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British

Journal o

Haernatology, 1973, 24 219.

Pregnancy and Idiopathic Autoimmune Haemolytic

Anaemia : A Prospective Study during 6 Months Gestation

and 3 Months Post-Partum

HUGH

CHAPLIN,

R,

ROBERT OHEN, ORDONLOOMBERG,AROLD

.

KAPLAN,

Departments o Preventive Medicine and Medicine (Division o Hematology), Obstetrics and

Gynecology, Pediatrics, and Barnes Hospital Blood Bank , Washington University School $Medicine,

St L ouis, Missouri

J O Y A. MOOREND IRENE DORNER

(Received 8 June

1972;

accepted f o r publication August

1972)

SUMMARY.31-yr-old woman with a 12 yr history of relapsing idiopathic auto-

immune haemolytic anaemia was studied prospectively during her first pregnancy.

Her serum contained

a

warm incomplete autoantibody

as

well

as

an elevated cold

agglutinin; her red blood cells were strongly coated with IgG and complement

(chiefly

a2D).

Haemolysis was active throughout pregnancy, accelerating from the

34th

to 40th week, with developing thrombocytopenia. Amniocentesis in the 8th

and 9th months suggested minimal foetal haemolysis. The maternal haemolytic pro-

cess went into complete clinical remission following delivery of a healthy appearing

infant whose red cells were coated with IgG. The infant developed mild hyperbili-

rubinaemia within 48 hr and experienced a fall in haemoglobin to

50

of the cord

level by the

8th

week. Abnormalities of maternal and infant C4 levels were ob-

served. Review of 19 reported instances of presumed autoimmune haemolysis

during pregnancy revealed life-threatening anaemia in nearly

50

of mothers,

with four still-births, one neonatal death, and three seriously affected infants. A

programme for prospective management of this serious clinical problem is discussed.

Acquired autoimmune haemolytic anaemia (AIHA)

is

not a rare haematologic disorder;

20-30

patients with this illness are treated annually at the Washington University Medical

Center. Approximately 30 of our cases are ‘idiopathic’; of these, one-fourth occur in

women in the child-bearing second to fifth decades (Allgood& Chaplin, 1967). It is surprising,

therefore, that a search of the literature for the past

5 0

years reveals only 19 reports of preg-

nancy in patients with presumed AIHA. Among these, seven mothers exhibited a positive

direct antiglobulin test; two of these delivered stillborn infants at 6 months gestation, a third

infant developed severe anaemia requiring transfusions at

2

mth of age. In none of the

reports were the serological findings in mothers and infants characterized in detail or followed

in

a

systematic sequential manner.

Recently, a 31-yr-old patient who had been followed by one of the authors (H.C.) for

Correspondence: Dr Hugh Chaplin, Jr, Department

of

Preventive Medicine, Washington University School of

Medicine,

4566

Scott Ave.,

St

Louis, Missouri

63110,U . S . A .

a19



220 Hugh Chaplin,]r et a1

12 yr with recurring idiopathic AIHA presented in the 3rd month of her first pregnancy.

She was haemolysing actively, with anaemia, marked reticulocytosis, aiid strongly positive

indirect and direct antiglobulin tests (IgG plus complement). She was eager to carry through

the pregnancy and declined

to

consider therapeutic abortion. The patient’s management,

anticipatory measures

to evaluate the condition of the foetus, and sequential studies of

serological aiid haematological findings in the mother and infant form the basis of this report.

MATERIALS AND METHODS

Cas e Presentation

The patient first presented in 1958 a t the age of 19 yr with severe haemolytic anaemia

(PCV

12 ,

reticulocytes 64%, platelet count

105

ooo/yl). The direct antiglobulin reaction

was strongly positive with a broad-spectrum antiserum,

with

only partial neutralization

following the addition of IgG globulin to the antiserum (‘mixed gamma and non-gamma’

reaction). The indirect antiglobulin reaction was also strongly positive, with no apparent

blood group specificity. She responded promptly to high doses ofadrenal corticosteroids, with

restoration

of

all

blood

findings

to

normal, except for persistence

of

the positive

direct

antigIobulin reaction. One month following discharge, haemolysis recurred and again

responded to vigorous steroid administration. One year later, haemolysis again recurred,

this time accompanied by frank thrombocytopenia (platelet count

7000/pl)

; she responded

to

splenectomy and corticosteroids. Examination of the spleen showed no remarkable

pathology. Over the ensuing 9 yr, haemolysis recurred two or three times annually, often

apparently in association with upper respiratory tract infections. Platelet counts ranged from

220 ooo to 680

o o o / ~ l

hroughout this period. She generally responded promptly

to

cortico-

steroid administration; occasionally one or two blood transfusions were required because of

severe anaemia. Tests for

LE

phenomena and more recently for antinuclear antibodies were

always negative. The direct antiglobulin reaction always remained positive, appearing some-

what stronger during haemolytic exacerbations than during remissions.

