Causes and outcomes of prenatally unexplained fetal anemia

Abstract

Purpose

Despite advances in diagnostic approaches, fetal anemia of unknown etiology continues to be observed in rare cases. This study aimed to assess the incidence of unexplained fetal anemia and to evaluate the associated perinatal outcomes.

Materials and Methods

We conducted an observational retrospective cohort study of all fetuses that underwent fetal blood sampling (FBS) due to an MCA-PSV>1.5 MoM at a tertiary center between 2007 and 2024. Fetuses were included if they had moderate or severe anemia defined as a hemoglobin (Hgb) deviation of more than 20g/L below a gestational age adjusted mean, with a negative anemia workup. Prenatal and postnatal outcomes were obtained.

Results

Among 376 fetuses that underwent fetal blood sampling for anemia, 361 (96%) had an identified cause, while 15 (4%) had moderate to severe anemia of unknown etiology. Seven fetuses presented with non-immune hydrops and eight with other major structural anomalies not typically associated with anemia. Eleven (73%) of the 15 fetuses with unexplained anemia had thrombocytopenia, with platelets below 100000/µL in 8 cases and below 50000/µL in 6 cases. Seven cases (47%) resulted in perinatal death. Rare causes of anemia were elucidated in only 5 cases (33%) postnatally despite extensive investigations.

Conclusion

Unexplained fetal anemia is uncommon and is associated with poor neonatal outcomes warranting close pre- and postnatal surveillance.

Zusammenfassung

Ziel

Trotz Fortschritten in der Diagnostik wird in seltenen Fällen noch immer eine fetale Anämie unklarer Ätiologie beobachtet. Ziel dieser Studie war es, die Inzidenz ungeklärter fetaler Anämien zu ermitteln und die damit einhergehenden perinatalen Folgen zu bewerten.

Material und Methoden

Wir führten eine retrospektive Kohortenstudie aller Feten durch, bei denen zwischen 2007 und 2024 in einem tertiären Zentrum aufgrund eines MCA-PSV>1,5 MoM eine fetale Blutentnahme (FBS) durchgeführt wurde. Eingeschlossen wurden Feten mit einer moderaten oder schweren Anämie, definiert als eine Abweichung des Hämoglobins (Hb) von mehr als 20g/l unter dem an das jeweilige Gestationsalter angepassten Mittelwert bei negativem Anämie-Befund. Es wurden pränatale und postnatale Outcomes erfasst.

Ergebnisse

Von 376 Feten, bei denen aufgrund einer Anämie eine fetale Blutentnahme durchgeführt wurde, konnte bei 361 (96%) die Ursache identifiziert werden, während bei 15 Feten (4%) eine mittelschwere bis schwere Anämie unklarer Ätiologie vorlag. Sieben Feten zeigten einen nicht immunen Hydrops fetalis und 8 weitere schwerwiegende strukturelle Anomalien, die typischerweise nicht mit Anämie assoziiert sind. Elf (73%) der 15 Feten mit ungeklärter Anämie wiesen eine Thrombozytopenie auf, mit Thrombozytenwerten unter 100000/µl in 8 Fällen und unter 50000/µl in 6 Fällen. Sieben Fälle (47%) führten zum perinatalen Tod. Postnatal konnten seltene Ursachen für Anämie trotz umfangreicher Untersuchungen nur in 5 Fällen (33%) aufgeklärt werden.

Schlussfolgerung

Eine ungeklärte fetale Anämie ist selten und mit einer schlechten neonatalen Prognose verbunden, weshalb eine engmaschige prä- und postnatale Überwachung erforderlich ist.

