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Haemolytic disease of the newborn due to anti-K antibodies
GYNE
European Journal of Obstetrics & Gynecology and ReproductiveBiology67 (1996) 69-72
ELSEVIER
Case report
Haemolytic disease of the newborn due to anti-K antibodies Niels de Jonge
a
~a
''
, J o l a n d a E. M a r t e n s b, A l f r e d o L. M i l a n i b, Jos6 L . M . K n j n e n , C e e s v a n K r i m p e n c, G a b r i e l l a A . E , P o n j e e a
C
Department of Clinical Chemistry, Diagnostic Center SSDZ, P.O. Box 5010, 2600 GA Delft, The Netherlands b Department of Gynaecology, Reinier de Graaf Hospital, P.O. Box 5010, 2600 GA Delft, The Netherlands c Department of Pathology, Diagnostic Center SSDZ, P.O. Box 5010, 2600 GA Delft, The Netherlands
Received 8 November 1995; revised 29 February 1996;accepted 6 March 1996
Abstract We describe a case of intrauterine foetal death at 32 weeks gestation with signs of hydrops foetalis without erythroblastosis. The hydrops foetalis appeared to be caused by blood group incompatibility. Irregular antibodies of anti-K specificity were found in the serum of the mother, while the father was positive for the K-antigen. The antibody dependent cell-mediated cytotoxicity (ADCC) test with serum of the mother was positive. This case shows the characteristics of haemolytic disease of the newborn by anti-K. Moreover, it underlines the necessity of both adequate follow-up of individual cases, and screening for irregular antibodies in all pregnancies as well as central registration of screening results. Keywords: Kell; Blood group incompatibility; Irregular antibodies; Hydrops foetalis; Haemolytic disease of the newborn
1. Introduction
2. Case history
We describe a case of intrauterine death at 32 weeks gestational age due to anti-K antibodies. The K-antigen belongs to the Kell blood group system [1]. The pathophysiological mechanism of the K-antibody seems to have another site of attack than the Rhesus antibodies [2]. The described case shows the characteristics of this blood group incompatibility. The consequences for diagnosis and policy in pregnancy with K-antibodies are discussed. In addition, this case underlines the necessity of both an adequate follow-up of individual cases, as well as general screening on irregular antibodies in all pregnant women. Primary prevention of blood group incompatibility, prevention of sensitization of women at fertile age and central registration of the results of such screening are discussed.
A 30-year-old woman was referred to the outpatient clinic after no foetal movements were detected by her midwife. This was her third pregnancy, amenorrhoea 32 2/7 week. Her previous two pregnancies and deliveries were uncomplicated. She had not received any blood transfusion previously. Physical examination showed a normotensive patient, the fundus uteri was half umbilical xyphoid (normal for the amenorrhoea). There were no uterine contractions and foetal heartbeats could not be heard. Ultrasound investigation confirmed the diagnosis of intrauterine foetal death. The foetus was hydropic, e.g. with ascites, subcutaneous oedema and hepatomegaly. Malformations of the foetus could not be seen. The placenta was rather thick and showed no signs of solutio placentae. The possible causes of this intrauterine foetal death were investigated by protocol. After consultation with the patient, delivery was induced with sulproston i.v. (Nalador~). The same day a stillborn boy was born, weight 2270 g, with second grade
* Correspondingauthor, Departmentof Clinical Chemistry,Leyenburg Hospital, P.O. Box 40.551, 2504 LN The Hague, The Netherlands. Tel.: +31 70 3592000; Fax: +31 70 3295046.