In January 1971she presented with symptoms of early pregnancy; the date of delivery was

estimated

to be early July. The patient was unaware of the recurrence

of

haemolysis (PCV

30 , reticulocytes 32 ). The direct and indirect antiglobulin tests were strongly positive

and autoagglutination of the patient’s red cells was striking in an EDTA sample a t room

temperature.

Prospective St ud y Protocol

Blood samples werc obtained from the patient a t 2 week intervals until the 8th

ante-

purtifni month, weekly thereafter until the first wcek post-purtunz, and at 2-4 week intervals

for an additional

3

months. Amniocentesis was performed

a t

the beginning

of

the

8th

and

9th months of gestation; urinary estriol excretion

was

obtained weekly in the 9th month.

Infant cord blood was obtained

a t

delivery; additional samples were obtained from the

baby

daily for the next 6 days and a t 2-4 weeks for an additional 3 months.

Laboratory Methods

Whole blood haemoglobin concentration, reticulocyte, white blood cell and platelet



Pregnancy and Idiopathic Autoimmune Huemolytic Anaemia

22

I

counts, serum bilirubin concentration, amniotic fluid creatinine concentration and osmolality

were determined by standard methods. Plasma haemoglobin concentration was determined

by

a

modification of the method described by Lathem Worley (1959). Serum C3 and C4

concentrations were determined by radial diffusion employing antisera rendered specific

for C3 and

C4

by suitable absorption. Maternal IgG was prepared by DEAE chromato-

graphy in 0.0175 M phosphate buffer, 6.4, by the method of Sober Peterson (1958). Eluates

from

well-washed maternal red blood cells were prepared by heating for

10

min

a t

56°C or

by elution from stroma at pH 3.5, as described by Hughes-Jones

et

a2 (1963). Maternal serum

and

red

blood cell eluates were examined for blood-group specificity by the indirect anti-

globulin reaction employing a commercial diagnostic cell panel.* Rh-null, U-negative and

Tja-negative test cells were obtained from supplies stored frozen in glycerol and processed

immediately prior to their use. Direct antiglobulin tests were carried out on an opaque

glass

tile employing equal volumes

of

ten serial dilutions

of

antiglobulin serum mixed with a

5 suspension of three-washed red cells. The plate was rocked gently at room temperature

for

5 min; reactions were graded by visual inspection. Anti-C3 (BIA) serum was obtained

from a commercial source.? The broad-spectrum, anti-IgG, anti-cq, and anti-Cj(crzD)

sera were prepared in the authors’ laboratory. All antisera were freed of species agglutinins

by repeated absorption with 10-times-washed normal human Al

,

B and 0 red blood cells;

specificity

was assessed by immunoelectrophoresis against fresh or aged human serum after

appropriate absorption with contaminating serum components. Neutralization of the broad-

spectrum antiserum was accomplished by addition of an equal volume of 0 1 IgG. Amniotic

fluid

pigment determinations were made as described by Liley (1961). Sphingomyelinl

lecithin

ratios in amniotic fluid were determined as reported

by

Gluck

et a1

(1971). Urinary

estriol was measured by the method of Huang (1968).

RESULTS

Muternal

Ante-Partum Course

Direct antiglobulin reactions. Strong reactions were observed with an antiserum specific

for the Fc portion of the IgG molecule, and with an antiserum which gave a moderately

strong precipitin reaction with the ctzD component of C3. The red cells failed to react with

serum specific for the / ~ I Aomponent of

C3

and with a serum specific for C4. The strength

of the positive direct antiglobulin reactions of the mother’s red blood cells on repeated

testing did not change throughout pregnancy and for 6 mth

post-purtum,

despite considerable

fluctuation in the rate of

in-vivo

haemolysis as judged by other haematological findings.