Keywords

Fetal anemia - Thrombocytopenia - Intrauterine transfusion - Prenatal diagnosis - Rare genetic disorder

Introduction

Fetal anemia is an important pregnancy complication most commonly caused by red blood cell alloimmunization, Parvovirus B19 infection, feto-maternal hemorrhage, and inherited conditions such as alpha thalassemia. Throughout the years, the routine administration of prophylactic Rh(D) immune globulin during the third trimester and postpartum period in Rh-negative pregnant individuals has resulted in a significant decrease in the incidence of alloimmunization from 16% after 2 pregnancies to less than 0.3% [1] [2] [3]. Additionally, a reduction in invasive procedures for the monitoring of cases of alloimmunization has been observed due to the use of non-invasive strategies, primarily the monitoring of the middle cerebral artery peak systolic velocity (MCA-PSV) and fetal blood group typing from fetal DNA in maternal blood [4] [5] [6] [7]. Lastly, the administration of maternal intravenous immunoglobulin or anti-neonatal Fc receptor blocker in high-risk alloimmunized pregnancies further delays or prevents fetal anemia and the need for intrauterine transfusions (IUT) [8] [9].

Overall, this reduction in fetal anemia secondary to alloimmunization has been paralleled by a relative increase in anemia due to rare causes, requiring invasive fetal blood sampling (FBS). Rare causes include fetal aneuploidies with transient abnormal myelopoiesis like that seen with Trisomy 21, fetal vascular tumors, most commonly sacrococcygeal teratomas, arteriovenous malformations in the fetus or placenta and genetic conditions [10]. However, even after excluding these potential causes, a small percentage of cases, estimated at 5–18% remain unexplained, following both extensive prenatal and postnatal investigations [11] [12].

Despite the critical importance of understanding rare causes of fetal anemia, the literature on the topic remains sparse, with most data limited to case reports or small case series. Furthermore, the perinatal outcomes associated with these rare etiologies are not well defined, hindering the development of evidence-based guidelines for their management.

Given the scarcity of data and relatively high variability in reported incidence, our aim was to investigate the incidence, diagnostic pathways, underlying causes, and perinatal outcomes of rare fetal anemias in a contemporary cohort of fetuses treated at a large tertiary center.

Methods

Study design and population

An observational retrospective single-center cohort study including all fetuses who underwent intrauterine fetal blood transfusion due to anemia at the fetal medicine unit of a large tertiary care hospital between 2007 and 2024 was performed. We included fetuses with unexplained moderate to severe anemia, defined as hemoglobin (Hgb) on fetal blood sampling (FBS) with a deviation equal to or greater than 20g/L from the gestational age (GA) adjusted mean, with negative routine anemia investigations [13]. For clarity, FBS refers to diagnostic cordocentesis performed to confirm fetal anemia, whereas intrauterine transfusion (IUT) refers to the therapeutic transfusion performed following FBS when anemia is confirmed. The anemia investigations included infectious serologies (IgG and IgM for Parvovirus B19, CMV, HIV and syphilis), indirect Coombs test, Kleihauer-Betke (KB) test, and parental Hgb electrophoresis with molecular testing for alpha thalassemia when indicated. In addition, genetic testing including karyotype, microarray, and in more recent cases whole exome sequencing (WES) were performed on the FBS. All fetuses underwent a detailed anatomical survey and echocardiogram at the time of diagnosis. Fetal platelet count was determined at the time of FBS, and a platelet count less than 150000/microliters was defined as thrombocytopenia. While clinical techniques and laboratory assays evolved during the 17-year study period, all fetuses were managed according to the contemporary institutional protocols in place at the time, following consistent principles for MCA-PSV surveillance, FBS, and IUT. Approximately 6% of the fetuses had a false-positive elevated MCA-PSV with normal or only mildly decreased Hgb on FBS. These were reported separately and excluded from the current analysis [14].

