimate FMH is the Kleihauer-Betke test (KBT). The KBT has proved to be insufficiently sensitive to detect low numbers of circulating fetal cells due to the presence of maternal F cells. At present, the prevalence of false positive KBT results due to raised maternal F cell population, defined as >5%, is poorly characterised. METHODS: A total of 120 specimens were tested for the presence of F cells and fetal cells by KBT and anti-HbF FC. The results calculated were compared to determine FMH overestimation. RESULTS: Of our cohort, 32% showed an elevated F cell population, of which 69% (27 of 39) were clinically significant according to KBT (>2 mL FMH). The mean FMH volumes by KBT and anti-HbF FC were 3·90 mL (0·20-35·40 mL) and 4·09 mL (0·20-9·70 mL), respectively. CONCLUSION: The study highlighted that an elevated F cell level could be found in the cohort tested, with an F cell level of >10% causing significant FMH overestimation by KBT.

Fetomaternal hemorrhage among pregnant women in Accra, Ghana.

OBJECTIVE: To determine the occurrence of and risk factors for fetomaternal hemorrhage (FMH) among pregnant women at Korle Bu Teaching Hospital in Accra, Ghana. METHODS: A prospective study of FMH among pregnant women without hemoglobinopathies in the second trimester attending prenatal care between October 2015 and May 2016 performed using the Kleihauer-Betke test. Volume of FMH was estimated; ABO and Rh blood groups of participants were determined. A data extraction form and structured questionnaire were used to collect demographic and clinical information, and data on risk factors. RESULTS: Of 151 participants, 32 (21.2%) had FMH. Almost 18% (n=27) had FMH at baseline (16-24 weeks), 10% (10/100) at 28-32 weeks, and 11.1% (11/99) at 34-37 weeks of pregnancy. Volume of FMH was less than 30 mL in 30 (19.9%) women, whereas it was greater than 30 mL in 2 (1.3%) women. No identifiable patient-specific factors were associated with occurrence of FMH. CONCLUSION: FMH is common among pregnant women in Ghana and can occur as early as 16 weeks, without identifiable risk factors. RhD negative women who may be pregnant with RhD positive fetuses should be screened early in pregnancy, not only at delivery, for occurrence of FMH.

Anemia neonatal grave secundaria a transfusion feto-materna: a proposito de un caso / Severe neonatal anemia due to fetomaternal hemorrhage: an ilustrative case

La transfusión feto-materna es el paso de eritrocitos fetales a la circulación materna. Cuando es masiva, tiene una incidencia aproximada del 0,2-0,9 %. Generalmente, se desconoce el agente desencadenante, pero, en ocasiones, se pueden identificar factores de riesgo. En el embarazo, suele ser asintomática; el síntoma más frecuente es la disminución de los movimientos fetales (el 26 %) en relación con la anemia grave. Se diagnostica mediante la detección de hemoglobina fetal en la sangre materna (test de Kleihauer o citometría de flujo). Se presenta a un recién nacido con anemia crónica secundaria a la transfusión fetomaterna, que, después del tratamiento con transfusión de concentrado de hematíes, tuvo como complicación síntomas de sobrecarga de volumen y empeoramiento clínico. Tras la realización de una exanguinotransfusión, evolucionó favorablemente, sin secuelas.

Fetomaternal transfusion (FMT) is defined by the transfer of fetal blood into the maternal circulation. The incidence of massive FMT is estimated to be approximately 0.2-0.9 % of births. Although a number of etiologies have been associated with FMT, most causes remain unidentified and the pregnancy is usually asymptomatic. The most frequent symptom is the decrease in fetal movements (26 %) in relation to severe anemia. Several diagnostic modalities for FMT are described (Kleihauer stain, flow cytometry). We describe a case of a newborn with chronic anemia secondary to FMT who, after treatment with transfusions of red blood cells, presented volume overload and clinical worsening as a complication. In this case, our patient needed exchange transfusion for definitive improvement without disability.

Intraplacental choriocarcinoma coexisting with fetomaternal hemorrhage: Case report, chemotherapy management, and literature review.