Activity o maternal in-vivo autohaemolysis. Selected haematologic parameters in relation

to prednisone therapy are illustrated in

Fig

I . When the mother first came under observation,

haemolysis was brisk

as

judged by

a

reticulocytosis of

32

and

a

whole blood haemoglobin

concentration of 10.0 g/Ioo ml. The total nucleated cell count was

3 0

800/~1;lood smear

revealed 14 normoblasts per IOO white blood cells, numerous spherocytes, occasional red-

cell inclusions, moderate anisocytosis, poikilocytosis and polychromasia. The plasma haemo-

globin-binding capacity (haptoglobin) was less than 5 mg/100 ml. The patient responded

* DATA-CYTER and SEARCH-CYTER, Dade Reagents, Div.

Am.

Hosp. Supply Corp., Miami, Fla.

Hyland, Div. Travenol Laboratories, Inc., Costa Mesa, Calif.



222 Hugh C h a p l i n , ] ~ t a1

promptly to 40 mg of prednisone daily, with a rise in haemoglobin concentration, fall in

reticulocytes and elevation in plasma haemoglobin-binding capacity to 50 mg/

100 ml.

Reduction of prednisone dosage to 10mglday was followed by increasing haemolysis, with

recurrence of reticulocytosis, falling haemoglobin concentrations and disappearance

of

haptoglobin. Evidence

of

haemolysis persisted throughout the pregnancy but anaemia

was well controlled until the 8th month by frequent adjustment of prednisone dosage in the

14

10

24

0 447

I10

0

40 --

Nucleated

RBC/100

WBC

Delivery

Feb March pril

May June July

ug Sept Oct

FIG I . Haematological findings

in

mother

10-1 mg/day range. Acceleration of autoimmune activity was evident in the final 6 weeks,

with an associated progressive decline in the platelet count from 250

ooo

to a low of 120 ooo/~l,

a

fall

in haemoglobin concentration to 10.7/100 ml,

a

rise in reticulocytes

to

22% and the

reappearance

of

nucleated red blood cells on the peripheral smear. Further deterioration of

the above parameters was halted by increasing the prednisone

to

20

mg/day in the

10

ays

prior to delivery. Throughout the patient's entire course, the total serum bilirubin concentra-

tion fluctuated in the range of 0.4-1.4

m g / ~ o o

l, the conjugated fraction in the range of

0.1-0.5

mg/Ioo ml.

Maternal

coniplemmt kcvcls. As measured by radial diffusion, serum

C3

remained normal

throughout pregnancy, wi th valucs in the range 98-137 nig/roo nil. C4 levels were consist-

ently depressed in the range of 4 7 nig/roo nil, as compared with a mean concentration

of



Pregnancy and Idiopathic Auto imm une Haem olytic Anae mia

223

immediate port-partum sera of 34.4 mg/Ioo ml (12 normal mothers, rangc 19.3-63.8 mg/Ioo

ml)

; the

small fluctuations had no apparent relationship

to

activity

of

the haemolytic process.

Autoantibody activity in sera and eluates. A cold agglutinin titre obtained

8

mth prior to

conception was 1/16 (normal in this laboratory up to 1/40). Throughout the pregnancy and

for

6

mth post-partum, an elevated titre

of

1/256 was obtained;

the

agglutinin

was

determined

to be an IgM and reacted equally strongly with group adult and cord red cells. A warm-

reactive IgG autoantibody was regularly demoiistrablc in maternal sera and in eluates from

maternal cells throughout pregnancy and for 6 mth post-partum. There was an apparent rise

in titre of serum antibody from 1/8 to 1/64 as the pregnancy progressed; however, the sera

were

all

titrated together 6 mth post-partum and the weaker reactions in the earlier sera could

possibly reflect instability of autoantibody during frozen storage at 2ooC.The sera and

eluates were tested against a diagnostic red cell panel aiid coated all cells, including Rh-null,

Amniotic fluid

O.D. 450

nm

Creatinine (mg/Ioo ml)

Lecithin/sphingomy elin

Maternal urinary oestriol

(%/24 hr)

TABLE

.