0301-2115/96/$15.00 © 1996 ElsevierScienceIreland Ltd. All rights reserved PII: S0301-2115(96)02441-4
70
N. de Jonge et al./ European Journal of Obstetrics & Gynecology and Reproductive Biology 67 (1996) 69-72
maceration and a hydropic aspect. Obduction of the foetus showed a boy with a foot length in conformity with the 32 weeks amenorrhoea, but a weight at the 90th percentile of the Kloosterman Table [3]. Congenital malformations could not be found. The clinical diagnosis of hydrops foetalis was confirmed. Cardiomegaly (heart weight 17.6 g; normally 9.1 ± 4.1 g) with hypertrophy of both ventricles. There was 25 ml dark yellow fluid in the pleural cavity and 50 ml in the abdominal cavity. The liver was extremely large, congested and showed haemosiderosis. The placenta looked very pale and the cotelydones were hydropic. Placental weight without umbilical cord and membranes was 805 g. Although microscopic investigation of the placenta showed some erythroblasts in the foetal capillaries no evident erythroblastosis could be established. A post partum blood sample from mother showed blood type O Rhesus(D) positive and irregular antibodies with Kell specificity. Other laboratory tests showed no abnormalities. The possible blood group incompatibility by anti-Kell was further investigated by an indirect antiglobulin test with serum from the mother. The test had a positive result; titre 512. The ADCC test, also postpartum, showed 45% lysis [4]. Blood retrieved from father showed Kell antigen on the erythrocytes. The father appeared to be heterozygous for the Kantigen, giving a 50% probability for the foetus to be Kpositive. It was concluded that the foetus probably died because of Kell incompatibility. 3. Discussion
Transfer of foetal erythrocytes and thrombocytes to the maternal circulation may lead to an immune response in which maternal antibodies, specific for the foetal erythrocytes or thrombocytes, are produced. These antibodies are of IgG class and can cross the placenta. Immunisation of the mother by erythrocyte antigens belonging to the Rhesus system, Kell, Duffy, Kidd or other (more or less well known) blood group antigens may give rise to foetal anaemia, hydrops foetalis and eventually intrauterine death. The differential diagnosis of hydrops foetalis is very extensive. Two groups of causes must be distinguished: immunological causes and non-immunological causes. The second group includes chromosomal aberrations, congenital abnormalities of the heart and/or lungs, and infections [5]. In this case non-immunological causes could be excluded. The hydrops foetalis in this case appeared to have an immunological cause. Rhesus-incompatibility as a cause for hydrops foetalis could be excluded since the mother was Rhesus(D) positive and no irregular antibodies with specificity to other antigens of the Rhesus system were found (c, C, e, E). However, irregular antibodies with Kspecificity were found in the blood of the mother. These
antibodies can cause hydrops foetalis, if the foetus possesses the K-antigen. The correlation between titre of erythrocyte-antibody and degree of haemolytic disease is poor [6]. The ADCC test is an in vitro test for the biological activity in vivo of the antibody [4]. This test is usually performed ante partum to get an impression of the seriousness of the blood group incompatibility. In contrast to the situation with Rhesus(D) incompatibility, there has been no study of the correlation between the result of the ADCC test and the degree of haemolytic disease of the newborn involving Kantibodies. There is evidence that serious pathology can be found at ADCC-test results >20% (M.A.M. Overbeeke, personal communication).
3.1. K-antibodies
The screening for Rhesus(D) antigens in pregnant women and the concommitant immunoprophylaxis has lead to a considerable decrease of Rhesus(D)sensitization as a cause of the haemolytic disease of the newborn. The incidence of haemolytic disease of the newborn due to Rhesus(D) antibodies has decreased from 3.5% to 0.6% in the Netherlands [7]. Consequently, a relative increase is seen in the frequency of haemolytic disease due to other irregular antibodies [7,8]. The incidence of stillbirths due to anti-K in The Netherlands is not known, but in the United Kingdom it is estimated at about 2 per million births [1]. The relative frequency of K-antibodies compared to that of Rhesus(D) antibodies is 60%. The relative frequency, though, of haemolytic disease of the newborn due to Kantibodies compared to that due to Rhesus-antibodies is 3% [9]. This is explained by the relatively frequent antibody formation after blood transfusion, combined with low frequency of the antigen in the population: 90% is K-negative. The literature is not clear about the degree of the haemolytic disease of the newborn due to anti-K [7,10]. Hydrops foetalis may develop fast, even in Cases where the determination of bilirubin concentration in amniotic fluid appears to indicate mild disease. The number of erythroblasts and reticulocytes in foetal blood may be very low in relation to the haemoglobin concentration of the foetus. A plausible explanation is the disproportional effect of anti-K on erythrocyte precursor cells compared to anti-D. This can lead to anaemia without jaundice. The anaemia is not due to enhanced breakdown of erythrocytes, but rather due to apparently decreased synthesis (Frigoletto in: [1]). This hypothesis was recently confirmed by Vaughan et al. [2]. Suppression of erythroproiesis and not haemolysis was the predominant mechanism of foetal anaemia caused by maternal K-alloimmunisation. In this case, indeed no erythroblastosis of any importance was found.