RATIONALE: Near-term intraplacental choriocarcinoma (IC) coexisting with massive fetomaternal hemorrhage (FMH) is rare, and its clinical course is poorly understood. Here, we report a new case from our hospital, with detailed discussion and literature review. PATIENT CONCERNS: A 21-year-old Chinese female at 35 weeks gestation was admitted to our hospital due to reduced fetal movement. Near-term IC coexisting with massive FMH was diagnosed after delivery. INTERVENTION: The mother and infant were followed 3 months after delivery. Beta-human chorionic gonadotropin (ß-HCG), pathological examination of the placenta, and computed tomography scans were performed for the mother and ß-HCG was performed for the infant. OUTCOMES: The mother's ß-HCG serum level increased from 31,280 IU/L (6 days postdelivery) to 192,070 IU/L (49 days postdelivery), and then steadily fell to 42,468 IU/L (3 months postdelivery) without chemotherapy. The mother died from metastasis and cerebral hemorrhage. The infant survived and his ß-HCG serum level fell to within the normal range without chemotherapy. LESSONS: FMH associated with near-term IC is a rare disease. Measurement of maternal ß-HCG may therefore represent a useful parameter when IC is a possible differential diagnosis. A pathological examination of the placenta should be performed in all cases of FMH to better identify cases of IC. Future research should aim to develop methods of identifying which patients with IC should receive chemotherapy, whether we should use single- or multiagent chemotherapies, and whether there is a positive correlation between chemotherapy regimen and ß-HCG serum levels.

Risk factors for fetomaternal bleeding after laser therapy for twin-twin transfusion syndrome.

OBJECTIVE: To quantify and assess potential risk factors for transplacental passage of fetal red blood cells (RBCs) into the maternal circulation (fetomaternal bleeding, FMB) after laser surgery for twin-twin transfusion syndrome (TTTS). STUDY DESIGN: A retrospective study of Rhesus-D negative patients that underwent laser surgery for TTTS. Patients with and without postoperative detectable fetal RBCs on Kleihauer-Betke (KB) testing were compared to determine risk factors for FMB. Patients were further sub-classified into those with a FMB < 20% and ≥20% of estimated fetoplacental blood volume. RESULTS: Of 60 studied patients, 26/60 (43%) had a positive postoperative KB test. The median fetal:adult RBC ratio was 0.00125, estimated to be a FMB volume of 6.25 mL. There were 17/26 (65%) of patients with FMB < 20% and 9/26 (35%) patients with ≥20% of the fetoplacental blood volume. Stage III-Recipient and III-Recipient/Donor patients were more likely to have a positive KB test (14/21 [66.7%] vs 12/39 [30.8%], OR = 4.50 [1.27-16.54], P = 0.0162). No other risk factors for FMB were apparent. CONCLUSIONS: Fetomaternal bleed appears to be a common finding after laser surgery for TTTS. TTTS Stage, particularly stage III-Recipient and III-Recipient/Donor, appears to be a risk factor for FMB.

Biochemical analysis of intraplacental choriocarcinoma and fetomaternal transfusion.

Intraplacental choriocarcinoma is one of the rarest forms of gestational tumors and is believed to be one of the causes of fetomaternal transfusion (FMT). A 35-year-old woman, gravida 2, para 2, with a history of two vaginal deliveries, was incidentally diagnosed as having stage I gestational intraplacental choriocarcinoma with a FIGO/World Health Organization 2000 risk score of 2 after term delivery. This disease caused neonatal anemia but did not metastasize to either the mother or infant. Short tandem repeat analysis with laser microdissection revealed that the tumor had originated from the current pregnancy. Serological test and immunohistochemical analysis revealed that the patient and her baby suffered from FMT. She has been free from disease without any medical intervention for the last 1 year. A combination of multiple biochemical analyses might help us diagnose the precursor pregnancy of a gestational choriocarcinoma and FMT.

Modification of host dendritic cells by microchimerism-derived extracellular vesicles generates split tolerance.

Maternal microchimerism (MMc) has been associated with development of allospecific transplant tolerance, antitumor immunity, and cross-generational reproductive fitness, but its mode of action is unknown. We found in a murine model that MMc caused exposure to the noninherited maternal antigens in all offspring, but in some, MMc magnitude was enough to cause membrane alloantigen acquisition (mAAQ; "cross-dressing") of host dendritic cells (DCs). Extracellular vesicle (EV)-enriched serum fractions from mAAQ+, but not from non-mAAQ, mice reproduced the DC cross-dressing phenomenon in vitro. In vivo, mAAQ was associated with increased expression of immune modulators PD-L1 (programmed death-ligand 1) and CD86 by myeloid DCs (mDCs) and decreased presentation of allopeptide+self-MHC complexes, along with increased PD-L1, on plasmacytoid DCs (pDCs). Remarkably, both serum EV-enriched fractions and membrane microdomains containing the acquired MHC alloantigens included CD86, but completely excluded PD-L1. In contrast, EV-enriched fractions and microdomains containing allopeptide+self-MHC did not exclude PD-L1. Adoptive transfer of allospecific transgenic CD4 T cells revealed a "split tolerance" status in mAAQ+ mice: T cells recognizing intact acquired MHC alloantigens proliferated, whereas those responding to allopeptide+self-MHC did not. Using isolated pDCs and mDCs for in vitro culture with allopeptide+self-MHC-specific CD4 T cells, we could replicate their normal activation in non-mAAQ mice, and PD-L1-dependent anergy in mAAQ+ hosts. We propose that EVs provide a physiologic link between microchimerism and split tolerance, with implications for tumor immunity, transplantation, autoimmunity, and reproductive success.

