Autoimmune hemolytic disease during pregnancy

Autoimmune DAVID

A.

LAWRENCE CAGE B~ll~Zow~.

hemolytic disease during pregnancy

SACKS, D.

M.D. PLATT.

S. JOHNSON, and

M.D. M.D.

Los A~~~P/P.~, Califortlin

Since autoimmune hemolysis is potentially dangerous to both mother and fetus, detection of it should prompt a search for underlying systemic autoimmune disease, neoplasm, or infection. The severity of maternal anemia and the time of appearance of antibodies do not necessarily correlate with neonatal outcome. Management should include identification of the antibody by class and specificity, serial indices of maternal hemolysis, amniocentesis, and ultrasonographic examinations. (AM. J. OBSTET. GYNECOL. 140:942, 1981.)

AUTOIMMUNE hemolytic anemia is not unusual during the reproductive years. The disease is characterized by the development by the patient of antibodies to her own red cell antigens. Antibodies may belong to different immunoglobulin classes. Only those of class IgG are known to cross the placenta, and subclasses IgG, and IgG, cross best. Thus, when a pregnant woman develops IgG autoantibodies, the condition is potentially dangerous to both the mother and fetus. The clinical implications go beyond the obvious threat of maternal and fetal hemolysis. Because of the possibility of underlying autoimmune disease, neoplasm, or infection, a search for these entities must be undertaken. From the Division vf Maternal-Fetal Medic&, Department of Obstetrics and Gynecology, Kaiser Foundation Hospital; the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Southern California School of Medicine and Women’s Hospital, Los Angeles CountylUSC Medical Center; and the Divisaon of Hematology, Department of’ Medicine, University of Southern CaliJornia School qf Medicine. Received for publication Accepted March

January

22, 1981.

2, 1981.

Reprint requests: David A. Sacks, M.D., Kaiser Foundation Hospital, 9400 East Rosecrans Ave.. Bel&ourer, California 90706.

942

Diagnosis of autoimmune hemolysis requires the identification of the same antibodies attached to the patient’s erythrocytes (direct Coombs test) and in the serum (indirect Coombs test). To date, only a felt well-documented cases of‘autoimmunity \vith antierythrocyte antibodies in pregnancy have been reported. The purpose of the present report is to discuss the serology, etiology, and clinical implications of autoimmune hemolytic anemia during pregnancy and to propose a plan of management in patients with this problem.

Case report A YG-year-old woman, gravida 2, para 1, was referred to the Division of Maternal-Fetal Medicine, Kaiser Foundation Hospital, for evaluation of positive direct and indirect antiglobulin (Coombs) tests. The pregnancy was also complicated by Class B diabetes mellitus, which was diagnosed during this pregnancy. During a pregnancy 1 year earlier, the patient’s antibody screen had been negative. The direct Coombs test was positive with anti-IgG sera. No reactions were seen with anticomplement serum. A Landsteiner heat eluate from the patient’s cells reacted strongly with an albumin-suspended panel, including the rare D- and Rhnw cells.’ The patient’s serum was tested with a battery of saline-suspended cells each lacking an antigen 000%9378/81/160942+05$00.50/O

0

1981

The

C. V. Mosby

Co.

