managing the difficult case of fetal anemia

Managing the difficult case of fetal anemia

EKO G. ZHANG1, FIONA REGAN2, MARK LAYTON2, GOWRISHANKAR PARAMASIVAM1,

JO WYATT-ASHMEAD3, IRENE ROBERTS2, & SAILESH KUMAR1

1Centre for Fetal and Maternal Medicine, Queen Charlotte’s and Chelsea Hospital, Imperial College London, London W12 0HS, UK,2Department of Hematology, Imperial College London, London W12 0HS, UK, and 3Department of Perinatal Pathology, Imperial College

London, London W12 0HS, UK

AbstractObjectives. To describe a series of complex fetal anemia cases, detail the appropriate investigations and management, and reviewthe literature.

Methods. Four cases of non-red cell alloimmunization or infective cases of fetal anemia are presented.

Results. Of the four cases presented, one was a neonatal death, one pregnancy was terminated, one case was diagnosed withDiamond Blackfan anemia, and one case was due to recurrent feto-maternal hemorrhages despite negative Kleihauer tests.

Conclusions. Non-alloimmune causes of fetal anemia can be difficult to manage. Some cases require repeated and frequentintrauterine transfusions. The perinatal mortality and preterm delivery rates are increased, and some cases require considerablelong-term treatment including regular transfusions. We present our experience of a series of non-immune fetal anemia managed ina tertiary unit, review the literature, and suggest appropriate management.

Keywords: Fetal anemia, fetal blood sampling, non-immune hydrops, red cell abnormalities, feto-maternal hemorrhage

Introduction

Although the commonest causes of fetal anemia remain red cell

alloimmunization and parvovirus infection, there will be

occasions when rarer etiologies are encountered. These cases

are challenging both in diagnostic terms as well as in clinical

management, both prenatally and in the longer term as well.

These rare cases of anemia usually require extensive investiga-

tions before a precise diagnosis is possible. Frequently, the

fetuses also need regular transfusions from an early gestation.

We present four cases of severe non-alloimmune/infective

fetal anemia treated by serial intrauterine transfusions and

discuss management of these challenging cases.

Patients and methods

Two cases (Cases 1 and 2) (Table I) were detected following

the midtrimester fetal anomaly scan. Cases 3 and 4 were

detected fortuitously following ultrasound for fetal wellbeing

in the third trimester. A history of consanguinity was present

in only one case (Case 1). The frequency of repeated

transfusions varied from less than 1 week to a maximum of

4-week intervals. In all cases, no abnormal red cell antibodies

were detected. Other infectious causes (parvovirus, toxoplas-

ma, and cytomegalovirus) were also excluded in maternal

serology and fetal blood testing for evidence of viral/parasite

DNA. Although overall the mortality rate associated with

non-immune fetal anemia is very high, unusually two of our

four cases had a good outcome and are still alive. Post-

mortem examination of the two cases (Cases 1 and 2), which

died, was unhelpful in identifying a specific diagnosis. Case 3

was diagnosed with Diamond Blackfan anemia after birth

and is now almost 7 years old. She has received almost 100

transfusions since birth and has had reconstructive surgery for

bilateral rudimentary thumbs and repair of an atrial septal

defect. She is currently being assessed for a bone marrow

transplant. Case 4 developed recurrent severe anemia requir-

ing weekly transfusions in utero. Although repeated Kleihauer

tests did not confirm significant feto-maternal hemorrhage,

this diagnosis was considered the most likely as the baby’s

hemoglobin was normal at delivery and remained normal

thereafter without further transfusions; the baby is now 4

months old and remains well and hematologically normal.

All cases were managed at the Centre for Fetal Care at

Queen Charlotte’s and Chelsea Hospital, Imperial College

London. This is a major tertiary unit for Fetal and Maternal

Medicine with comprehensive adult and pediatric hematology

expertise.

Discussion

The incidence of fetal anemia due to red cell alloimmuniza-

tion is decreasing worldwide primarily due to the introduction

(Received 2 October 2010; revised 12 December 2010; accepted 23 December 2010)

Correspondence: Dr. Sailesh Kumar, Centre for Fetal and Maternal Medicine, Queen Charlotte’s and Chelsea Hospital, Imperial College London,

Du Cane Road, London W12 0HS, UK. Tel: þ44-0208-3833998. Fax: þ44-0208-3833507. E-mail: [email protected]

The Journal of Maternal-Fetal and Neonatal Medicine, December 2011; 24(12): 1498–1503

� 2011 Informa UK, Ltd.

ISSN 1476-7058 print/ISSN 1476-4954 online

DOI: 10.3109/14767058.2010.551149

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Table I. Cases of complex fetal anemia.

