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Hemolytic Disease of the Newborn
Qun Lu, M.D.
Assistant Professor
Dept. of Pathology and Laboratory Medicine
David Geffen School of Medicine at UCLA
Los Angeles, CA
Clinical History
06/25/05: 36 y o, gravita 3, para 0, 10 1/7
weeks pregnant AA female, came to ER due
to left-sided abdominal pain
PMH:
– lost two pregnancies in first trimesters, no
RhoGam administration, her blood type is B
negative,
– last pap was 3 y ago and normal
– Hypothyroidism diagnosed at age of 8, not
compliant with med
PE
General: BP 110/50, HR 112. T and R normal, a
well- developed, well-nourished, in mild distress.
LUNGS /HEART: WNL
ABDOMEN: Some guarding, but bowel sounds
and had bilateral fullness in both quadrants.
PELVIC: normal external female genitalia, scant
discharge was noted from the cervix. The GC and
Chlamydia cultures were obtained. No blood was
noted. Pelvic bimanual examination revealed
masses up to the umbilicus.
ER work-up
Lab: WBC of 16, HB 3.9, HCT 12.8, PLT
287,000, MCV 64.7, BMP- normal, UA - 1+
Hb and 1+ leukocyte esterase, beta HCG -
291,000.
Pelvic US: IUP at 10-1/7th weeks and also
complex bilateral adnexal masses with
cysts. Each was approximately 10 x 14 x 7
and 10 x 12 x 8 centimeters.
ER Treatment
Admission
IV fluids
Evaluation of her anemia
Transfusion with 2 units of blood
Evaluation of bilateral adnexal masses: CA-
125. Consider further imaging.
Issues
Blood Bank issues: B negative, anti-D (1:256)
and anti-C(1:1) present, concerned with HDN,
currently 10+ weeks pregnancy, not a
candidate for RhoGam
Anemia: iron deficient, started on iron
supplement, no source of bleeding found,
smear – 2+ spherocytes, 3+ microcytes, 2+
fragmented cells, HB studies – 98% Hb A, 1.2%
Hb A2, 0.5%Hb F, no Hb S, C
Issues Adneal masses: CT - no lymphadenopathy, no
metastasis, cystic mass with no papillary
projections or solid part, c/w overstimulation
syndrome. TSH high (41.7), T4 <1mcg/dl, T3 23
ng/dl, both low
Cardiovascular. a right sided DVT, starting
heparin, possibly secondary to venous stasis
from her adnexal masses. Base PTT 25, PT
11.6, INR 1.1, lupus anticoagulant +, further
rheumatology studies ordered
Hemolytic Disease of Newborn
Definition: a hemolytic disease in the newborn
caused by blood-type incompatibility between
mother and child
Maternal Ig G antibodies can cross the placenta
and coating fetal RBCs – hemolysis
Maternal sensitization: history of transfusion or
pregnancy
Common RBC antigens causing
HDN
--Rh antigens. Most common is D antigen, next is c
antigen. IgG can cross placenta.
– ABO antigens: only in infants born to group O
mothers because some have IgG anti-A, anti-B,
anti-A,B antibodies without sensitization, usually
mild HDN
– Kell: Kell antigens are expressed in early fetal
RBCs and bone marrow hematopoietic cells –
cause hemolysis and bone marrow suppression –
severe and early HDN
– Kidd, MNSs, Duffy antigens: rare, but increasing
Prevention of HDN
Nearly all women with Rh negative or weak D
type are identified in early pregnancy by blood
testing.
If mother is Rh-, anti-D is negative,usually given
Rh immunoglobulin (RhIg), also known as
RhoGAM
– 1 vial (300 mcg), around the 28th week of
pregnancy
– at time when vaginal bleeding occurs (calculate)
– at the time of delivery within 72 hours
Maternal-Fetal Bleeding Screening
After vaginal bleeding or delivery, if
screening is negative, just give 1 vial (300
mcg) RhIG. If +, give minimal 2 vials and
add more vials after calculation
Calculating Dosage of RhoGam
First perform the Kleihauer-
Betke test to get the
percentage of fetal red
cells in the mother
Mechanism
Blood smear stained with
acid elution
Hb F is more acid resistant
Fetal RBC darkly stained,
Maternal RBC "ghosts"
Fetal Blood
Maternal Blood
Calculating Dosage of RhoGam
Hemoglobin electrophoresis on
cellulose acetate Hemoglobin HPLC
Calculating Dosage of RhoGam
Method 1:
% of fetal RBC X 50 / 30
Method 2:
If the decimal <0.5,
round up; if the decimal
is >0.5, round up and
then round up again
First Sensitized Pregnancy
Father RBC phenotyping:
– negative for the offending antigen then no further
testing is necessary
– positive for the antigen, serial antibody titer
monitoring is required
Anti-K: HDN tends to happen early and severe
– Frequency of monitoring: every 4 weeks to 28
weeks, then every 2 weeks until birth
– Critical titer: 1:8 or above
First Sensitized Pregnancy
Non anti-K antibodies– Frequency of monitoring: first at 12 weeks gestation,
then at 28, 32 weeks gestation
– Critical titer : the IAT titer is > 1:32 or albumin titer > 1:16 (it varies from hospital to hospital)
– IAT titers of < 1:32 or less are managed non-invasively with repeat antibody titers every 2-4 weeks.
