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The Rh Program of Nova Scotia, 1964–2000
The Rh Program of Nova Scotia,
1964-2000 B.Anthony Armson, MD Margaret L. Parsons, BN Thomas F. Baskett, MB
Abstract: the Rh Program of Nova Scotia was established in 1964, modelled on the Manitoba example. The history, evolution and results of the first 35 years are presented. During the life of the program the incidence of Rh(D) alloimmunization in Nova Scotia has fallen from ten to 0.4 per thousand births. Fetal survival in severe cases is 93 percent.
Department of Obstetrics and Gynaecology Dalhousie University Halifax NS
Resume : le programme d'allo-immunisation anti-D de la Nouvelle-Ecosse a ete etabli en 1964 it partir du modele du Manitoba. Cet article presente I'historique, I'evolution et les resultats des 35 premieres annees. Depuis que ce programme existe, I'incidence d'alloimmunisation freto-maternelle en Nouvelle-Ecosse est passee de dix it 0,4 pour 1000 naissances. Le taux de survie des cas graves est de 93 pour cent.
J Soc
Obstet Gynaecol Can 2000;22( I 1):954-8
HISTORY OF THE PROGRAM
Key Words History of medicine, Rh alloimmunization Received on March 21. 2000. Revised and accepted on June 26, 2000.
In the early 1960's, the incidence of Rh(D) alloimmunization was approximately ten per 1,000 births. Before the development of intrauterine fetal transfusion and prevention protocols, the perinatal mortality associated with Rh(D) alloimmunization in Nova Scotia was among the highest in Canada. In 1963, a group of obstetricians and paediatricians from Halifax met to discuss this situation and review the available literature on treatment and prevention of maternal alloimmunization. With the support of the Nova Scotia Department of Health, Bruce Morton from the Department of Paediatrics visited Winnipeg to study the Manitoba Rh Program, at that time under the direction of Bruce Chown. I The Neonatal Jaundice Committee was formed in January 1964 under the auspices of the Nova Scotia Medical Society through the Standing Committee of Child Health. A project funded by a federal-provincial grant was initiated to study the latest methods of management of Rh(D) alloimmunization and to disseminate available information to physicians in Nova Scotia in an effort to improve survival rates. With the assistance and support of the postgraduate office of the Dalhousie Medical School, teams of obstetricians and paediatricians travelled throughout the province of Nova Scotia discussing the problem of neonatal jaundice with branch medical societies. Following a number oflively and controversial discussions regarding the management of haemolytic disease in pregnancy, the decision was made to establish a standing committee. Thus, the Medical Society of Nova Scotia established its Rh Program in June 1964, with the Committee on Fetal-Maternal Incompatibility. The primary function of this committee of obstetricians and paediatricians, modelled on the Manitoba example,2 was to evaluate and discuss all cases of maternal Rh(D) alloimmunization and provide management recommendations for referring physicians;' James Corston of the Department of Obstetrics and Gynaecology was the first chair of the Committee, and Bruce Morton became medical director of the Program. Other members of the Committee were Irving Perlin and Ethel Pereira (Obstetrics and Gynaecology), and Robert Grant (Paediatrics). The Committee subsequently became known as the Rh Committee of the Medical Society of Nova Scotia, and since that time has continued to meet on a weekly basis to discuss the optimum management of pregnancies complicated by alloimmunization. In October 1963, William Liley of Auckland, New Zealand reported the first cases of intrauterine fetal transfusion. 4 Using this technique, the first successful intrauterine fetal JOURNAL SOGe
NOVEMBER 2000
transfusion in Canada was performed in Winnipeg in February 1964 by Rhinehart Friesen and Jack Bowman. s The first intraperitoneal fetal transfusion in Halifax was performed by James Corston on June 14, 1964, at 31 weeks gestation. 6 The infant was subsequently delivered at 35 weeks gestation and survived following three exchange transfusions. This important milestone in the management of maternal isoimmunization in Nova Scotia was summarized by Corston who wrote: 7 The publication by William Liley in the British Medical Journal in November, 1963, of his method of intrauterine transfusion was indeed a great stimulus to those of us in the disciplines of obstetrics and paediatrics. The heart rending histories of repeated deaths in utero and in the neonatal period left us feeling helpless. We had established a very keen Rh Committee at Dalhousie and, therefore, when Liley's paper appeared we seized upon it with enthusiasm. Five months later a suitable case was referred to us and she was successfully treated by means of intrauterine transfusion. My feelings on the day of the transfusion, June 14, 1964, ranged from apprehension, in case our manoeuvre might kill the fetus in utero,
to
a feeling of great satisfaction when all went well
and the baby survived.