Case 1 Case 2 Case 3 Case 4

Obstetric history 25 years old, para 1,

one normal delivery.

27 years old, para 1,

one normal delivery.

37 year old, para 3, three

normal deliveries.

31 years old, para 0þ1,

one miscarriage.

Family history None None None None

Consanguineous

relationship

First cousins None None None

Onset and

presentation

22þ5 weeks’ gestation 19þ3 weeks’ gestation 28 weeks’ gestation (follow

up for fetal growth)

28þ2 weeks’ gestation

Mild cardiomegaly and

small pericardial effusion

on anomaly scan. Raised

MCA PSV: 55 cm/s.

Incidental finding of skin

edema, pleural effusions,

and ascites at routine

anomaly scan. Raised

MCA PSV: 67 cm/s.

Incidental finding of

skin edema,

cardiomegaly, pericardial

and pleural effusions,

and ascites on scan.

Initial MCA PSV was

normal.

Reduced fetal movements

with abnormal CTG.

Raised MCA PSV: 126

cm/s.

Weekly surveillance. Weekly surveillance. Weekly surveillance. Weekly surveillance.

Maternal blood

group

RhD positive RhD positive RhD positive RhD positive

No antibodies detected No antibodies detected No antibodies detected No antibodies detected

Fetal karyotype Normal; 46 XY Normal; 46 XX Normal; 46 XX Normal; 46 XX

Parvovirus serology Negative (no evidence of

recent infection)

Negative (no evidence of

recent infection)


recent infection)


recent infection)

Fetal blood sampling and intrauterine transfusions

First 22þ6 weeks’ gestation 19þ3 weeks’ gestation 28 weeks’ gestation 28þ2 weeks’ gestation

Pre-transfusion:

Hb 2.0 g/dl, Hct 7.8%;

IUT: 54 mls.

Pre-transfusion: Hb 4g/dl;

IUT: 30 ml.

Pre-transfusion:

Hb51g/dl, Hct 4.4%;

IUT: 95 ml.

Pre-transfusion: Hb less

than 1g/dl, Hct 4.8%;

IUT: 138 ml.

Post-transfusion:

Hb 14.7g/dl; Hct 43%.

Post-transfusion: Hb not

obtained due to technical

difficulty.

Post-transfusion:

Hb 13.7 g/dl, Hct 38.7%.

Post-transfusion:

Hb 18.9 g/dl; Hct 52.3%.

Blood film:

Erythroblastosis,

polychromasia,

anisopoikilocytosis, some

spheroechinocytes, and

red cell fragments.

Blood film: No diagnostic

features.

Blood film: Normochromic,

normocytic, no

polychromasia, or

nucleated red cells

consistent with red cell

aplasia.

Blood film: Mainly

normochromic,

normocytic with

some spherocytes,

marked polychromasia,

and increased

numbers of nucleated

red cells consistent

with feto-maternal

hemorrhage.

Second 25þ6 weeks’ gestation 20þ4 weeks’ gestation 32 weeks’ gestation 29 weeks’ gestation

Pre-transfusion: Hb 2.8g/dl,

Hct 7.3%; IUT 80ml.

Pre-transfusion:

Hb 5.9 g/dl, Hct 16%;

IUT 60 ml.

Fetal distress, procedure

abandoned.

Pre-transfusion:

Hb 2.7g/dl, Hct 8.2%;

IUT: 136 ml.

Post-transfusion:

Hb 13.1g/dl, Hct 36.5%.

Post-transfusion:

Hb 16.1g/dl, Hct 46%.

Post-transfusion:

Hb 16 g/dl, Hct 49.2%.

Third 28þ0 weeks’ gestation 29þ6 weeks’ gestation

Pre-transfusion:

Hb 5.2 g/dl, Hct 14.8%;

Pre-transfusion:

Hb 2.5 g/dl, Hct 6.8%;

IUT: 136 ml.

IUT 120 mls. Post-transfusion:

Hb 19 g/dl, Hct 57%.

Post- transfusion:

Hb 16.9 g/dl; Hct 49.3%.

Fourth Planned at 34 weeks’

gestation

30þ6 weeks’ gestation

Emergency CS performed

due to abnormal CTG.

Pre-transfusion:

Hb 3.6 g/dl, Hct 10.5%;

IUT: 175 ml.

Post-transfusion:

Hb 18.6 g/dl, Hct 54.6%.