– IAT > 32: Doppler Ultrasound to measure peak systolic velocity of middle cerebral artery or amniocentesis or umbilical blood sampling q 2 to 3 weeks to detect fetal anemia . (N Engl J Med. 2000 Jan 6;342(1):9-14 )
Open circles indicate fetuses with either no anemia or mild anemia ( 0.65 multiples of
the median hemoglobin concentration). Triangles indicate fetuses with moderate or
severe anemia (<0.65 multiples of the median hemoglobin concentration). The solid
circles indicate the fetuses with hydrops. The solid curve indicates the median peak
systolic velocity in the middle cerebral artery, and the dotted curve indicates 1.5
multiples of the median.
Amniocentesis
Bilirubin level: measured by spectrophotometrically measuring absorbance at the 450-nm wavelength in a specimen of amniotic fluid that has been shielded from light ---- Liley curve
Fetal genotyping– For RhE, Rhe, RhC, Rhc, Kell ,and Cellano (k) the
parents' DNA should be tested concurrently
Cytogenetic testing to screen for congenital disease
The Liley Curve
Amniotic fluid bilirubin level (log), vs weeks of pregancy
Zone 1: low risk
Zone 2: intermediate
risk
Zone 3: high risk
Umbilical Cord Blood Sampling
Direct measurement of fetal blood bilirubin
and hemoglobin level
Fetal RBC phenotyping
Technique can be used for fetal blood
transfusion or exchange
More complications
Hemoglobin Concentrations in 265 Normal Fetuses and 111 Fetuses That
Underwent Cordocentesis
Previously Affected Pregnancy
For patients with a previously affected
pregnancy, the timing of the initial procedure
(serial amniocentesis) is determined by past
clinical history. It is usually performed at
least 4-8 weeks earlier than the prior
gestational age at which significant
morbidity occurred.
In women with extremely high titers ( > 256), at
less than 28 weeks, where the fetus does not
demonstrate hydrops, and there is a documented
history of fetal death due to hydrops ---- IVIG
might be offered. The dose is 400 mg/kg per day
for 5 days, with repeat infusions every 15 to 21
days. Specific contraindications to intravenous
immunoglobulin use include a previous episode of
IVIG-induced anaphylaxis (rare) and selective IgA
deficiency.
Symptoms of HDN During pregnancy:
Mild anemia, hyperbilirubinemia, and jaundice
Severe anemia with enlargement of the liver and spleen
Hydrops fetalis - The heart begins to fail due to severe anemia and large amounts of fluid build up in the tissues and organs, at great risk of being stillborn.
After birth:
Severe hyperbilirubinemia and jaundice
Kernicterus - the most severe form of hyperbilirubinemia and results from the buildup of bilirubin in the brain. This can cause seizures, brain damage, deafness and death.
Diagnosis
Mother’s blood: RBC antibodies
Doppler Ultrasound - to detect organ enlargement or fluid buildup in the fetus.
Amniocentesis - to measure the amount of bilirubin in the amniotic fluid.
Fetal umbilical cord blood: antibodies, bilirubin, and anemia
Newborn: umbilical cord blood for blood group, red blood cell count and antibodies, newborn peripheral blood testing for bilirubin levels.
Treatment
During pregnancy:
– Intrauterine blood transfusion of red blood cells, into the
abdominal cavity of the fetus or directly into the umbilical
cord vein
– Early delivery if the fetus develops complications -prevent
worsening of HDN.
After birth:
– Blood transfusions (for severe anemia).
– Phototherapy
– Intravenous fluids (for low blood pressure).
– Help for respiratory distress using oxygen or a mechanical
ventilation
– Exchange transfusion
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