Volume Number

140 8

Autoimmune hemolytic disease during pregnancy

Table I. Serial laboratory

values during

pregnancy

White blood cell PlateletsI countlcu mm cu mm 32 34 35 36 37

13 13.4 13.6 13.4

9,200 9,400 9,500 8,800

273,000 298,000 283,000 244,000

943

Reticulocytes Direct Coombs f%) 2.9 2.3 3.3 1.4

of high frequency in the random population. All cells were incompatible with the serum. These findings were compatible with IgG autoantibodies to either multiple red cell antigens or a “public” antigen present on virtually all red blood cells. The patient denied any intake of drugs other than prenatal vitamins and iron. On examination, there was no hepatosplenomegaly, and no palpable cervical, supraclavicular, axillary, or inguinal lymphadenoapathy. Tests for antinuclear antibodies and rheumatoid factor were both negative. A bone marrow biopsy was unsuccessful because of limitations imposed by the patient’s obesity (350 Ibs). Serial hemoglobin, platelet, and reticulocyte counts, antiglobulin (Coombs) tests, haptoglobin, and bilirubin showed no marked changes as pregnancy advanced (Table I). Biweekly nonstress tests and daily determinations of urinary estriol begun at 34 weeks (time of referral) remained normal. Because of the presence of IgG antibodies and the possibility of fetal hemolysis, amniocenteses were performed at 34,35, and 37 weeks. Optical densities at 450 mu were 0.035, 0.012, 0.012, respectively. These fell within the low zone of the Liley2 graph. Ultrasonography revealed no evidence of fetal hemolytic disease. Specifically, no fetal hepatic enlargement, ascites, or scalp edema were found. Normal amounts of amniotic fluid were seen. A lecithin/sphingomyelin (L/S) ratio at 37 weeks was 2.8, and labor was induced at 38 weeks’ gestation. After an uneventful labor with no fetal heart rate abnormalities, the patient was delivered of a female infant who weighed 3,500 gm and had Apgar scores of 8 at 1 minute and 9 at 5 minutes. The placenta was grossly normal. Microscopic examination showed mild villous capillary dilatation, with no erythroblasts seen in the capillaries. The immediate postpartum course was unremarkable. Five months post partum, both direct and indirect Coombs tests were negative. Physical examination of the neonate gave normal findings. No hepatosplenomegaly was noticed. The baby’s blood type was B positive, as was the mother’s. Cord blood bilirubin was 1.5 mg/ 100 ml; the hematocrit was 51%, with a reticulocyte count of 3.4%. Both direct and indirect Coombs tests were positive. An eluate of the baby’s cells agglutinated all cells in com-

Optical Bilkbin Density (m~l100 ml) at 450 mu LIS ratio

;;A.;;1HJ$$

4+

3+

3+ 2+ 2+

1+ 1+ 1+

158 101 87 95

0.3 0.3

0.035 0.012

1.3 1.2

0.012

2.8

mercial test panels.* Therefore, the belief was that these antibodies were attributable to maternal passage. At 5 weeks of age, the baby’s direct antiglobulin (Coombs) test was still positive, and the hemoglobin was 12.5 gm/lOO ml. At 8 months of age, both direct and indirect Coombs tests were negative.

Comment The diagnosis of autoimmune hemolytic anemia (AIHA) rests on the demonstration that antibodies directed against red cell surface antigens have been attached in vivo. In practice, this is detected by a positive direct antiglobulin (Coombs) test. The antibody can be further identified by immunoglobulin class, and by specificity for red cell antigens. Most autoantibodies detected at 37” C (warm type) belong to the IgG class.” Antibodies detected at 4” C (cold type) are most often IgM-’ and are less often the cause of autoimmune hemolysis.” Of those cases reported in pregnancy, some have both cold and warm antibodies,“. 12. I’ warm antibodies alone,‘. 8. lo. ‘I and cold antibodies alone.‘fi-‘X The latter would seemingly pose no threat to the fetus, since the IgM molecule is too large to cross the placenta. However, some IgG molecules are detectable only at temperatures below 10” C, probably because of a temperature-dependent configurational change of the molecule on the cell membrane.s This mechanism may have been operating in the case reported by Grislain and associates” when cold antibodies were detected in both maternal and fetal circulations. Patients with AIHA may form either a single antibody to a public antigen or a mixture of antibodies to several red cell antigens. I. ’ The mechanism of formation of multiple antibodies is unclear. However, regardless of origin, the presence of these antibodies in AIHA makes unlikely the possibility of finding compatible cells for transfusion. *Selectogen Jersey.

I and

II,

Ortho

Diagnostics,

Raritan,

New

944

Sacks,

Table

Platt, and Johnson

II. Reported

cases of autoimmune

Author

Case No.

hemolysis

Week at detection of antibodies

Chaplin et al.” Baumann and Rubin’ Burt and Prichard’”

1 2 3

Kageyama et al.”

4 5* 6 7 8

“4th month” NR NR

9t 10 11

9 24

Jain et al.” Lens and Kredenster* Wirtheimer13 Vanhaeverbeek

et aLi

16

Ei

12

i;

Zara and Bolis’”

13

“7th month” “9th month” “4 % month”

G&lain

et a1.17

15

Lowest maternal hemoglobin (gmi100 ml)

15 37

de Groot15

14

in pregnancy

10.0 3.0 4.3 NR NR 7.0 4.0 7.0 12.0 21% 6.4 3.2 8.0

Lowest neonatal hemoglobin @n/l00 ml) 9.4 9.7

Highest neonatal bilirubin (mgllO0 ml)

11.1

8.5 13.2 27.0

NR NR NR

NR NR NR

NR NR

NR NR

“Normal” NR 14.7 NR NR

“Normal” NR 13.5 NR NR

Neonatal

outcome

Live-born

Live-born I.ive-born (2 exchanges) Stillborn

Live-born Live-born Neonatal

death

E:rythroblastotic stillborn Live-born Stillborn Live-born live-born Live-born I .ive-born,

9.0 NR

NR

NR

NR

NR

twins Neonatal death

4.7

NR

NR

Stillborn

(2 exchanges)