Predictive ante-partum studies (full-term delivery, 9 July 1971)

12 May

16

June 23 Jcme 28June 3 J u l y

0.047 0.037

1.4 2.8

0.64 4.25

10.9 22.9 17.3 19.0

U-negative, and Tj”-negative cells. The eluates demonstrated no specificity. Slightly stronger

serum indirect antiglobulin reactions were observed with some cells than

with

others, suggest-

ing anti-Kell plus anti-rh”(E) specificity. The patient’s red cells were rh”(E) and Kell negative;

her husband’s red cells were rh”(E) negative and Kcll positive. The infant’s red cells were

subsequently shown to be rh”(E) aiid Kell negative.

Predictive

ante-partum

studies.

The results of studies designed to predict the severity of

foetal haemolysis, the risks of complicating hyaline membrane disease in the event of pre-

mature delivery,

aiid

general evidence of foetal distress are summarized in Table I. The

amniotic fluid piginelit levels were in the lower midzoiie area a t the beginning of the 8th

and 9th months, consistent with either a normal foetus or one afflicted with mild haeinolytic

dqsease. Amniotic fluid crcatiiiiiie levels were consistent

with

the predicted gestational agc

of the foetus. Th e lecithin/sphingomyeliii ratio in the 9th month was in the high ‘mature’

range. Urinary estriol levels were not indicative

of

foetal distress.

Mdternal Post-Partuni Coiirsc

The expected date of delivery w a s in the first week of July. Spontaneous labour did not

occur. The foetal size

was

coiisisteiit with 40 weeks gestation

aiid

pelviiiictry revealcd outlet

narrowing by marked aiitcrior angulation of the coccyx. I11 light of these obstetrical con-

siderations and the evidence of accelerated maternal autoimmune activity, labour w a s



224

Hugh Chaplin,J r et a1

induced on 9 July and proceeded uneventfully to the forceps-assisted delivery of a normal-

appearing female infant. Maternal blood loss was estimated a t approximately 500 ml.

Serologic jndings. Although the patient’s haemolytic process went progressively into

remission from the time of delivery, the direct antiglobulin reactions showed very

little

change over the 3-6 mth post-parturn, the only alteration being slightly diminished reactions

with the anti-C3(azD) serum. The titres of circulating warm and cold autoantibodies and

the serum concentrations of

C3

and C4 remained unchanged.

Ac ti vi ty of‘rnaternal in vivoautohaemolysis.It

is

evident from Fig I that the haemolytic process

subsided following delivery. Nucleated red blood cells disappeared from the blood smear

and the platelet count rose promptly from

180

ooo to approximately 450 ooo/pl. The f ll

in haemoglobin concentrations from I I . ~ / I O Ol I day ante-parturn to 10.4 and IO.I/IOO ml

on days

3

and post-parturn

is

accountable by blood loss at delivery. Thereafter, haemoglobin

concentrations rose progressively to normal and reticulocytes fell to normal as the dose of

steroids was tapered and discontinued. At the time of writing (6 mth post-parturn), the

patient

remains in complete clinical remission

off

steroids.

Infant’s Cord Blood Findings and Clinical Course

The infant appeared clinically normal a t delivery: birth weight 3160

g,

length 52 cm,

skin colour pink, ‘no aundice, no oedema,

no

abnormal neurological findings. Cord blood

haematological values were within normal limits (haemoglobin 18.4 g/Ioo ml, PCV

60 ,

total nucleated cell count 17 3001~1 ,reticulocytes 6.5%, nucleated red blood cells

9

per IOO

WBC, platelets 200 ooo/~l) .Cord serum bilirubin concentration was 2.8 mg/Ioo

ml.

Detailed antiglobulin testing revealed relatively weak red blood cell sensitization, account-

able entirely by the presence of IgG on the infant’s cells. These findings are in contrast

to the much stronger sensitization of the mother’s red cells by IgG, accompanied by the

a2D component of C3. Free autoantibody was demonstrable in the cord serum at a titre

of

118

and could be eluted from the cord red cells. Neither serum nor eluate demonstrated

blood group specificity. Comparison of the infant’s red-cell phenotype with the mother’s

revealed none of the incompatibilities commonly responsible for isoimmune haemolytic

disease of the newborn. Cord serum C3 concentration was normal (105 mg/roo ml);

the C4 concentration of 14 mg/roo ml was significantly below the adult normal range

but was more than twice the level found in the majority of the mother’s samples.

C4 levels in cord sera from 10 normal full-term infants averaged 28.6 mg/Ioo ml (range

During the first 36 hr of life, the infant’s serum bilirubin concentration rose from 2.8

to

8.5 mgiroo ml. Fluorescent

light

treatment was instituted and continued for

7 2 hr.