Flow Cytometry in Detection of Fetal Red Blood Cells and Maternal F Cells to Identify Fetomaternal Hemorrhage.

Accurate detection and quantitation of fetomaternal hemorrhage (FMH) is critical to the obstetric management of rhesus D alloimmunization in Rh-negative pregnant women. The flow cytometry is based on the detection of fetal red blood cells using a monoclonal anti-HbF antibody, and is the method most indicated for this estimation. The objective of this study was to quantify fetal red blood cell levels of pregnant women using flow cytometry. We analyzed 101 peripheral blood samples from Rh-negative and Rh-positive women, whose mean age was 24 years (20-32 years), after vaginal delivery or cesarean section. Our study showed that 53% of pregnant women had fetal red blood cells levels <2.0 mL, 31% between 2.0-3.9 mL, 16% between 4.0-15.0 mL, and 1% >15.0 mL. Accurate quantitation of fetal red blood cells is necessary to determine the appropriate dose of anti-D (RHD) immunoglobulin to be administered to pregnant or postpartum women.

Occult fetomaternal hemorrhage in women with pathological placenta with respect to permeability.

AIM: Women with pre-eclampsia (PE), placenta previa (PP), placental abruption (PA), and placental mesenchymal dysplasia (PMD) have been described as having placental permeability dysfunction. This study was performed to determine whether occult fetomaternal hemorrhage (FMH) is common in women with such complications and in women with non-reassuring fetal status. METHODS: Forty-one antenatal and 39 postnatal blood samples were obtained from 46 women, including 11 with placental permeability dysfunction (5, 3, 2, and 1 with PE, PP, PA, and PMD, respectively) and 35 controls without such complications. To estimate the amount of fetal red blood cells, flow cytometry was performed using the fetal cell count system with two antibodies against fetal hemoglobin and carbonic anhydrase and the ß-γ system with two monoclonal antibodies against hemoglobin ß-chain and hemoglobin γ-chain. A diagnosis of FMH was made when the fraction size of the isolated cell population on scatter plots expressing fetal hemoglobin alone or hemoglobin γ-chain alone accounted for ≥0.02% of the total cell population on scatter plots. RESULTS: FMH was identified in five women, including one each with PE, PA, PP, PMD, and no complications. Thus, the prevalence rate of FMH was significantly higher in women with complications than in controls (36% [4/11] vs 2.9% [1/35], respectively, P =  0.009). The FMH occurrence rate did not differ between women with and without non-reassuring fetal status (7.7% [1/13] vs 12% [4/33], respectively, P =  1.000). CONCLUSION: The risk of fetal red blood cells trafficking into the maternal circulation may be increased in women complicated with PE, PA, PP, and PMD.

Fetomaternal hemorrhage complicated pregnancy: risks, identification, and management.

PURPOSE OF REVIEW: This article aims not only to review recent literature about the clinical features of massive fetomaternal hemorrhage (FMH) and identification of risk factors, but also to alert obstetricians and pediatricians to this underdiagnosed and underestimated severe obstetrical issue. In addition, a simplified flow chart for the antenatal management of suspected FMH is proposed. RECENT FINDINGS: Improvements in obstetrical and neonatal care have decreased perinatal morbidity and mortality and the rate of stillbirth. Unfortunately, because of the nonspecific signs on presentation, adverse outcome associated with massive FMH has not followed this trend and still has devastating consequences. As even the definition varies among publications and there is lack of universal screening, the real nature still remains obscure. Improvements in the diagnosis of fetal anemia, laboratory and intrauterine transfusion techniques, and the implementation of prenatal and postnatal neuroprotection give some hope for the better outcome in the most severe cases. Unfortunately, obstetricians' awareness of the massive FMH remains still at an unacceptably low level. SUMMARY: There is an urgent need for the internationally accepted definition, standardized pregnancy management protocol, and structured follow-up of neonates from such pregnancies. We suggest the international registry of massive FMH cases.

[Fetomaternal transfusion and diagnosis of gestational choriocarcinoma]. / Transfusion materno-fœtale et diagnostic de choriocarcinome gestationnel.

Choriocarcinoma is a rare but agressive malignant trophoblastic neoplasm. Fetomaternal transfusion can be the first sign of choriocarcinoma. We describe two cases of gestational choriocarinoma whose first manifestation was a fetomaternal transfusion. Fetomaternal transfusion is a rare demonstration of choriocarcinoma but its diagnosis must lead to a placenta examination with specific research of choriocarcinoma. The more the therapeutic care is precise, the better is the forecast.