N. de Jonge et al. /European Journal of Obstetrics & Gynecology and Reproductive Biology 67 (1996) 69-72
3.2. Monitoring of pregnancies complicated by Kell antibodies Once anti-K antibodies are detected in pregnancy and if the father of the unborn child possesses the K-antigen then careful foetal monitoring is indicated. In the case of the presence of Rhesus(D) antibodies, tests are known and available for good policy making. These tests however are only partly useful if anti-K antibodies are present. The anti-K antibody titre is of relatively little value in predicting haemolytic disease of the newborn. Both high and low antibody-titres have been associated with haemolytic disease of the newborn. The correlation between the ADCC test result and the severity of the haemolytic disease in the newborn caused by anti-K antibodies has so far not been sufficiently investigated. The ADCC test is a good guide for further policy making if Rhesus(D) antibodies are present. If the percentage of cytotoxic lysis is >30%, then an amniocentesis is indicated; the amniotic fluid will be spectrophotometrically examined. The difference between the normal and measured optical density at a wavelength of 450 nm is a measure of bilirubin concentration. Liley showed that the measured concentration of bilirubin correlates with the severity of haemolytic disease and pregnancy outcome [11]. Unfortunately there is no good correlation between the Liley index and the severity of the foetal anaemia when Kincompatibility complicates pregnancy [12]. While the anti-K antibody titre, ADCC test and Liley index are not able to predict serious haemolytic disease or foetal hydrops, ultrasound however, can detect hydropic changes as a result of Kell antagonism. Foetal hydrops, though, is a very late and severe sign of the disease and is related to a bad pregnancy outcome. For that reason it is important to start serial ultrasound examinations early in pregnancy (e.g. from 18 weeks onwards). An umbilical cord puncture can be performed in order to determine the blood group and the haemoglobin concentration of the foetus. In the case of severe foetal anaemia, intrauterine transfusion can be performed [13]. Good monitoring and, if necessary, intrauterine transfusion may prolong pregnancy to a viable period of around 36 weeks, after which a vaginal delivery of the affected foetus should be planned. Clearly the monitoring of such a high risk pregnancy should be performed in, or in close cooperation with a specialised centre.
3.3. Screening In this case the diagnosis of K-incompatibility was made post partum. Screening of pregnant women for the presence of irregular antibodies allows for anticipation of K and other blood group incompatibilities. Therefore, intrauterine foetal death can potentially be prevented.