Quinlivan and Goldberg’*

16

14

NR = Not reported. *Same patient as Case 4. Same patient as Case 8. AIHA has been reported in association with a variety ot’ clinical conditions, including such neoplastic disorders as chronic lymphocytic leukemia, malignant lymphoma, and ovarian teratomas. It has been reported accompanying and following acute episodes of both infectious mononucleosis and mycoplasma pneumonia. Warm antibodies have also been reported with collagen vascular disease and with certain drugs.” It is of interest that both diabetes mellitus and autoimmune hemolytic disease were first detected within weeks of each other in our patient. An 1gG islet-cell antibody has been isolated early in the course of insulin-dependent diabetes mellitus. In addition, diabetes mellitus has been reported in association with a variety of autoimmune endocrinopathies.‘” Therefore, it seems possible that, in selected instances, diabetes mellitus and AIHA may be causally linked. It is tempting to speculate on the relationship between pregnancy and autoimmunity. Chaplin and associates” suggested that paternal antigens on fetal cells which cross to the maternal circulation stimulate maternal autosensitized immune-competent cells. The disappearance of autoantibodies after delivery in the present case and in those reported by others’. I’. IBsupports this hypothesis. However, the disappearance of antibodies during the third trimester in the case reported by Letts and Kredenster” raises doubts in regal-d to its universality. The detection of autoantibodies is not predictive of the severity of hemolysis. Hemolytic anemia is accom-

panied by signs of increased red cell dcsuuction (e.g., increased serum bilirubin, decreased haptoglobin) and accelerated red cell production (e.g., reticulocytosis). Although these values may be altered by pregnant-y, there is little to suggest active hemolysis in our patient (Table I). The observed slight elevation of reticuloqte levels may be explained by a low-grade. compctlsated hemolysis. However, such levels are seen in normal pregnant women from the fifth through nimh months.“” The reasons for this apparent lack of red cell destruction are conjectural. Of the four IgG molecules. subclasses IgG, and IgG, are most efficient in binding to macrophages. Furthermore, IgG, and Ig& most efficiently activate complement.“’ Thuh. a hemolytit anemia in which the IgG molecules are predominanrl> of subclasses 2 and 4 may have a more benign course. Alternatively, as suggested by MacKenzie.!’ the densit) of antigenic sites and/or avidity of antibody for antigen may have been insufficient to achieve the threshold necessary for active hemolysis. A major concern in pregnancy is the possibility ot severe fetal hemolysis being induced by maternal IgG autoantibodies. Baumann and Rubin’ have suggested that good fetal outcome correlates with either the lateness of appearance of the antibodies or with the efl’ectiveness of treatment. Chaplin and associates” and Jain and associates’2 suggest that fetal death is a reflection ot the severity of maternal anemia and/or illness. However, a review of published cases shows no clear relationship between the severity of maternal anemia 01

Volume Number

140 8

the time of appearance of antibodies during the course of pregnancy and neonatal outcome (Table II). Three of four perinatal deaths (where maternal hemoglobin was reported) were associated with a hemoglobin less than 5 gm/lOO ml. However, of six women whose hemoglobin fell below 5 gmiml, three were delivered of surviving neonates. Furthermore, in Case 8, maternal hemoglobin was controlled between 7 and 9 gm/lOO ml, and yet the neonate was an erythroblastotic stillborn. Therefore, it seems possible that maternal and fetal hemolysis may proceed at different rates. A similar relationship has been reported in autoimmune thrombocytopenic purpura.” From these observations, a plan of management for the patient with antierythrocyte antibodies in pregnancy is suggested (Fig. 1). All patients should have their blood typed and screened for antibodies. If the indirect antiglobulin (Coombs) test is positive and the direct antiglobulin (Coombs) test is negative, the patient should be followed for isoimmunization. If both direct and indirect antiglobulin (Coombs) tests are positive, and the class and, if possible, subclass of antibody should be identified. In all cases, evidence of mycoplasma or mononucleosis infection should be sought. A history of recent ux of drugs should be obtained. Bone marrow biopsy for leukemia or lymphoma should be considered. Indices of accelerated red cell production and destruction should be followed serially. If the patient has IgG antibody, tests for autoimmune disease should be performed. Because of the risk of fetal hemolysis, serial ultrasonographic examination of the fetu?‘l and analysis of amniotic Huid should be performed. Tests of fetal well-being, e.g., antepartum biophysical testing, may also be appropriate. Prior to scheduled delivery, the laboratory should be allowed