Further tests for

inherited red cell

disorders

DBA – excluded by high

reticulocyte and

nucleated red cell count


reticulocyte and

nucleated red cell count

DBA – blood film

consistent with, but

not diagnostic of,

DBA; parents

blood counts and films

normal.


reticulocyte and

nucleated red cell count.

(continued )

Complex fetal anemia 1499

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of routine antenatal and postnatal prophylaxis with anti-D

immunoglobulin. Indeed, non-immune causes of fetal anemia

(Table II) now account for the majority of antenatal cases

[29]. The advent of non-invasive fetal monitoring using

middle cerebral artery velocimetry and prenatal fetal genotyp-

ing using free fetal DNA in maternal plasma [30] has obviated

many of the invasive risks of this condition. It is now possible

to monitor the development of fetal anemia regardless of

cause, very sensitively using fetal middle cerebral artery peak

systolic velocities, and timing the first and subsequent

intrauterine transfusions with remarkable accuracy [31].

Although the management of fetal anemia due to red cell

alloimmunization is relatively straightforward with good long-

term outcome for the fetus, this is not always the case with

Table I. (Continued ).

Case 1 Case 2 Case 3 Case 4

CDA – no evidence of

diagnostic morphological

features on postmortem

bone marrow sections













PK – normal enzyme levels

in fetus and parents



PK –normal enzyme levels




G6PD – normal enzyme

levels in parents

G6PD –normal enzyme

levels in parents


levels in parents


levels in parents

Hemoglobinopathy –

no evidence of

hemoglobinopathy on

fetal blood films and

parental Hb HPLC

normal


no evidence of

hemoglobinopathy on


parental Hb HPLC

normal


no evidence of

hemoglobinopathy on


parental Hb HPLC

normal


no evidence of

hemoglobinopathy on


parental Hb HPLC

normal

Kleihauer – negative. Kleihauer – negative. Kleihauer – negative. Kleihauer – weakly positive.

Delivery 34 weeks 23þ5 weeks 32 weeks 34 weeks

Emergency CS due to

abnormal CTG

Emergency CS due to fetal

distress during FBS

Elective CS after IUT the

same day

Outcome Male baby, dysmorphic

with low set ears.

TOP due to severe fetal

hydrops and maternal

complication of mirror

syndrome.

Female baby, BW 1116 g.

Bilateral hypoplastic

thumbs, atrial septal

defect, pulmonary vein

stenosis and bilateral

displacement of both

second toes.

Female baby, BW 2080 g.

NND at 3 weeks of age

due to pulmonary

hemorrhage.

Admitted to SCBU: Hb

21.1 g/l at birth and

19.3 g/l at age 3 weeks.

No transfusions given.

Extensive investigations

for fetal anemia all

negative.

Postmortem Massively enlarged fibrotic

spleen. The ongoing

anemia and

thrombocytopenia may

have been due to trapping

of red blood cells and

platelets in spleen.

Marked extramedullary

hemopoiesis, visceral

congestion, pericardial,

pleural, and peritoneal

effusion, congested heart

and brain, and massive

cerebellar hemorrhage

– –

Final diagnosis and

follow-up

Probable autosomal

recessive inherited red

cell disorder (possible red

cell enzymopathy)

Unknown DBA confirmed on clinical

examination and on

cytogenetic analysis

Presumed recurrent

feto-maternal

hemorrhage.

Now aged 7 years and has

required almost 100

transfusions. Currently

being considered for

bone marrow

transplantation.

No postnatal transfusions.

Healthy baby with no

hematological

abnormalities now aged

4 months.

CTG, Cardiotocograph; FBS, Fetal blood sampling; IUT, Intrauterine transfusion; CS, Caesarean section; Hb, Hemoglobin; Hct, Hematocrit;

MCA PSV, Middle cerebral artery peak systolic velocity; DBA, Diamond Blackfan anemia; CDA, Congenital dyserythropoietic anemia; PKD,

Pyruvate Kinase deficiency; HPLC, High performance liquid chromatography.

1500 E. G. Zhang et al.

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some of the rarer conditions. These cases may be diagnosti-

cally very challenging and require extensive fetal and parental

investigations. Close collaboration between the fetal medicine

specialist and pediatric hematologist is essential to ensure that

the appropriate investigations are performed. The causes of

non-immune fetal anemia are extensive (Table II) and range

from hemolysis (e.g. due to pyruvate kinase deficiency, alpha

thalassemia major, or Kasabach-Merritt syndrome from a

fetal hemangioma), hemorrhage (twin-to-twin transfusion

syndrome, feto-maternal hemorrhage, fetal hemorrhage),

impaired red cell production (e.g. parvovirus B19, Diamond

Blackfan anemia, congenital dyserythropoietic anemia), or

genetic syndromes (e.g. Pearson syndrome). Unexplained

anemia has also been reported in cases of cardiac anomalies

(for reasons that are not clear) [9,10], skeletal abnormalities

(e.g. Fanconi’s syndrome), and aneuploidy (e.g. Trisomy 21)

[9,10]. In about 18% of cases of non-immune fetal anemia, an

obvious etiology is not present despite extensive parental and

fetal investigations [29,32].