71
The follow-up of K-incompatibility in pregnancy is intensive and not always easy. The primary target is the prevention of sensitization of women. Clearly, sensitization due to pregnancy can not be avoided, but sensitization due to blood transfusion can be prevented by transfusing girls and women in the fertile age with erythrocytes that are matched more extensively than for ABO and Rhesus(D) only, i.e. at least for K but preferably also for Rhesus(c) and Rhesus(E) [14]. Secondly, one could anticipate the occurrence of irregular antibodies by screening all pregnant women. The majority of cases of irregular antibodies in pregnancy are due to earlier pregnancies [7,15]. This screening should preferably take place at intake (first trimester), so that early monitoring is possible, and again at 32 weeks to demonstrate boostering or immunisation which has taken place at a later stage. Screening is not only of benefit for the child, but also for the mother. Screening may prevent unexpected transfusion problems at delivery when a calamity may occur. It goes without saying that it is important to investigate the expression of the antigen (phenotyping) in the biological father once irregular antibodies have been found. The frequency of irregular antibodies in pregnancy is estimated at 5% [7]. With a yearly number of pregnancies in The Netherlands being about 193 000 (data Central Bureau of Statistics and National Obstetric Registration) this means approximately 10 000 women per year. Most of the antibodies have specificity anti-c, anti-E, or anti-K. Pregnant women in The Netherlands are, in contrast to what is common in other western European countries (UK, Germany, France, Norway), not screened for the presence of irregular antibodies with other specifities than Rhesus(D) [14,16,17]. Both in Rhesus(D)-positive and Rhesus(D)-negative pregnant women new antibodies against the Rhesus-system (namely anti-E and anti-c) and other irregular antibodies (anti-K, anti-Fy a) are found [16]. Therefore, in our view, screening of all pregnant women is justified [7]. 4. Conclusion
With this case report we want to give publicity to the difficulties surrounding irregular antibodies in pregnancy. This case illustrates the specific behaviour of the K-antibody and the consequence of this behaviour for medical policy. We would like to support Van Dijk and Castel et al., in their respective recommendations to screen pregnant women early in pregnancy for irregular antibodies and to organize a central registration of erythrocyte antibodies. Central registration will prevent essential data remaining unknown when a patient is admitted to another hospital. Central registration is not only advantageous for the pregnant woman and her child, but for all possible receivers of blood transfusion.
72
N. de Jonge et al./ European Journal of Obstetrics & Gynecology and Reproductive Biology 67 (1996) 69-72
Acknowledgements The authors wish to thank Ms M.A.M. Overbeeke, at the Central Laboratory of the Blood Transfusion Service in Amsterdam for helpful discussion and critical comments on the manuscript. We thank Ms M.S. van de Waardt for her help in the translation of the manuscript.
References [1] Mollison PL, Engelfriet CP, Contreras M. Blood transfusion in clinical medicine. 9th ed. Oxford: Blackwell, 1993. [2] Vaughan Jl, Warwick R, Letsky E. Erythropoietic suppression in fetal anemia because of Kell alloimmunization. Am J Obstet Gynecol 1994; 171: 247-252. [3] Kloosterman GJ. On intrauterine growth, lnt J Gynaecol Obstet 1970; 8: 895-912. [4] Engelfriet CP, Ouwehand WH. ADCC and other cellular bioassays for predicting the clinical significance of red cell alloantibodies. Baillieres Clin Haematol 1990; 3 (2): 321. [5] Wigglesworth JS, Singer DB. Textbook of fetal and perinatal pathology. Boston: Blackwell Scientific Publications, 1991; 442: 437-439. [6] Van Dijk BA, Dooren MC, Overbeeke MAM. Red cell antibodies in pregnancy: there is no critical titre. Transfus Med 1995; 4: 199-202. [7] Van Dijk BA. lrregulair bloedgroepantagonisme: een geregeld probleem. Leiden, 1991. Thesis. [8] Castel A, Drejer GF, Verwey RA. Hemolytic disease in a neo-
[9]
[10]
[11]
[121 [13]
[14]
[15]
[161
[17]
nate due to rare maternal anti-erythocyte antibodies, and exchange transfusion with maternal blood frozen earlier. Ned Tijdschr Geneeskd 1993; 137: 2713-2715. Wenk RE, Goldstein P, Felix JK. Kell alloimmunization, hemolytic disease of the newborn, and perinatal management. Obstet Gynecol 1985; 66 (4): 473-476. Bowman JM, Pollock JM, Manning FA, Harman CR, Menticoglou S. Maternal Kell blood group alloimmunization. Obstet Gynecol 1992; 79 (2): 239-244. Liley AW. Liquor amnii analysis in management of pregnancy complicated by rhesus immunization. Am J Obstet Gynecol 1961; 82: 1359-1370. Leggat HM, Gibson JM, Barron SL, Reid MM. Anti-Kell in pregnancy. Br J Obstet Gynaecol 1991; 98 (2): 162-165. Kanhai HHH, Bennebroek Gravenhorst J, Van Kamp IL, Meerman RH, Brand A, Dohmen-Feld MWA, Ruys JH. Management of severe hemolytic disease with ultrasound-guided intravascular fetal transfusions. Vox Sang 1990: 59: 180-184. Overbeeke MAM, Dudok de Wit D. Preventie van de immunisatie tegen erytrocyten antigenen c, E en K veroorzaakt door bloedtransfusie. Ned Tijdschr Geneeskd 1994; 138 (22): 1116-1118. Tamminga RYJ, De Wolf JThM. Preventie van de immunisatie tegen erytrocyten antigenen c, E en K veroorzaakt door bloedtransfusie. Ned Tijdschr Geneeskd 1994; 138 (36): 1833. Kornstad L. New cases of irregular blood group antibodies other than anti-D in pregnancy. Frequency and clinical significance. Acta Obstet Gynecol Scand 1983; 62 (5): 431-436. Bowell PJ, Allen DL, Entwistle CC. Blood group antibody screening tests during pregnancy. Br J Obstet Gynaecol 1986; 93: 1038-1043.