Diagnostic evaluation and etiological workup of fetal anemia

Middle cerebral artery peak systolic velocity (MCA-PSV) was measured in all high-risk pregnancies with alloimmunization, fetal growth restriction, antepartum hemorrhage, or monochorionic twins, and when ultrasound findings were suggestive of possible fetal anemia. For the MCA-PSV measurements, a transabdominal approach was utilized using either Philips iU-22 (Philips Healthcare, PA, USA) or Voluson E10 (GE Healthcare, Zipf, Austria) ultrasound machines. A transverse section of the fetal head was obtained, and color flow mapping was used to identify the circle of Willis and the MCA. The pulsed-wave Doppler gate was placed on the proximal one-third of the MCA and the angle of insonation was less than 20°. Attention was taken to avoid any unnecessary pressure on the fetal head, and the mechanical and thermal indices were kept low. At least 3 consecutive waveforms, in the absence of fetal body or breathing movements, were recorded and the highest point of the Doppler waveform was considered as the PSV [15] [16].

All FBS results were obtained within 24 hours of the initial elevated MCA-PSV measurements.

FBS was performed using an aseptic technique under ultrasound guidance, and after skin infiltration with local anesthetics. The fetal puncture site was either at the placental cord insertion or in the intrahepatic portion of the umbilical vein, based on accessibility and while avoiding the cord insertion when thrombocytopenia was suspected. Three 0.5–1ml blood samples were obtained, and the complete blood count, reticulocyte count, viral PCR and genetic testing were analyzed in suspected cases. QF-PCR and chromosomal microarray (CMA) were performed in all cases, whereas genetic panels, whole exome sequencing (WES), and whole genome sequencing (WGS) were conducted only in more recent cases at the discretion of the geneticist involved in the case and with permission from the Ministry of Health. All fetuses were monitored regularly until delivery and postnatally. A post-mortem examination was offered to the parents in cases of intrauterine fetal death (IUFD) or neonatal death (NND). Placental pathology was completed in most cases.

Statistical analysis

Descriptive statistics were used to summarize maternal, fetal, and neonatal characteristics. Continuous variables are presented as medians with interquartile ranges (IQR) and categorical variables are expressed as counts and percentages. Due to the small sample size and retrospective nature of the study, no formal hypothesis testing was conducted. Data extraction and analysis were performed using Microsoft Excel, with all entries cross-checked for accuracy by 2 independent reviewers.

Ethical approval

The study was approved by our hospital ethics review board.

Results

Incidence of anemia of unknown etiology

Between 2007 and 2024, 376 fetuses were diagnosed with anemia on FBS following MCA-PSV monitoring and underwent a total of 802 FBS procedures ([Fig. 1]). Of the 376 fetuses, 361 had anemia of known etiology and were therefore excluded. A total of 15 fetuses (4.0%) had moderate to severe anemia of unknown prenatal etiology meeting our inclusion criteria and required at least one IUT. The median age of fetal anemia at diagnosis was 29.3 weeks (IQR 26.9, 33.7) and the median fetal Hgb prior to the first transfusion was 65.5g/L (IQR 48.3, 89.0) ([Table 1]). Fetuses received a median of one IUT of packed red blood cells with only one fetus requiring more than one IUT (case 13:3 IUTs). Eleven (73%) fetuses had thrombocytopenia. Platelets were below 100000/microliter in 8 cases and below 50000/microliter in 6 cases. Seven (46.7%) fetuses required a single platelet transfusion (46.7%) (cases 4, 6, 7, 12, 13, 14, 15, [Table 2]).

Fig. 1 Study cohort of anemic fetuses requiring IUT.

Table 1 Maternal and pregnancy characteristics in cases of unexplained anemia.