In all cases of fetal anemia, basic maternal investigations

should include a full blood count and screening for red cell

antibodies and hemoglobinopathies (Table III). If clinically

significant red cell antibodies are detected and the fetal blood

film is consistent with hemolysis, it is likely that this is the

cause of the fetal anemia and the pregnancy is managed along

usual lines. However, when red cell antibodies are not

present, it is possible that a non-immune cause is responsible

for the fetal anemia and more extensive investigations are then

necessary. When a case of non-alloimmune fetal anemia is

suspected, a full structural survey of the fetus is essential.

Relevant structural anomalies such as abnormal thumbs

and radii (Diamond Blackfan anemia, Fanconi anemia),

hepatosplenomegaly (possible viral infection or evidence of

extramedullary hematopoiesis), and intrafetal calcification

(possible viral infection) should be excluded. Fetal biometry,

liquor volume, and umbilical and middle cerebral artery

Doppler should be measured. If aneuploidy is suspected,

karyotyping should be offered and the cytogenetics laboratory

should be asked to store a sample of fetal DNA for future

analysis, if required. Maternal parvovirus serology should

be checked. Evidence for other infectious agents such as

cytomegalovirus should also be specifically looked for.

Structural abnormalities such as fetal hepatic hemangioma

or placental chorioangioma may be evident on ultrasound and

therefore clarify the diagnosis.

Evaluation of the fetal blood film and measurement of the

reticulocyte count are essential as they allow red cell aplasia to

be distinguished from other causes of anemia. In addition,

specific red cell abnormalities, such as red cell membrane

disorders or haemoglobinopathies, can often be diagnosed

from the blood film. Some disorders (e.g. red cell enzymo-

pathies) are difficult to diagnose in the fetus after blood

transfusion, since the transfused cells make interpretation

difficult. In this situation, it is often helpful to carry out further

investigations on both parents, in particular, red cell enzyme

Table II. Causes of non-immune fetal anemia.

Conditions References

Destruction/Loss

of erythrocytes

Hemoglobinopathies a thalassemia major HbH disease [1]

Erythrocyte enzyme disorders Glucose-6-phosphate dehydrogenase deficiency [2–4]

Pyruvate kinase deficiency [5–7]

Glucose phosphate isomerase deficiency [3]

Erythrocyte membrane disorders Hereditary pyropoikilocytosis [8]

Hemorrhage Twin-to-twin transfusion syndrome [9,10]

Fetal maternal hemorrhage [11]

Fetal hemorrhage [12]

Kasabach-Merritt syndrome Microangiopathic hemolytic anemia, thrombocytopenia,

vascular malformation, hemangioma

[13,14]

Impaired RBC

production

Transient myeloproliferative disorder Confined to infants with Down syndrome and rarely, Noonan

syndrome. In Down syndrome, almost all cases have an

acquired GATA1 mutation and *30% subsequently

develop acute megakaryoblastic leukemia.

[15]

Congenital leukemia Malignancy [16]

Infection Parvovirus B19 [17,18]

Diamond-Blackfan anemia (DBA) Mutations of ribosome protein genes are identified in *50% of

cases; these may be inherited or de novo.

[19–21]

Congenital dyserythropoietic anemia (CDA) Inherited red cell disorders, characterized by life-long anemia

which varies from mild to transfusion-dependent.

[22,23]

Chromosomal abnormalities Trisomy 21, 13, and 18 [9,10]

Bone marrow failure syndromes (anemia plus

reduction in other hemopoietic lineages,

particularly thrombocytopenia)

Pearson syndrome, Aase syndrome, Fanconi Anemia [24–27]

Fetal tumors Congenital fibrosarcoma [28]

Table III. Parental and fetal investigations.

Investigations

Maternal/paternal Both parents: Full blood count and blood film,

Hb HPLC, red cell enzyme assays (pyruvate

kinase, G6PD), Mother: viral serology

(especially parvovirus), red cell antibody

quantification, Kleihauer

Fetal Full blood count and film, reticulocyte count,

chromosome analysis, chromosome fragility

studies, PCR for viral DNA

DNA, Deoxyribonucleic acid; PCR, Polymerase chain reaction;

G6PD, glucose-6-phosphate dehydrogenase.


