Fetal anemia: diagnosis & management

Stavros Sifakis, MD, PhDHeraklion Crete, Greece

Fetal anemia

Main causes

immunological Non-immunological

anti-D antibodies (Rh iso-immunization)

anti-K antibodies (Kell)

anti-Fya antibodies (Duffy)

Parvovirus Β-19

Thalassemias (α- β-)

chronic fetomaternal transfusion

twin-to-twin transfusion

chorioangiomas

others

Sensitization to fetal cells antigens

Detti et al, 2001, 64 casesZimmerman et al, 2002, 124 cases

Mari et al, 2005, 39 cases

Scheier et al, 2004, 56 cases

Sonographic findings in fetal anemia

Early sonographic markers of prediction and/or diagnosis of fetal anemia

Spleen Circumference

Liver circumference

Late sonographic findings in fetal anemia

Hydrops fetalisascitespleural effusion (hydrothorax)pericardial effusion

Only when the fetal Hb deficit is ≥7g/dl less than the expected in the given gestational week

Fetal anemia diagnosis in Rh sensitization

- assessment of billirubin levels in amniotic fluid

- measurement ΔΟD450

- Queenan & Lilly curves

Queenan curve

Doppler measurements for fetal anemia diagnosis

Fetal vessels studies

Umbilical artery Copel et al, AJOG 1988; Copel et al, AJOG 1989; Hecher et al, AJOG 1995

Thoracic aorta Nicolaides et al, AJOG 1990

Splenic artery Bahado-Singh et al, AJOG 1999

Ductus venosus Hecher et al, AJOG 1995

Umbilical vein Kirkinen et al, BJOG 1983; Jouppila et al, Ultras Med Biol 1984;

mean cerebral artery – MCA

Vyas et al, AJOG 1990:

- detection of 50% of the cases

Mari et al, 2000:

- threshold of 1.5 ΜοΜ for the peak systolic velocity (PSV)

Zimmerman et al, 2002:

- the first multicenter study

- 98% detection of moderate-severe degree of anemia (using prospective measurements)

Doppler ultrasonography versus amniocentesis to predict fetal anemia. Oepkes et al, N Engl J Med 2006

MCA-PSV Amniotic fluid ΔOD450

Doppler ultrasonography versus amniocentesis to predict fetal anemia. Oepkes et al, N Engl J Med 2006

Doppler ultrasonography versus amniocentesis to predict fetal anemia. Oepkes et al, N Engl J Med 2006

MCA-PSV has replaced the evaluation of ΔOD450

in amniotic fluid

The use of subsequent MCA-PSV measurements has led to a reduction of invasive approaches ~70%

advantages

- avoid adverse-effects e.g. rupture of the membranes

- avoid the further maternal sensitization from the transplacental amniocentecis

Assessment of PSV-MCA (1)

>16-18 weeks

>35 weeks: risk of false positive increased measurements for fetal anemia prediction

Transverce section at the anterior wing of the sphenoid bone near the base of the skull

Assessment of PSV-MCA (2)

The measurement in periods of fetal apnea & absence of fetal movements (false positive increase in PSV during decelerations of FHR)

the angle of insonsation to be <15ο (software: correction at 0ο)

2-mm pulsed Doppler wave

3 measurements: taken into consideration the highest value

Reference value of PSV-MCA

Curves of Moise 2002 or

Conversion to MoMs (www.perinatology.com)

Assessment of PSV-MCA in a fetus with increased risk for fetal anemia

(Imbar et al, 2006)

Intrauterine treatment: history

Transfusion in anemic fetuses

- Transfusion of red cells in peritoneal cavity – empiric protocols

- Afterwards the first trials of approach in the fetal circulation

- It was understood that there was the need of non-invasive assessment of fetal anemia

Red cells velocity: is increased as a result of increased cardiac output & decreased blood viscosity (Fan et al, 1980)

The predictive value of Doppler measurements:

- descending aorta, umbilical vein, splenic artery, common carotide, mean cerebral artery

J Perinat Med 2012

J Perinat Med 2012

Ενδομήτρια μετάγγιση

Α. Εισαγωγή βελόνης στην ομφαλική φλέβα

Β. Ροή μεταγγιζόμενου αίματος στην ομφαλική φλέβα

C.D. Μετάγγιση πακεταρισμένων RBCs στην εμβρυική κυκλοφορία

Papantoniou N, Sifakis S, Antsaklis A. Therapeutic management of fetal anemia: review of standard practice and alternative treatment options. J Perinat Med.2013 ;41(1):71-82.