Reticulocytes rose to

9.1

on the 3rd day but fell to normal by the 6th

day.

Otherwise,

the immediate post-natal clinical course was unremarkable. There was no evidence of

an

effect of the maternal steroid therapy.

Haematological and serologic changes during the first 3 mth o f life are illustrated in Fig 2

Although whole blood haemoglobin values had been within the normal range during

the

first week of life, subsequent values were somewhat lower than expected, with a nadir of

9.4/1oo ml on the 56th day. At this point, despite persistently normal MCHC values, oral

iron administration was begun as

a

precautionary measure. Coating of the infant’s red blood

22-3 5 ) .



Pregnancy and Idiopathic Autoim mun e Huemolytic Anaem ia

22

cells by IgG,

as

demonstrable by the direct antiglobulin test, diminished slowly over the

first

z mth, becoming barely detectable by day 70 and negative by day 110. Serum C3

levels showed a modest decline (to 72 mg/roo ml) over the 3 mth interval; C4 levels rose to

21-27 mg/roo

ml during the first 2 weeks, but then declined to values slightly below

that

of

c

0

20

40

€

80

100

Days from

birth

FIG

2

Haematological findings in infant.

the cord serum. Clinically, the infant progressed satisfactorily, nursed well, gained weight,

and

developed normally.

DISCUSSION

Previous

Reports o f AIHA in Pregnancy

Assessment of reports of AIHA in pregnancy published over the past 5 yr

is

di&cult,

particularly for the

1920-45

pre-antiglobulin test era, because evidence for the autoimmune

basis of haemolysis

is

often incomplete. We have assembled 19 pregnancies occurring in 16

mothers, requiring in each instance that there be unequivocal evidence for acquired haemolysis

nd wherever possible serologic confirmation of autoimmunity or evidence of a response to

corticosteroid therapy (Bateman

et

a l 1959; Bromberg

et

a l 1948; Burt Prichard, 1957;

Craig

Turner,

1955;

Frumin

et al,

1953;

Jankelowitz

et

a l

1960;

Mallarm6

et

a ,

1965;

Osler,

1919; Priofsky, 1969; Quinlivan Goldberg, 1967; Seip, 1960; Soderhjelm, 1959;

Swisher,

1966;

Wagner Maresch,

1955;

Wirtheimer,

1956;

Witts Manch,

1932).

Direct antig fobul in reactions. The direct antiglobulin test on maternal red cells was positive

in

seven, negative

in

five and not performed in seven. Four of the five mothers with negative

direct antiglobulin reactions showed at least some abatement of haemolysis

in

response to

corticosteroids the fifth mother did not receive corticosteroids. In seven pregnancies in



226

Hugh Chaplin,]r

et a1

which maternal antiglobulin tests were not performed, corticosteroids were not administered;

the patients are included because the clinical course

of

the haemolysis was consistent with

AIHA, but the autoimmune aeeio ogy remains in doubt.

Severity.

The hazard

to

maternal survival was variable but in s o n e instances w a s extremely

serious. Haematologic data were available for

I

8

pregnancies; in nine the haemoglobin

concentration fell below

5 g/Ioo

ml, in eight the values were in the range from to

8

g Ioo

ml, in one the lowest PCV was

3 0 .

Vigorous transfusion therapy, high doses

of

cortico-

steroids and/or early induction of labour were employed as life-saving measures in critically

ill

patients. There was evidence that the autoimmune process may not always have

been

confined to maternal red cells; leucopenia ( WBC less than 5ooo/pl) was recorded in four

pregnancies, thrombocytopenia (platelets less than

I 5

ooo/pl) in three pregnancies. Mild

elevation

of

cold agglutinin titre

was

reported in three instances.

Course

o f

maternal haemolysis

ante-partum

and

post-partum. Autoimmune haemolysis was

known to be present at the time ofconception in four instances; in the remaining

1 5

haemoly-

sis w a s first documented within the first

6

mth in

11

and within the third trimester in the

remaining four. Haemolysis worsened as the pregnancy progressed in

18

of the

19

patients.

Following delivery, complete (eight) or partial (eight) remissions

of

haemolysis occurred

within 3 mth i n

16

patients. Two patients, both of whom were subsequently diagnosed as

having systemic lupus erythematosus

(SLE),

showed no reduction in haemolysis post-partum.