Variable
Data are reported as median with IQR or n (%) as appropriate. BMI: body mass index; ART: assisted reproductive technology; MCA-PSV: middle cerebral artery; PSV: peak systolic velocity; Hgb: hemoglobin; FBS: blood sampling; Hct: hematocrit; PLT: platelets
Maternal age, years	34 (29.37)
Pre-pregnancy BMI, kg/m2	27 (23.30)
Primiparity	9 (60%)
Reported maternal chronic disease	3 (20%)
Maternal ethnicity
White/Light Skin Black Asian Missing/other	5 (33.3%) 2 (13.3%) 5 (33.3%) 3 (20%)
ART (n, %)	4 (27%)
Gestational age at diagnosis of anemia (weeks)	29.3 (26.9, 33.7)
Fetal Hgb (g/L) at diagnosis	65.5 (48.3, 89.0)
Fetal Hct (%) at diagnosis	21.0 (14.2, 28.0)
Thrombocytopenia	11 (73.3%)
Fetal PLT (x109 /L) at diagnosis	75.5 (22.8, 134.3)
Platelet transfusion	7 (46.7%)

Table 2 Antenatal and postnatal findings in anemic fetuses of unknown etiology.

	Reason for referral	Prenatal ultrasound findings	Gestational age at anemia diagnosis	Fetal Hgb g/L	HCT %	PLT X 109/L	Gestational age at delivery	Outcome to discharge from hospital	Genetic testing, autopsy, and placental pathology	Cause of anemia
NIH: Non-immune hydrops; SVT: Supraventricular tachycardia; pRBC: Packed red blood cells; QFPCR: Quantitative fluorescent polymerase chain reaction; CMA: Chromosomal microarray analysis; RASopathy panel: Genetic panel testing for RAS/MAPK pathway disorders; VSD: Ventricular septal defect; CSP: Cavum septi pellucidi; IVH: Intraventricular hemorrhage; SGA: Small for gestational age; WES: Whole exome sequencing; WGS: Whole genome sequencing; FVM: Fetal vascular malperfusion; VUS: Variant of uncertain significance; IUFD: Intrauterine fetal demise; NND: Neonatal death; Hgb: Hemoglobin; HCT: Hematocrit; PLT: Platelets
1	NIH	Hydrops	36.4	85	0.25	103	38.0	Live birth Neonatal SVT Required pRBC transfusion	Normal QFPCR, CMA, and RASopathy panel. No placental pathology.	Unknown cause
2	NIH	Hydrops Fetal bradycardia IVH	29	79	0.27	122	29.0	IUFD	Normal QFPCR and CMA. Declined autopsy. Placental pathology noncontributory.	Unknown cause
3	NIH	Hydrops VSD & wide CSP	26.1	101	0.32	22	27.2	NND	Normal QFPCR. Autopsy revealed lysosomal storage disease in macrophages. Placental pathology noncontributory.	Gaucher’s disease
4	Ascites	Minimal ascites, cardiomegaly	37.1	49	0.14	29	38.1	Live birth	Normal QFPCR and CMA. Severe anemia panel diagnosed Pyruvate kinase deficiency. Placental pathology noncontributory.	Pyruvate kinase deficiency
5	Suspected hydrops	Ascites Splenomegaly	29.3	107	0.31	165	30.0	Live birth	Normal QFPCR and CMA. No placental pathology.	Unknown cause
6	Polyhydramnios	Hydrops	33.4	28	0.08	3	33.5	NND	Normal QFPCR and CMA. Abnormal trio WES. Autopsy with poor RBC production. Placental pathology noncontributory.	Kat6 mutation
7	Polyhydramnios	Hydrops	27.2	62	0.2	247	27.2	Live birth Required pRBC transfusion prior to discharge	Normal QFPCR and CMA. Placental pathology with high-grade FVM.	Unknown cause
8	SGA	Placentomegaly	29.5	62	0.2	69	34.0	NND	Normal QFPCR. Declined autopsy and placental pathology.	Unknown cause
9	Reduced Fetal movements	Hepatosplenomegaly, pelviectasis, absent nasal bone	31.3	108	0.41	29	32.3	IUFD	Abnormal QFPCR. Autopsy suggestive of hematopoietic disease. No placental pathology.	Trisomy 21 with hematopoietic disease
10	Bowel obstruction	Intra-amniotic clots, echogenic bowel, duodenal atresia	34.1	83	0.25	124	34.4	IUFD	Normal QFPCR. Autopsy and placental pathology noncontributory.	Unknown cause
11	Cardiomegaly	Cardiomegaly	36	69	0.22	82	38.0	Live birth Cardiac hypertrophy resolved at 3 months	Normal QFPCR. Placental pathology with focal infarcts and fetal thrombotic vasculopathy.	Unknown cause
12	Preterm premature rupture of membranes	Cardiomegaly and short femur	28.3	46	0.14	6	28.4	Live birth	Normal QFPCR, CMA, and WES. Placental pathology noncontributory.	Unknown cause
13	History of agenesis of corpus callosum	Borderline cardiomegaly	19.3	15	0.05	182	38.0	Live birth	WES 2 VUS not associated with anemia. Placental pathology noncontributory.	Unknown cause
14	Non-immune hydrops	Hydrops, cardiomegaly, ascites, echogenic kidneys, echogenic bowel, hepato-splenomegaly, bilateral talipes, placentomegaly	26.7	45	0.14	23	27.3	NND	Normal QFPCR and CMA. Abnormal trio WGS. Autopsy describing multifocal cerebral, choroid plexus, and subarachnoid hemorrhages. Placental pathology noncontributory.	Congenital erythropoietic porphyria
15	Non-immune hydrops	Hydrops, intracranial calcifications	21.7	56	0.17	260	38.3	Live birth	Normal QFPCR, CMA, and WES. Placental pathology noncontributory.	Unknown cause