Ομάδα Ο RhD αρνητικό RBCs

Νωπό (εντός 5 ημερών για υψηλά επίπεδα 2,3DPG)

Έλεγχος για HBV, HCV, HIV, CMV

Χρήση φίλτρων

Irradiation 25Gy (καθαρισμός από λευκοκύτταρα- αποφυγή GVHD)

Πλυμένα πακεταρισμένα RBCs σε μονάδες με τελικό Ht 75-85%

Αυτόλογη μετάγγιση με μητρικό αίμα (αποφυγή ευαισθητοποίησης σε ξένα RBC αντιγόνα, απαιτεί επίπεδο Hb>12.5g/dl)

Αίμα δότη για ενδομήτρια μετάγγιση

Schonewille H, Klumper FJ, van de Watering LM, et al. High additional maternal red cell alloimmunization after Rhesus-and K-matched intrauterine intravascular transfusions for hemolytic disease of the fetus. Am J Obstet Gynecol 2007; 196:143.e1.

Watson WJ, Wax JR, Miller RC, Brost BC. Prevalence of new maternal alloantibodies after intrauterine transfusion for severe Rhesus disease. Am J Perinatol 2006; 23:189.

Ενδοαγγειακή μετάγγιση: >24εβδ κύησης: Ht στόχος 40-50%Φυσιολογικός εμβρυικός Ht στις 17εβδ: 37+/-4, σε τελειόμηνο: 43+/-7.

<24εβδ κύησης: Ht στόχος έως 25% ή ×4 αρχικού Ht (1η

μετάγγιση)2η μετάγγιση: εντός 48ωρών, 3η μετάγγιση: σε 7-10ημέρες

Ενδοπεριτοναϊκή μετάγγιση:

Αναμενόμενη απορρόφηση αίματος εντός 7-10 ημερών

Όγκος μεταγγιζόμενου αίματος & Ht-στόχος σε ενδοαγγειακή μετάγγιση

Mandelbrot L, Daffos F, Forestier F, et al. Assessment of fetal blood volume for computer-assisted management of in utero transfusion. Fetal Ther 1988; 3:60.

Radunovic N, Lockwood CJ, Alvarez M, et al. The severely anemic and hydropic isoimmune fetus: changes in fetal hematocrit associated with intrauterine death. Obstet Gynecol 1992; 79:390.

V(ml) μεταγγιζόμενου αίματος= V(ml) μητροπλακουντιακής μονάδας × (τελικός Ht- αρχικός Ht)÷ Ht μεταγγιζ/νου αίματος

V(ml) μητροπλακουντιακής μονάδας= 1.046+ EFW(gr)× 0.14

V(ml) μεταγγιζόμενου αίματος=20- ηλικία κύησης(εβδ) × 10

Ενδοαγγειακή- ομφαλική φλέβα: σημείο εισόδου ομφάλιου λώρου στον πλακούντα ή ελεύθερη έλικα (ταχεία & αποτελεσματική σε υδρωπικά έμβρυα)

Ενδοηπατική πορεία της ομφαλικής φλέβας (εμβρυικός πόνος- stress, τραυματισμός ενδοκοιλιακών οργάνων)

Ενδοκαρδιακή: δεξιά κοιλία (μεγαλύτερο ποσοστό εμβρυικού θανάτου)

Ενδοπεριτοναϊκή (προβληματική απορρόφηση σε υδρωπικά έμβρυα)

Θέσεις ενδομήτριας μετάγγισης

Dodd JM, Windrim RC, van Kamp IL. Techniques of intrauterine fetal transfusion for women with red-cell isoimmunisation for improving health outcomes. Cochrane Database Syst Rev 2012; 9:CD007096.