[Prognostic factors of perinatal short-term outcome in severe placental insufficiency using Doppler sonography to assess end-diastolic absent and reverse blood flow in umbilical arteries]. / Prognosefaktoren des perinatalen Kurzzeitergebnisses bei schwerer Plazentainsuffizienz mit dopplersonografisch enddiastolischem Null- und Rückfluss in der Art. umbilicalis.

Significant placental insufficiency, indicated by Doppler ultrasound findings of absent or reverse end-diastolic flow velocities (AREDV), is associated with increased morbidity and mortality. Analysis of blood flow in the ductus venosus should assist in early intrauterine recognition of threatened foetuses. 58 high-risk pregnancies with umbilical AREDV were repeatedly examined (n=364). Doppler findings were correlated with neonatal signs of deterioration (ratio of normoblasts to leukocytes, pH, base excess, Apgar score), as well as short-term morbidity [need for intubation, duration of assisted respiration, evidence of respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), necrotising enterocolitis (NEC), intraventricular haemorrhage (IVH grade III+IV)] against the analysis of the blood flow findings (normal or increased pulsitility, absence or reverse end-diastolic flow) in the umbilical arteries (AU), the middle cerebral arteries (ACM) and ductus venosus (DV) relating these to birth weight and the duration of the pregnancy. The median period of observation was 12.8 days, 48% of the foetuses showed an abnormal ductus venosus flow and 26% an absent venous or reverse end-diastolic flow. The median date of delivery was 30 weeks, with a mean birth weight of 816 g. 93% were live births with 12% dying postnatally. Although the criteria for postnatal morbidity (BPD, NEC, IVH III+IV) and mortality did not correlate with changes in arterial and venous Doppler parameters in our group, there was a significant relationship between the normoblast count, known to be a marker of chronic hypoxia. The Apgar 10 minte score, umbilical arterial pH and base excess were correlated with changes in the DV flow curves. Healthy survival started, irrespective of arterial or venous blood flow criteria, from 27+0 weeks of pregnancy. If born between 27.0 and 30+6 weeks, the infants were more likely to be healthy the less the blood flow had been compromised. A birth weight of 590 g (sensitivity 62.5%; specificity 93.5%) and gestational age of 28+5 weeks (sensitivity 87.5%; specificity 90.3%) were shown to be cut-off points between healthy survival and survival with serious neonatal complications.

Assessment of feto-maternal hemorrhage among rhesus D negative pregnant mothers using the kleihauer-betke test (KBT) and flow cytometry (FCM) in Addis Ababa, Ethiopia.

BACKGROUND: This study aimed to assess fetomaternal hemorrhage (FMH) among RhD negative pregnant mothers using two techniques, Kleihauer-Betke (KBT) and Flow cytometry (FCM). To determine if patient-specific doses of prophylactic anti-D warrant further investigation in Ethiopia and wider Africa. METHODS: Hospital- based cross-sectional study was conducted among 75 RhD negative pregnant mothers using convenient sampling technique. RESULT: FMH has been detected in 52% and 60% by KBT and FCM techniques, respectively. The volume of FMH quantified in the majority of the cases (92.5% and 87%) was <10 mL fetal blood while >30 mL in 1.3% (1/75) and 2.7% (2/75) as calculated by KBT and FCM, respectively. The FMH calculated by the two methods have good correlation; r = 0.828 (p = 0.000) for categorized and r = 0.897 (p = 0.000) for continuous values and the agreement between the FCM and KBT was moderate with kappa (κ) value of 0.53 (p = 0.000). CONCLUSION: Most of FMH calculated (<10 mL) could have been neutralized by lower doses which might have lower costs than administering 300 µg dose which is currently in practice in our country for affording mothers. Besides, it also showed that the volume of FMH was >30 mL in 1.3% and 2.7% of the cases as calculated by KBT and FCM, respectively, which need more than 300 µg dose RhIG for neutralization. Further investigation into the cost- effectiveness and scalability of patient- specific dosing of prophylactic anti-D appears warranted.

Intrauterine blood transfusion: current indications and associated risks.

Fetal anemia is a serious complication in pregnancy and associated with perinatal mortality and morbidity. During 25 years of worldwide experience with intravascular intrauterine blood transfusion, a variety of indications have been described. Intrauterine transfusion (IUT) treatment is considered most successful for fetal anemia due to red cell alloimmunization. Moreover, the use of this procedure has also been reported in pregnancies with parvovirus B19 infection, fetomaternal hemorrhage and placental chorioangiomas, for example. This review focuses on the current indications of intrauterine blood transfusions. In addition, we describe the potential complications of IUT treatment.