Imaging findings

In our cohort of 15 fetuses, the indication for MCA-PSV sampling in all fetuses was the presence of abnormal ultrasound findings ([Table 2]). Seven fetuses (47%) presented with non-immune hydrops and/or polyhydramnios. Of these fetuses, 4 presented with additional findings including one fetus with bradycardia, one with ventricular septal defect, one with cardiomegaly, echogenic kidneys and bowel, hepato-splenomegaly and bilateral talipes and one with diffuse intracranial echogenic foci. The remaining 8 fetuses (53%) were not hydropic but had abnormal nonspecific prenatal ultrasound findings including cardiomegaly (n=3), ascites (n=2), hepato-splenomegaly (n=2), fetal growth restriction (n=1), placentomegaly (n=1), pelviectasis (n=1), absent nasal bone (n=1), amniotic clots (n=1), echogenic bowel (n=1), dilated esophagus and small bowel, suggestive of small bowel obstruction (n=1) and short femur (n=1).

Additional investigations

Genetic investigations included QF-PCR (n=15), CMA (n=10), WES (n=5), and WGS (n=1). Autopsies were conducted on 5 of the 7 cases with perinatal death. Among these 5, the cause was elucidated in 3: 2 demonstrated evidence of bone marrow failure, one with confirmed trisomy 21 and myelodysplasia and one with a pathogenic KAT6A mutation. The third demonstrated multifocal cerebral, choroid plexus and subarachnoid hemorrhages. Placental pathology was available in 11 cases but was non-contributory.

Overall, the underlying cause of the anemia was identified in 5 cases by means of postnatal investigations. Causes included Gaucher disease, trisomy 21 with myelodysplastic syndrome, KAT6A variant reported to be associated with bone marrow failure, pyruvate kinase deficiency, and congenital erythropoietic porphyria [17]. Notably, WES/WGS contributed to the diagnosis in 2 of these cases.