Ε ν δ ο μ ή τ ρ ι ο ς θ ά ν α τ ο ς : 1.6% ανά επέμβαση

Επείγουσα ΚΤ: 2% ανά επέμβαση

Λοίμωξη- αμνιονίτις: 0.3% ανά επέμβαση

ΠΡΕΥ: 0.1% ανά επέμβαση

Τρώση ομφαλικής αρτηρίας: 3% ανά επέμβαση

Βραδυκαρδία ή ταχυκαρδία: 5% ανά επέμβαση (57% περιπτώσεων περιγεννητικού θανάτου ή επείγουσας ΚΤ)

Αιμορραγία στο σημείο καθετηριασμού: (23-53%)

Αιμάτωμα ομφάλιου λώρου: (17% περιπτώσεων περιγεννητικού θανάτου)

Εμβρυομητρική αιμορραγία: από διαπλακουντιακή είσοδο (40%)

Βαριά εγκεφαλική βλάβη

Επιπλοκές ενδομήτριας μετάγγισης

Van Kamp IL, Klumper FJ, Oepkes D, et al.. Am J Obstet Gynecol 2005; 192:171

PSV-MCA: could it be used to estimate the time intervals in sequential transfusions ?

Mari et al, 2005:

- 39 fetuses

- threshold 1.5 ΜοΜ before the 3rd transfusion

- failure of correct diagnosis in 5/12 cases of moderate-severe anemia

Detti et al, 2001:

threshold 1.32 ΜοΜ after the 1st transfusion

transfusion DR (%) FPR (%)

1st 96 14

2nd 100 46

3rd 64 70

Scheier et al, 2004:- diagnostic criterion of anemia: deficit of Hb> 6gr/dl

- by the estimation of Hb decrease at0.3gr/dL/day between the 2nd & 3rd

transfusion a correct deficit of Hb >5gr/dl was predicted in 90% of the cases (FPR: 25%)

Possible explanation for the reduced sensitivity of PSV-MCA for the diagnosis of moderate-severe anemia after

sequential transfusions

After the 3rd transfusion

1) The majority of the circulating red cells are those of the donor. Adult red cells have rhoologic properties that increase blood viscosity (El Bouhmadi et al, 2000)

2) The anemia “correction” via transfusions increases the Ht that leads in increased blood viscosity (Welch et al, 1994)

3) The increased Ο2 supply to the tissues (due to the anemia “correction”) is related with a decrease in the previously enhanced fetal cardiac output

studies showed that PSV-MCA is correlated not only with the Hb levels but also with the Ο2 saturation (Picklesheimer 2008)

Clinical experience and practice in setting out the sequential transfusions

Severe anemia < 24 weeks: A partial “correction” of Hb is indicated to allow a progressive adaptation to the

viscosity changes (Moise 2008)

increase of Ht not greater than 4-fold or to reach to Ht 25%; otherwise there is a risk of fetal death after the procedure

Repeat the transfusion after 48 hrs with object normal levels of Hb (Radunovic et al 1992)

Severe anemia > 24 weeks: - interval 7-10 days between 1st & 2nd transfusion- » 2 weeks » 2nd & 3rd transfusion- » 3 weeks » >3rd transfusion (Moise 2008)

Calculation of Hb decrease- 0.4 gr/dL/day between 1st & 2nd transfusion- 0.3 gr/dL/day » 2nd ς & 3rd »- 0.2 gr/dL/day » 3rd & 4th » (Scheier et al, 2004)

More large scale studies are required

How useful is Doppler assessment of MCA in the evaluation of fetal anemia associated with other conditions

(non Rh-alloimmunization) ?

Kell allo-immunizationSequential amniocentesis for the evaluation of ΔOD450 are not useful

(Vaughan et al, AJOG 1994)

anti-Kell antibodies direct suppress fetal erythropoiesis

(Vaughan et al, NEJM 1998)

PSV-MCA in anemia (30 cases):

sensitivity & specificity ~89% (van Dongen et al, Ultras Obstet Gynecol 2005)

Parvovirus B19

A transient suppress of erythroblasts in bone marrow– aplasticanemia

MCA Doppler in fetal anemia diagnosis– 1.29 ΜοΜ

(Delle Chiaie et al, UOG 2001; Hernandez-Anrade et al, UOG 2004)