European Journal of Obstetrics & Gynecology and ReproductiveBiology67 (1996) 69-72
ELSEVIER
Case report
Haemolytic disease of the newborn due to anti-K antibodies Niels de Jonge
a
~a
''
, J o l a n d a E. M a r t e n s b, A l f r e d o L. M i l a n i b, Jos6 L . M . K n j n e n , C e e s v a n K r i m p e n c, G a b r i e l l a A . E , P o n j e e a
C
Department of Clinical Chemistry, Diagnostic Center SSDZ, P.O. Box 5010, 2600 GA Delft, The Netherlands b Department of Gynaecology, Reinier de Graaf Hospital, P.O. Box 5010, 2600 GA Delft, The Netherlands c Department of Pathology, Diagnostic Center SSDZ, P.O. Box 5010, 2600 GA Delft, The Netherlands
Received 8 November 1995; revised 29 February 1996;accepted 6 March 1996
Abstract We describe a case of intrauterine foetal death at 32 weeks gestation with signs of hydrops foetalis without erythroblastosis. The hydrops foetalis appeared to be caused by blood group incompatibility. Irregular antibodies of anti-K specificity were found in the serum of the mother, while the father was positive for the K-antigen. The antibody dependent cell-mediated cytotoxicity (ADCC) test with serum of the mother was positive. This case shows the characteristics of haemolytic disease of the newborn by anti-K. Moreover, it underlines the necessity of both adequate follow-up of individual cases, and screening for irregular antibodies in all pregnancies as well as central registration of screening results. Keywords: Kell; Blood group incompatibility; Irregular antibodies; Hydrops foetalis; Haemolytic disease of the newborn
1. Introduction
2. Case history
We describe a case of intrauterine death at 32 weeks gestational age due to anti-K antibodies. The K-antigen belongs to the Kell blood group system [1]. The pathophysiological mechanism of the K-antibody seems to have another site of attack than the Rhesus antibodies [2]. The described case shows the characteristics of this blood group incompatibility. The consequences for diagnosis and policy in pregnancy with K-antibodies are discussed. In addition, this case underlines the necessity of both an adequate follow-up of individual cases, as well as general screening on irregular antibodies in all pregnant women. Primary prevention of blood group incompatibility, prevention of sensitization of women at fertile age and central registration of the results of such screening are discussed.
A 30-year-old woman was referred to the outpatient clinic after no foetal movements were detected by her midwife. This was her third pregnancy, amenorrhoea 32 2/7 week. Her previous two pregnancies and deliveries were uncomplicated. She had not received any blood transfusion previously. Physical examination showed a normotensive patient, the fundus uteri was half umbilical xyphoid (normal for the amenorrhoea). There were no uterine contractions and foetal heartbeats could not be heard. Ultrasound investigation confirmed the diagnosis of intrauterine foetal death. The foetus was hydropic, e.g. with ascites, subcutaneous oedema and hepatomegaly. Malformations of the foetus could not be seen. The placenta was rather thick and showed no signs of solutio placentae. The possible causes of this intrauterine foetal death were investigated by protocol. After consultation with the patient, delivery was induced with sulproston i.v. (Nalador~). The same day a stillborn boy was born, weight 2270 g, with second grade
* Correspondingauthor, Departmentof Clinical Chemistry,Leyenburg Hospital, P.O. Box 40.551, 2504 LN The Hague, The Netherlands. Tel.: +31 70 3592000; Fax: +31 70 3295046.