Neonatal outcome to discharge from hospital

Of the 15 cases with unexplained fetal anemia, 12 (80%) were liveborn, 3 (20%) were cases of IUFD, and 4 (27%) were cases of NND. The survival rate was comparable in the hydropic and non-hydropic groups (42.9% vs. 62.5% respectively, p=0.62). For all liveborn babies, the median gestational age at delivery was 33.8 weeks (IQR 28.1, 38.0) and the birthweight was 1950g (IQR 1575, 2785) ([Table 3]). The majority (66%) were delivered by Cesarean section due to various indications (abnormal fetal heart rate tracing in labor (n=1), breech presentation (n=3), worsening hydrops (n=2), and decelerations post IUT [n=2]). Eight neonates survived to discharge from hospital with perinatal complications including arrhythmia (n=1), cardiomegaly (n=3), ascites (n=1), and hydrops (n=2). Two neonates (cases 1 and 7, [Table 2]) required postnatal packed red blood cell (pRBC) transfusions, while the remaining 6 had normal Hgb levels after birth.

Table 3 Neonatal outcomes in cases of unexplained anemia.

Variable
Data are reported as median with IQR, n (%) as appropriate.
Gestational age at delivery, weeks	33.5 (28.7, 38.0)
Cesarean delivery	8 (53.3%)
Birthweight, grams	1950 (1720, 2773)
Female sex	10 (67%)
5’ Apgar score	9 (5,9)
Intrauterine fetal death	3 (20%)
Neonatal death prior to discharge from the hospital	4 (27%)

Three causes of NND were associated with the etiology of fetal anemia: Gaucher’s disease with worsening hydrops (case 3, [Table 2]), KAT6A variant with respiratory failure, severe metabolic acidosis and disseminated coagulopathy (case 6, [Table 2]), and congenital erythropoietic porphyria with worsening hydrops and multiple cerebral hemorrhages (case 14, [Table 2]). The fourth NND occurred after preterm birth for abnormal Doppler examinations and anhydramnios and was complicated by persistent pulmonary hypertension and necrotizing enterocolitis with the cause of anemia remaining unknown (case 8, [Table 2]).

Discussion

Main findings

This study presents a unique population of fetuses with moderate to severe anemia of rare or unknown cause. Over 17 years, unexplained fetal anemia accounted for 4.0% of all cases requiring an IUT after a positive screen with an elevated MCA-PSV>1.5 MoM. Of these, 73% also had thrombocytopenia. The etiology of the anemia remained unknown in 67% of these cases despite detailed prenatal and postnatal investigations. Rare causes of anemia, all identified postnatally, included Gaucher disease, Trisomy 21 with myelodysplastic syndrome, KAT6A pathogenic variant associated with bone marrow failure, pyruvate kinase deficiency, and congenital erythropoietic porphyria [17].

Comparison to the literature

These findings are consistent with the limited published literature. Amann et al. described 15 cases (18%) of unexplained anemia in a total of 82 fetuses that underwent IUT [11]. Further evaluations revealed that only 6 (7.3%) cases were indeed secondary to rare conditions including Diamond-Blackfan anemia, neonatal hemangiomatosis with chorangioma, Kaposi-like hemangioendothelioma, elliptocytosis, neonatal hemochromatosis, and mucopolysaccharidosis type VII. Another study by Zhang et al. reported 4 cases with severe non-alloimmune or infectious fetal anemia treated by serial IUT [18]. Of these, 2 survived, including a suspected case of recurrent feto-maternal hemorrhage and another one diagnosed with Diamond-Blackfan anemia confirmed by cytogenetic analysis. Of the remaining 2 cases, one resulted in NND due to pulmonary hemorrhage thought to be secondary to an autosomal recessive red cell disorder and one was terminated for severe fetal hydrops at 23.7 weeks of gestation with the cause remaining unknown.

A similar rate of rare causes of anemia to the one detected in our cohort was described in a more recent study of 13 (5.1%) fetuses from a cohort of 253 undergoing FBS, with 46% remaining unknown postnatally [12]. In the study by Maisonneuve et al., diagnoses included infection, conditions associated with RBC membrane disorders associated with hemolysis, bone marrow failure syndromes, and genetic variants associated with vascular fragility [12].