C o d i t i o n o the infant.

Haematological-characterization of the infants was inadequate for

evaluation in

16

of the

19

pregnancies. Four of the

19

pregnancies resulted in delivery of

a

stillborn premature infant, and

a fifth

premature infant died at

48

hr

of

‘bronchopneumonia’.

No hacniatological o r serological studies are reported for any of the five; the inference is

that their appearance did not suggest haemolytic anaemia (pallor, jaundice) or its consequence

(hydrops).

I t is

striking

that all

five deaths occurred in infants born

to

mothers with severe

anaemia

(Hb

lcss than

5

g / ~ o o

il) , suggesting that the foetal demise was more a reflection

of

the nearly moribund maternal state than

a

result of placental transfer of autoantibody with

rcsultaiit autohaemolytic disease of the newborn. This concept

is

supported

by

the inferred

normal condition

of I

I infants wh o survived past

48

hr, despite clear evidence

of

brisk haemo-

lysis

in the mothers during the latter months

of

pregnancy. That placentally transferred auto-

haemolytic disease of the newborn can occur, however,

is

strongly suggested by evidence

of severe post-natal hacmolysis in three surviving infants. In one, anaemia and deep jaundice

developed within

48

hr of delivery and required two exchange transfusions (Burt Prichard,

1957).

The mother and infant were both blood group

A ,

Rh-positive and there was no

evi-

dence

of

maternal isosensitization.

A

second infant became severely anaemic and jaundiced

in

the 4th week of life and apparently respoiided to steroid therapy (Sodcrhjelm,

1959).

The

third infant was noted to be severely anaemic (Hb

2.5/100

nil, reticulocytes 2 2 % ) at 2 mth

of age, with accompanying leucopeilia

(WBC

I

Soo/pl) and required multiple transfusions

(Seip,

1960).

The mother, who

had

systeniiL lupus erythematosus, also exhibited leucopeilia

during prcgnancy. The equivocal (one) and negative (two) antiglobulin reactions reported

in

thesc thrcc infants are unexplained.

Prererrt Prospctivc Study

The mother described in the present rcport pursucd

a

rclatively favourable clinical course.



Pregnancy and Idiopathic Autoimmune Huemolytic Anaemia

227

This almost certainly reflected a milder autoimmune haemolytic process in her case, although

the

close clinical follow-up

(at

I or

2

week intervals) with frequent adjustment of cortico-

steroid dosage may have prevented the development of severe anaemia with its attendant

h z rd to

the

mother and foetus. Evidence for a multiplicity of autoimmune processes was

suggested by the development of a cold agglutinin titre of 1/256 and the progressive fall

in

platelets noted during the 8th and 9th months.

The infant almost certainly exhibited

a

mild, passively transmitted autoimmune haemolytic

syndrome. The amniotic fluid pigment levels are consistent with this interpretation

as

is the

5 7 mg/Ioo ml rise in serum bilirubin concentration on the 2nd day of life (Zeulzer Brown,

1961). Antiglobulin studies revealed IgG on the infant’s red blood cells in diminishing amounts

during

the

first

z mth of life, during which time the haemoglobin concentration fell to 50%

ofthe

level observed during the first 48 hr. In

this

instance, no transfusions or steroid therapy

were

required

and the infant’s generally satisfactory health was such that haemolysis would

likely

have been unsuspected had the haematological follow-up been less rigorous.

Since the mother’s autoantibody was IgG, presumably capable of placental transfer, and

since free autoantibody was demonstrable in maternal serum throughout the pregnancy, it

is

interesting

that

the infant’s red

blood

cells in the cord sample were much less strongly

sensitized than the mother’s. Comparative

in-vitro

titration of maternal IgG (prepared by

DEAE chromatography) against multiple ABO-compatible cord blood cells and against

her own infant’s cells at 3 mth (after the cells became direct antiglobulin negative) revealed

equ lly

strong sensitization of

all

cell samples. Thus, a ‘weak’ or incompletely developed foetal

red cell

antigen does not appear to be

a

likely explanation. More likely, the maternal IgG

autoantibody (like certain Rh antibodies, Hughes-Jones et al, 1971) could not pass the placental

barrier freely and, therefore, was more readily available to maternal than to foetal erythrocytes.