0301-2115/96/$15.00 © 1996 ElsevierScienceIreland Ltd. All rights reserved PII: S0301-2115(96)02441-4
70
N. de Jonge et al./ European Journal of Obstetrics & Gynecology and Reproductive Biology 67 (1996) 69-72
maceration and a hydropic aspect. Obduction of the foetus showed a boy with a foot length in conformity with the 32 weeks amenorrhoea, but a weight at the 90th percentile of the Kloosterman Table [3]. Congenital malformations could not be found. The clinical diagnosis of hydrops foetalis was confirmed. Cardiomegaly (heart weight 17.6 g; normally 9.1 ± 4.1 g) with hypertrophy of both ventricles. There was 25 ml dark yellow fluid in the pleural cavity and 50 ml in the abdominal cavity. The liver was extremely large, congested and showed haemosiderosis. The placenta looked very pale and the cotelydones were hydropic. Placental weight without umbilical cord and membranes was 805 g. Although microscopic investigation of the placenta showed some erythroblasts in the foetal capillaries no evident erythroblastosis could be established. A post partum blood sample from mother showed blood type O Rhesus(D) positive and irregular antibodies with Kell specificity. Other laboratory tests showed no abnormalities. The possible blood group incompatibility by anti-Kell was further investigated by an indirect antiglobulin test with serum from the mother. The test had a positive result; titre 512. The ADCC test, also postpartum, showed 45% lysis [4]. Blood retrieved from father showed Kell antigen on the erythrocytes. The father appeared to be heterozygous for the Kantigen, giving a 50% probability for the foetus to be Kpositive. It was concluded that the foetus probably died because of Kell incompatibility. 3. Discussion
Transfer of foetal erythrocytes and thrombocytes to the maternal circulation may lead to an immune response in which maternal antibodies, specific for the foetal erythrocytes or thrombocytes, are produced. These antibodies are of IgG class and can cross the placenta. Immunisation of the mother by erythrocyte antigens belonging to the Rhesus system, Kell, Duffy, Kidd or other (more or less well known) blood group antigens may give rise to foetal anaemia, hydrops foetalis and eventually intrauterine death. The differential diagnosis of hydrops foetalis is very extensive. Two groups of causes must be distinguished: immunological causes and non-immunological causes. The second group includes chromosomal aberrations, congenital abnormalities of the heart and/or lungs, and infections [5]. In this case non-immunological causes could be excluded. The hydrops foetalis in this case appeared to have an immunological cause. Rhesus-incompatibility as a cause for hydrops foetalis could be excluded since the mother was Rhesus(D) positive and no irregular antibodies with specificity to other antigens of the Rhesus system were found (c, C, e, E). However, irregular antibodies with Kspecificity were found in the blood of the mother. These
antibodies can cause hydrops foetalis, if the foetus possesses the K-antigen. The correlation between titre of erythrocyte-antibody and degree of haemolytic disease is poor [6]. The ADCC test is an in vitro test for the biological activity in vivo of the antibody [4]. This test is usually performed ante partum to get an impression of the seriousness of the blood group incompatibility. In contrast to the situation with Rhesus(D) incompatibility, there has been no study of the correlation between the result of the ADCC test and the degree of haemolytic disease of the newborn involving Kantibodies. There is evidence that serious pathology can be found at ADCC-test results >20% (M.A.M. Overbeeke, personal communication).