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assays (initially pyruvate kinase and G6PD deficiency),

hemoglobinopathy screening, and assessment of red cell

morphology on the blood film as a screen for red cell

membrane disorders. A history of consanguinity or previous

family history (e.g. alpha thalassaemia, G6PD deficiency) may

suggest a genetic cause and help guide investigations.

In most cases, invasive fetal testing will also be required.

Fetal blood sampling has the dual purpose of obtaining a

blood sample for diagnostic investigations as well as for

performing an in utero transfusion of the anemic fetus. Fetal

blood sampling and transfusion can be performed via the

intrahepatic or umbilical vein. In the presence of severe

hydrops, caution is required in transfusing a large volume of

blood as some fetuses tolerate this poorly. In our experience,

however, it appears reasonable to raise the fetal hemoglobin to

within the normal range at the first transfusion, provided the

volume of blood transfused is administered slowly. We have

not had any adverse procedure-related complications with this

policy. Furthermore, in our experience, fetal brain develop-

ment (as assessed by fetal MRI) in cases of severe fetal anemia

appears not to be perturbed. Clearly, longer term neurode-

velopmental outcome data is required but the available

evidence from the red cell alloimmunization literature

suggests that the fetal anemia is corrected appropriately and

the long-term outcome is comparable with controls.

The recommended investigations on fetal blood will vary

depending on the individual situation. It is essential that as a

minimum, a full blood count, reticulocyte count, and blood

film is performed. Depending on the initial results, additional

tests may need to be considered including red cell enzyme

assays (pyruvate kinase and G6PD) and hemoglobin electro-

phoresis. We also recommend carrying out a full blood count

and film þ/7 red cell enzyme assays and/or Hb HPLC on

samples from both parents as this often helps identify or

exclude genetic causes of severe fetal anemia, including

hemoglobinopathies. Indeed, parental samples are essential

where the fetus is transfused before further investigations can

be arranged. Several of these investigations are highly

specialized and should be arranged in advance with the

relevant laboratories, e.g. cytogenetic laboratories require

advance warning (and often a normal control sample as

closely age-matched as possible) in order to perform chromo-

some fragility studies which are used to diagnose Fanconi

anemia (Table III). It is important to note that occasionally,

despite extensive prenatal and postnatal investigations, the

etiology of some cases of fetal anemia will remain elusive.

In cases of recurrent and rapid fetal anemia such as seen in

Case 4, feto-maternal hemorrhage must be considered.

Kleihauer testing on a maternal blood sample is helpful but

may sometimes deceptively indicate a small volume hemorrhage

not in keeping with the degree of fetal anemia. The fetus in this

situation may require very frequent intrauterine transfusions.

Hydrops may not always be a feature particularly if blood loss is

acute. Cerebral injury is possible if very large volumes are lost

acutely and the development of ventriculomegaly is a poor

prognostic feature of long-term outcome. Fetal MRI may be

helpful to confirm normal brain development prior to delivery.

The mode and timing of delivery must be individualized.

An analysis of the benefits and risks of intrauterine transfu-

sions beyond 32 weeks suggests that the upper gestational

limit for intrauterine therapy is 35 weeks [33].

In general, fetuses are able to tolerate large volumes of

transfusions better than neonates because of the placental

reservoir of blood. However, the risks of frequent invasive

procedures must be balanced against the risks of iatrogenic

prematurity and parents must be counseled appropriately. In

some cases, termination of pregnancy may be appropriate,

particularly, when there is non-resolution of hydrops or if a

genetic syndrome has been identified. Parents must be advised

that in some cases, regular life-long blood transfusions may be

necessary. The consequences such as multiorgan dysfunction

due to iron overload secondary to the repeated transfusions

should not be underestimated. The need for long-term

chelation therapy, repeated hospital visits, and reduced life

expectancy are all issues which must be covered wherever

possible prior to delivery.

Conclusions

Given the decreasing incidence of fetal anemia, it is likely that

fewer clinicians will have the experience or expertise in invasive

procedures to adequately manage complex cases which

frequently require multidisciplinary input. It is therefore

important that these cases are managed in tertiary centers with

appropriate fetal medicine, hematology, and pediatric experi-

ence to optimize perinatal outcome. In many instances, the

outcomes for these fetuses are poor and parents need to be

counseled as such.

Acknowledgements

The authors wish to thank Mrs. Sheila Jacques and Ms.

Marcia Wilson for their help in obtaining case notes and help

with patient follow-up.

Declaration of interest: The authors report no conflicts of

interest. The authors alone are responsible for the content and

writing of the paper.

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