REFERENCES

1. Vos, G. H., Petz, L. D., and Fudenberg, H. H.: Specificity and immunoglobulin characteristics of autoantibodies in acquired hemolytic anemia, J. Immunol. 106: 1172, 1971. 2. Liley, A. W.: Liquor amnii analysis in management of pregnancy complicated by rhesus sensitization, AM. J. OBSTET. GYNEC~L. 82: 1359, 1961. 3. Dacie, J. V., and Worlledge, S. M.: Autoimmune hemolytic anemias, Prog. Hematol. 6:82, 1969. 4. Dausset, J., and Colombani, J.: The serology and the prognosis of 128 cases of autoimmune hemolytic anemia, Blood 14: 1280, 1959. 5. Gell, P. G. H., Coombs, R. R. A., and Lachmann, P. J.: Clinical Aspects of Immunology, ed. 3, Oxford, 1975, Blackwell Scientific Pub., pp. 1149. 6. Chaplin, H., Cohen, R., Bloomberg, G., et al.: Pregnancy and idiopathic autoimmune haemolytic anemia: A prospective study during 6 months gestation and 3 months post partum, Br. J. Haematol. 24:219, 1973.

Autoimmune

1. 2.

hemolytic

T Blood Type: ABO Indirect Coombs

disease during pregnancy

and

Rh

tl T

mbstetric

Care

‘“““i”““““\ jFzziq 1. 2. 3.

[Negative]

History of drugs, viral diseasa. neopkm Bone marrow biopsy Serial hemoglobin, platelets. haptoglobin. bilirubin ldentiflcation

1. 2. 3.

of abtibodies

for isoimmunization

reticulocytes. by cla:s

Serial amniotic fluid O.D.; Fetal maturity studies Serial fetal ultrasonographic examination Tests of fetal Fell-being [4[

Cord blood hemoglobin. bilirubin

Management

Dellvery

antibody identific&ion. reticulocytes. haptoglobin.

Fig. 1. Management

at term

1

-Moiher to continue Hematology follow-up

of autoimmunity

in pregnancy.

ample time to attempt to locate the least incompatible blood. Blood should be available for neonatal exchange, if that proves to be necessary. The close collaboration of obstetrician and hematologist is necessary during pregnancy. After delivery, the patient should be observed closely by the latter for potential exacerbations of the AIHA. Because it is theoretically possible for the neonate to develop its own autoantibodies, cord blood antibodies should be identified and their similarity to maternal antibodies tested. The neonate should be monitored serially for hemolysis and for persistence of antibodies.

7. Baumann, R., and Rubin, H.: Autoimmune hemolytic anemia during pregnancy with hemolytic disease in the newborn, Blood 41:293, 1973. 8. Letts, H. W., and Kredentser, B.: Thrombocytopenia, hemolytic anemia, and two pregnancies, Am. J. Clin. Pathol. 49:481, 1968. 9. MacKtnzie, M. R.: Disorders of immunohaematology in pregnancy, Clin. Haematol. 2:515, 1973. 10. Burt, R. L., and Prichard, R. W.: Acquired hemolytic anemia in pregnancy, Obstet. Gynecol. 10:444, 1957. 11. Kagyama, T., Iwakoshi, K., Tsumoto, S., et al.: A case of autoimmune hemolytic anemia in pregnancy and delivery, Bull. Osaka Med. Sch. 21:140, 1975. 12. Jain, S., Agarwal, S., Dash, S. C., et al.: A case of autoimmune hemolytic anemia and foetal loss, J. Assoc. Physicians India 25:765, 1977. 13. Wirtheimer, C.: Grossesse et anemie hemolytique, Brux. Med. 37:539, 1957. 14. Vanhaeverbeek, M., Delvoye, P., Gausset. P., et al.:

946

15. 16.

17.

1X.

Sacks,

Platt,

and Johnson

Anemie hemolytique auto-immune au tours de la grossesse. I. Gvnecol. Obstet. Biol. Reorod. (Paris) 4:22i. 1971. ” de<;root, A. CZ;.: Ken Zwangere met hemolytiche anemia, Ned. Tiidschr. Verloskd. Gvnaecol. 69:2X:%. 1969. /.ara, C.‘:and Bolis, P. F.: Anemia emolitica da anticorpi in gravidanra. Ann. Ostet. Ginecol. Med. Perinat. 93:468, 1972. Grislain, J. R., Mainard, R., and de Berranger. I’.: Icte~-e hemolytiqur neonatale pal- anticorps l’roids d’origine maternelle, Arch. Fr. Pediatr. 20:X53. lYti3. Quinlivan. W. L. G., and Goldberg, S.: Autoimmune hemolytic anemia of the cold antibody type associated with pregnancy, AM. J. OBSTET. GYNECOL. 98:I 102, 1967.

.hqplst 15, 19x1 .41n. J. Obstet. Gynerol.

19.