3.1. K-antibodies
The screening for Rhesus(D) antigens in pregnant women and the concommitant immunoprophylaxis has lead to a considerable decrease of Rhesus(D)sensitization as a cause of the haemolytic disease of the newborn. The incidence of haemolytic disease of the newborn due to Rhesus(D) antibodies has decreased from 3.5% to 0.6% in the Netherlands [7]. Consequently, a relative increase is seen in the frequency of haemolytic disease due to other irregular antibodies [7,8]. The incidence of stillbirths due to anti-K in The Netherlands is not known, but in the United Kingdom it is estimated at about 2 per million births [1]. The relative frequency of K-antibodies compared to that of Rhesus(D) antibodies is 60%. The relative frequency, though, of haemolytic disease of the newborn due to Kantibodies compared to that due to Rhesus-antibodies is 3% [9]. This is explained by the relatively frequent antibody formation after blood transfusion, combined with low frequency of the antigen in the population: 90% is K-negative. The literature is not clear about the degree of the haemolytic disease of the newborn due to anti-K [7,10]. Hydrops foetalis may develop fast, even in Cases where the determination of bilirubin concentration in amniotic fluid appears to indicate mild disease. The number of erythroblasts and reticulocytes in foetal blood may be very low in relation to the haemoglobin concentration of the foetus. A plausible explanation is the disproportional effect of anti-K on erythrocyte precursor cells compared to anti-D. This can lead to anaemia without jaundice. The anaemia is not due to enhanced breakdown of erythrocytes, but rather due to apparently decreased synthesis (Frigoletto in: [1]). This hypothesis was recently confirmed by Vaughan et al. [2]. Suppression of erythroproiesis and not haemolysis was the predominant mechanism of foetal anaemia caused by maternal K-alloimmunisation. In this case, indeed no erythroblastosis of any importance was found.
N. de Jonge et al. /European Journal of Obstetrics & Gynecology and Reproductive Biology 67 (1996) 69-72
3.2. Monitoring of pregnancies complicated by Kell antibodies Once anti-K antibodies are detected in pregnancy and if the father of the unborn child possesses the K-antigen then careful foetal monitoring is indicated. In the case of the presence of Rhesus(D) antibodies, tests are known and available for good policy making. These tests however are only partly useful if anti-K antibodies are present. The anti-K antibody titre is of relatively little value in predicting haemolytic disease of the newborn. Both high and low antibody-titres have been associated with haemolytic disease of the newborn. The correlation between the ADCC test result and the severity of the haemolytic disease in the newborn caused by anti-K antibodies has so far not been sufficiently investigated. The ADCC test is a good guide for further policy making if Rhesus(D) antibodies are present. If the percentage of cytotoxic lysis is >30%, then an amniocentesis is indicated; the amniotic fluid will be spectrophotometrically examined. The difference between the normal and measured optical density at a wavelength of 450 nm is a measure of bilirubin concentration. Liley showed that the measured concentration of bilirubin correlates with the severity of haemolytic disease and pregnancy outcome [11]. Unfortunately there is no good correlation between the Liley index and the severity of the foetal anaemia when Kincompatibility complicates pregnancy [12]. While the anti-K antibody titre, ADCC test and Liley index are not able to predict serious haemolytic disease or foetal hydrops, ultrasound however, can detect hydropic changes as a result of Kell antagonism. Foetal hydrops, though, is a very late and severe sign of the disease and is related to a bad pregnancy outcome. For that reason it is important to start serial ultrasound examinations early in pregnancy (e.g. from 18 weeks onwards). An umbilical cord puncture can be performed in order to determine the blood group and the haemoglobin concentration of the foetus. In the case of severe foetal anaemia, intrauterine transfusion can be performed [13]. Good monitoring and, if necessary, intrauterine transfusion may prolong pregnancy to a viable period of around 36 weeks, after which a vaginal delivery of the affected foetus should be planned. Clearly the monitoring of such a high risk pregnancy should be performed in, or in close cooperation with a specialised centre.
3.3. Screening In this case the diagnosis of K-incompatibility was made post partum. Screening of pregnant women for the presence of irregular antibodies allows for anticipation of K and other blood group incompatibilities. Therefore, intrauterine foetal death can potentially be prevented.