Since i t

is clear from reports in the literature

that

pregnancy in association with AIHA

may provoke life-threatening anaemia in 4030% of mothers and stillbirth or severe post-

partum haemolytic anaemia in

35-40

of their infants, the present prospective study was

designed

so

that

measures could be taken promptly to protect the

health

of the mother

nd

maximize the possibility of a viable infant. The mother was instructed to inform

us

immediately

of increasing pallor, dyspnoea, aundice or dark urine. The frequency of detailed

ante-parturn maternal haematological evaluation (every 2 weeks until the 8th month, weekly

thereafter

until

delivery) enabled frequent adjustment of corticosteroid dosage in an effort

to maintain her haemoglobin level above

10

/Ioo ml and her platelet count above

120

OOO/

~ 1 . e were particularly concerned that the foetus might be experiencing a brisk haemolytic

syndrome in

utero

since the maternal red cells were coated by complement as well as by IgG;

amniocenteses were performed

so

that early induction of labour could be considered if the

findings

suggested severe foetal haemolysis. Recognizing that the haemolytic hazard should

be

weighed against the hazard of pulmonary complications

of

prematurity, the lecithin/

sphingomyelin ratio was determined in the amniotic samples to aid decision in the event that

early induction of labour was indicated. The minimal abnormalities in the amniocentesis

samples were reassuring in

this

instance and encouraged

us

to allow the pregnancy to go to

term despite acceleration of maternal haemolysis and threatening thrombocytopenia in the

9th month.

It

is tempting to speculate on the mechanism of acceleration of autoimmune haemolysis



228

Hugh Chaplin

Y

et a1

by

pregnancy. In essentially all

of

the patients described in the literature, haemolysis

was

manifest by the end of the second trimester and worsened thereafter until delivery of the

foetus. The often expressed view that any ‘stress’ (e.g. pregnancy, infections, surgical

pro-

cedures) will aggravate autoimmune haemolysis

is

too vague

to

illcminate the problem. Preg-

nancy is not invariably associated with worsening of several disease states commonly thought

of as autoimmune. While a proportion

of

patients with systemic lupus erythematosus

(SLE) become worse during the first and second trimesters of pregnancy, exacerbations during

the third trimester are uncommon. Up to

50

of patients with SLE are actually improved

during pregnancy (Dubois,

1966)’

as are the majority

of

patients with rheumatoid arthritis.

An important consideration may be that in AIHA the target cell resides in the circulation and

its foetal counterpart is known to pass across the placenta into the maternal circulation in

increasing numbers as pregnancy progresses (Sullivan Jennings,

1966).

It is possible that

foetal red cells, possessing paternal isoantigens as well as maternal autoantigens, serve as

particular stimulus

to

maternal autosensitized immune-competent cells, increasing their auto-

antibody production as pregnancy progresses much as Rh antibody production accelerates

in the isosensitized mother dur ing the third trimester. The cessation of transplacental foetal

red cell stimulation following delivery could account for the improvement in maternal auto-

haemolysis usually observed post-parttrm. The validity of this hypothesis could be examined

in a patient such as ours if, during a clinical remission, an exacerbation were produced by

frequent injections of small numbers of red cells from her surviving infant. Such a procedure

is precluded by the possibility of isosensitization

to

paternal antigens with its accompanying

hazards for future transfusion therapy.

Although the cause of autohaemolytic exacerbation remains obscure, the potential serious-

ness of pregnancy in autoimmune haemolytic anaemia would appear

to

justify prospective

management along the lines described in the present report. Frequent laboratory evaluation

of all aspects of the immune process employing the most sophisticated methods available

will provide essential guidelines for optimum management of mother and infant and hope-

fully will help to elucidate the pathogenesis of this challenging clinical problem.

ACKNOWLEDGMENTS

The authors are grateful to Dr Louis Gluck (University of California, Sail Diego School of

Medicine) for measuring lecithin and sphingomyelin in the amniotic fluid samples. Thanks

are also expressed to the technicians

of

the Special Hematology Laboratory, Department of

Medicine. Particular appreciation is due to the patient’s primary physician, Dr I. Jerome

Flance,

for

his facilitation and support, and above

all

to the patient, MrsJ.B., who was a model

of enlightened cooperation throughout the clinical investigation.

This work was supported in part by Grant CA 02918 from the National Cancer Institute,

NIH.

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