Thrombocytopenia in conjunction with anemia was a prevalent finding within our cohort, indicating potential bone marrow involvement. In cases with thrombocytopenia, ultrasound findings included hydrops, cardiac failure with cardiomegaly, ascites, hepato-splenomegaly, placentomegaly and fetal growth restriction. These findings have been described in the literature and in some severe cases may result in NND [19] [20]. Identifying these features should prompt further investigation, including targeted testing for more common infectious causes (Parvovirus, CMV, and syphilis) as well as rare congenital causes of bone marrow failure (including Diamond-Blackfan anemia, Fanconi anemia, MIRAGE syndrome, and leukemia among others).

Our findings contribute to the expanding understanding of rare fetal anemias and the increasing complexity of intrauterine therapy, as recently summarized by Gottschalk et al. [21].

Clinical implications

Although the approach to and management of alloimmune anemia has been standardized, management and counselling in the case of fetal anemia of unknown etiology remain challenging and require a multi-disciplinary approach involving maternal-fetal medicine, pediatrics, genetics, and hematology. Excluding fetal infection and feto-maternal hemorrhage promptly has become more feasible due to enhanced efficiency in laboratory investigations such as PCR and flow cytometry. A comprehensive diagnostic algorithm was previously published, highlighting the importance of standardizing the diagnostic approach and ensuring that investigations are performed in a step-wise fashion [12]. Such an approach prevents the overlooking of specific disorders such as red cell enzymopathies prior to a fetal transfusion, which could impact the interpretation of the results, further complicating the diagnosis. In addition, recent physiologic data suggest that hemodynamic adaptations to anemia may begin as early as the second trimester, as demonstrated by Luewan et al. using Hgb Bart’s disease as a model, underscoring the importance of early recognition and timely diagnostic intervention [22]. FBS and transfusion remain an essential part of the diagnosis and treatment of such cases. In our population, given the increased incidence of thrombocytopenia, preparing for platelet transfusion and an intrahepatic transfusion approach, as opposed to the placental cord root, are important strategies to minimize therapeutic delays and procedure-related complications. Finally, both the mode and timing of delivery should be individualized to optimize outcomes.

Strengths and limitations

This study has several strengths. First, gestational age adjustments were made to enhance the accuracy of MCA-PSV as a screening test for fetal anemia. Second, an extensive number of FBS procedures were conducted within a single tertiary center and were all analyzed by the same laboratory. Third, to ensure diagnostic accuracy, 3 blood samples were obtained in all cases. However, it is important to acknowledge certain limitations of this study. Primarily, its retrospective design and the fact that it spanned over a 17-year period introduce potential biases. Additionally, there was no standardization for the investigative stepwise approach during this timeframe. Lastly, significant advancement has occurred in genetic investigations over recent years, including the advent of next-generation sequencing and microarray analysis. Therefore, it is possible that the earlier cases of fetal anemia of unknown etiology might have been resolved by utilizing contemporary techniques.

Conclusion

Fetal anemia of unknown etiology is a rare condition often seen with thrombocytopenia. Advanced genetic investigations including chromosome microarray analysis, WES, and WGS may play a pivotal role in the diagnosis of rare etiologies of fetal anemia. Given the complexity of these cases, a multidisciplinary approach in a tertiary care center is required to provide adequate management and counselling. Due to the poor overall prognosis, increased fetal surveillance should be considered.

Contributorsʼ Statement

Saja Anabusi: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing - original draft. Charles Litwin: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing - original draft, Writing - review & editing. Greg Ryan: Data curation, Writing - review & editing. David Chitayat: Validation, Writing - review & editing. Shiri Shinar: Conceptualization, Data curation, Methodology, Project administration, Supervision, Validation, Writing - original draft, Writing - review & editing.

Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgement

We sincerely thank the parents of the patients who participated in this study for their invaluable contribution to this research.

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Publication History

Received: 10 September 2025

Accepted after revision: 15 December 2025

Accepted Manuscript online:
15 December 2025

Article published online:
11 February 2026