A spontaneous resolve of hydrops fetalis-anemia in 30% of the cases – threshold 1.,5 ΜοΜ? (Rodis et al, AJOG 1998)

Fetomaternal transfusion

Diagnosis using PSV-MCA (Eichbaum et al, FDT 2006; Wong et al, JUM 2005)

Sonographic findings of fetal anemia & fetal distress- US: ascites, pericardial effusions- Decreased fetal movements- sinusoidal pattern FHR

Transfusions have only a transient effect as the entrance of fetal blood into the maternal circulation is continued

(Montgomery et al, AJOG 1995)

PSV-MCA: 84.2 cm/s

24 weeks of gestation

Fetal Hbred: pretransfusionwhite: expected after IVTblack: measured after IVT

27 wks: intracranial echogenic areas around the posterior horns of the lateral ventricles & the cerebral cortex

Postmortem: Microscopic hemorrhages & calcifcations in the white matter of the cerebral hemispheres

In theory TTTS should result in an anemic donor and a polychytemic recipient. …..The reasons why anemia of the donor and polycythemia of the recipient do not occur in all cases are not clear……

TTTS after laser coagulation

In about 13% of the cases a reverse TTTS condition occurs:“twin anemia polycytemia sequence”

- Reripient becomes anemic (MCA >1.5 MoM)- Donor becomes plethoric (MCA <1 MoM)

- Repeated transfusions may be required(Robyr et al, Prevalance and management of late fetal complications following successful selective

laser coagulation for TTTS syndrome, AJOG 2008)

Follow up of the PSV-MCA alterations in a weekly base for at least 4 weeks after the laser therapy (Moise K, AJOG 2009)

IUGR

In initial stages of early-onset IUGR: increased levels of fetal erythropoietin and polycytemia

This compensatory mechanism is gradually getting lost as hypoxemia is continued

73 IUGR pregnancies: fetal anemia in 29% (total) & 43% (in cases with absent UA-EDF) (Kush et al, Early Hum Dev 2006)

PSV-MCA in anemia detection in IUGR fetuses- 48% sensitivity – 82% specificity (Mach et al, UOG 2003)

- not established threshold- possible explanation: a variety of changes in cerebral blood flow in fetuses with severe IUGR

- PSV-MCA: may be a more sensitive predictive marker of imminent perinatal death compared to PI-MCA ?? (Mari et al,

UOG 2007)

Cell free fetal DNA in maternal circulation

25.4ge/ml3.4%

292.2ge/ml

6.2%

0

50

100

150

200

250

300

11-17 wks 37-42 wks

fetal DNA

% total-free DNA

Lo et al. 1998 Am J Hum Genet

ge= genome equivalent / ml

• D+ ή D- phenotype

• Presence or absence of RHD gene

• Sequences of RHD in the plasma of D- pregnant women:

- present: the fetus is D+

- absent: the fetus is D-

cell ffDNA in the management of Rh(-) pregnancies

RHD

RHCE

D+

RHD

RHCE

or

D-

a 44% reduction of anti-D prophylaxis

avoidance of blood products use

Reduced cost UK: £1,000,000/year

The clinical use of cell-ffDNA in the management of Rh(-) pregnancies

AntiD 28 weeks

AntiD 34 weeks

AntiD 40 weeks

+ve

investigation of cell-ffDNA for fetal RHD -ve

No Anti-D

J Perinat Med 2012

Conclusive Remarks

Sonographic markers of established anemia (immune and non-immune origin):- hydrops fetalis (ascites, pleural and pericardial effusion)- increases peak systolic velocity in MCA (PSV-MCA)

Assessment of PSV-MCΑ:It is a diagnostic marker of fetal anemia before the demonstration of

the sonographic findings (that indicate a severe degree of anemia) Has better sensitivity and specificity compared to the measurement of

ΔOD450 in the amniotic fluid (Lilley & Queenan curves) in the hemolytic form of fetal anemia

Displays a diagnostic value (more or less) in any type of fetal anemia (it is better or well-studied in Rh-alloimmunization)

Its use after the 1st transfusion for both the follow up of fetal anemia and the establishment of the time intervals for the subsequent IUTs, requires further investigation Thank you