71
The follow-up of K-incompatibility in pregnancy is intensive and not always easy. The primary target is the prevention of sensitization of women. Clearly, sensitization due to pregnancy can not be avoided, but sensitization due to blood transfusion can be prevented by transfusing girls and women in the fertile age with erythrocytes that are matched more extensively than for ABO and Rhesus(D) only, i.e. at least for K but preferably also for Rhesus(c) and Rhesus(E) [14]. Secondly, one could anticipate the occurrence of irregular antibodies by screening all pregnant women. The majority of cases of irregular antibodies in pregnancy are due to earlier pregnancies [7,15]. This screening should preferably take place at intake (first trimester), so that early monitoring is possible, and again at 32 weeks to demonstrate boostering or immunisation which has taken place at a later stage. Screening is not only of benefit for the child, but also for the mother. Screening may prevent unexpected transfusion problems at delivery when a calamity may occur. It goes without saying that it is important to investigate the expression of the antigen (phenotyping) in the biological father once irregular antibodies have been found. The frequency of irregular antibodies in pregnancy is estimated at 5% [7]. With a yearly number of pregnancies in The Netherlands being about 193 000 (data Central Bureau of Statistics and National Obstetric Registration) this means approximately 10 000 women per year. Most of the antibodies have specificity anti-c, anti-E, or anti-K. Pregnant women in The Netherlands are, in contrast to what is common in other western European countries (UK, Germany, France, Norway), not screened for the presence of irregular antibodies with other specifities than Rhesus(D) [14,16,17]. Both in Rhesus(D)-positive and Rhesus(D)-negative pregnant women new antibodies against the Rhesus-system (namely anti-E and anti-c) and other irregular antibodies (anti-K, anti-Fy a) are found [16]. Therefore, in our view, screening of all pregnant women is justified [7]. 4. Conclusion
With this case report we want to give publicity to the difficulties surrounding irregular antibodies in pregnancy. This case illustrates the specific behaviour of the K-antibody and the consequence of this behaviour for medical policy. We would like to support Van Dijk and Castel et al., in their respective recommendations to screen pregnant women early in pregnancy for irregular antibodies and to organize a central registration of erythrocyte antibodies. Central registration will prevent essential data remaining unknown when a patient is admitted to another hospital. Central registration is not only advantageous for the pregnant woman and her child, but for all possible receivers of blood transfusion.
72
N. de Jonge et al./ European Journal of Obstetrics & Gynecology and Reproductive Biology 67 (1996) 69-72
Acknowledgements The authors wish to thank Ms M.A.M. Overbeeke, at the Central Laboratory of the Blood Transfusion Service in Amsterdam for helpful discussion and critical comments on the manuscript. We thank Ms M.S. van de Waardt for her help in the translation of the manuscript.
References [1] Mollison PL, Engelfriet CP, Contreras M. Blood transfusion in clinical medicine. 9th ed. Oxford: Blackwell, 1993. [2] Vaughan Jl, Warwick R, Letsky E. Erythropoietic suppression in fetal anemia because of Kell alloimmunization. Am J Obstet Gynecol 1994; 171: 247-252. [3] Kloosterman GJ. On intrauterine growth, lnt J Gynaecol Obstet 1970; 8: 895-912. [4] Engelfriet CP, Ouwehand WH. ADCC and other cellular bioassays for predicting the clinical significance of red cell alloantibodies. Baillieres Clin Haematol 1990; 3 (2): 321. [5] Wigglesworth JS, Singer DB. Textbook of fetal and perinatal pathology. Boston: Blackwell Scientific Publications, 1991; 442: 437-439. [6] Van Dijk BA, Dooren MC, Overbeeke MAM. Red cell antibodies in pregnancy: there is no critical titre. Transfus Med 1995; 4: 199-202. [7] Van Dijk BA. lrregulair bloedgroepantagonisme: een geregeld probleem. Leiden, 1991. Thesis. [8] Castel A, Drejer GF, Verwey RA. Hemolytic disease in a neo-
[9]
[10]
[11]
[121 [13]
[14]
[15]
[161
[17]
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