Patient files were maintained by obstetrical residents until a permanent office for the Program was established at the Grace Maternity Hospital in 1967. Fran Irwin, herself an Rh negative mother with a history of perinatal loss due to haemolytic disease, was hired as secretary to and coordinator of the Program. Her dedication and compassion for the women whose pregnancies were complicated by alloimmunization provided the essential framework for the success of the Program. With the introduction of prevention strategies in 1968, volunteers with high anti-D antibody titres in previous pregnancies were persuaded by Irwin to donate blood on a weekly basis at the Grace Maternity Hospital. Whole blood obtained from twelve such women, including Irwin herself, was taken to the pathology laboratory for plasmaphoresis and, following plasma extraction, the packed red blood cells were returned to the donors later in the day by transfusion. The plasma was sent to the Connaught Laboratory in Toronto for preparation of Rh immune globulin (RhIG) which was subsequently returned to Halifax and distributed to hospitals throughout the province to be made available to all Rh negative women in Nova Scotia. The first postpartum RhIG injection in Nova Scotia was administered in June 1968 after involvement in a multicentre Canadian trial to evaluate the efficacy of postpartum RhIG prophylaxis. A news release by the Halifax Chronicle Herald announced the availability ofRhIG free of charge to all Rh negative women and the cooperation of physicians and nurses throughout Nova Scotia was sought. Periodically, Nova Scotia physicians were sent clinical updates regarding the prevention of Rh disease, and a reminder to ensure that Rh testing was done on all pregnant women. In 1968, Robert Grant assumed the position of co-director with Bruce Morton, and later became medical director of the JOURNAL SOGe
Rh Program until 1979. Grant worked tirelessly to obtain government funding and sustained the administrative success of the Program. In 1971, RhIG was made available to Rh negative women following miscarriage or ectopic pregnancy. Blood group and antibody testing was advocated for all women at the first prenatal visit to ensure that RhIG was provided in the event of early pregnancy loss. Ultrasonic placental localization before amniocentesis was introduced in an effort to reduce the procedure-related sensitization rate. Postpartum Kleihauer-Betke testing was recommended in 1972; and in that year, five patients required more than the standard 300 ]lg dosage of Rh immune globulin on the basis of this testing. Since the 1970's, the indications for RhIG prophylaxis were expanded to include any procedure or event that increased the risk of feto-maternal bleed, such as: amniocentesis, cordocentesis, external cephalic version, antepartum bleed or platelet transfusion. Other individuals who played significant roles in the early years of the Rh Committee were Douglas Cudmore, Murray Davis, Rudolph Ozere, S.c. Robinson, Kenneth Scott, Pius Sigsworth, and Donald Smith. Leo Peddle became medical director in 1979. He had been involved as an Rh Fellow in the Winnipeg Rh Laboratory with Bowman and in the early work on antenatal prophylaxis. 8 Based on this work, Peddle advocated administration ofRhIG at 28 weeks to all Rh negative women. 1 The first such injection in Nova Scotia was given in January 1979. In addition to receiving copies of Red Cross blood group and antibody reports for Rh negative and Rh positive women with antibodies, the Rh Program office began to receive maternal antibody tests for all Rh negative women. Attending physicians were sent letters to remind them to administer RhIG at 28 weeks gestation in these women. Reports of antepartum injections were then sent to and recorded by the Rh Program office, a practice which continues to the present day. In addition, monthly antibody screening for all Rh negative pregnant women was recommended, changing in 1997 to the first antenatal visit, 28 weeks and delivery. In 1981, following 14 years of dedicated service to the Rh Program, Fran Irwin retired as secretary and coordinator. Margaret Parsons was hired as nurse coordinator and continues to function in that role. In 1983, when Peddle became Head of the University Department of Obstetrics and Gynaecology at Dalhousie, Tom Baskett was appointed medical director of the Rh Program. Baskett documented the first twenty years of experience and effectiveness of the Nova Scotia Rh Program from 1964 to 1984,9 demonstrating the improvement in survival of fetuses requiring intrauterine transfusion and the significant reduction in the incidence of Rh(D) alloimmunization during this period. Baskett and Parsons subsequently examined the costeffectiveness of the Rh Program by comparing the cost of prevention with the cost of health care services required for women with severe Rh(D) alloimmunization treated from NOVEMBER 2000
ing intrauterine fetal transfusion were sent to Winnipeg for direct intravascular transfusion INCIDENCE OF RH(D) ALLOIMMUNIZATION until 1990 when the procedure became availIN NOVA SCOTIA 1982-1999 able in Halifax. Rate of new alloimmunized pregnancies per 1,000 total births (500+ g) In April 1988, the Rh Committee became a 1.6.-------------------------,1.6 sub-programme within the Reproductive Care Program (RCP) of Nova Scotia, while continu1.4 I----''''--~------------------i 1.4 ing to be endorsed by the Medical Society of Nova Scotia. The Rh Committee now became 1 . 2 1 - - - - - \ - - - - - - - - - - - - - - - - - - - - \ 1.2 officially known as the Rh Program of Nova Scocia. A computer data base was established. Tony Armson became Medical Director of 0.8 1--------"--..,....--f--+--......,.-----7'---~-__j 0.8 the Program in 1990. In 1995, he was suc0.6 I - - - - - - - - - - \ - - - / - - + - - + - - - - - \ - _ _ j 0.6 ceeded by Michiel Van den Hof, who continues in that position. Armson, Robert Liston, 0:4 / - - - - - - - - - - - " - - - - - - ' f I . . - - - - - + - - - f ! 0.4 and Van den Hof all gained experience with cordocentesis and this diagnostic procedure, 0.2/---------------------;-.,'-10.2 along with intravascular fetal transfusion, O~-------------------~O became available in Halifax. The first intravas82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 cular fetal transfusion in Halifax was performed at 25 weeks gestation on April 27, 1990 by Armson and Van den Hof. Three further 1982 to 1986.10 Neonatal intensive care accounted for 80 perintravascular transfusions culminated in the delivery of a live cent of the additional health care expenses, with 66 percent of female infant at 36 weeks gestation. Since that time, intravascular fetal transfusion has been available for the management the cost related to extra hospital days needed for such care. The cost per case prevented ($1,495) was 2.7 times less than the of the approximately three severely immunized women per year cost per case treated ($3,986), with an annual cost saving of from Nova Scotia, New Brunswick, and Prince Edward Island. approximately $340,000 per year. 10 The number ofIVTs performed from 1990 to 1992 was 36 in Following several reports of direct intravascular blood trans12 fetuses, and from 1997 to 1999 there were 25 in six fetuses. fusion by fetoscopy and cordocentesis, 11-13 the Rh Committee Although the numbers are small and falling, other indications made the decision in 1987 to discontinue performing for cordocentesis, one to two per month, ensure that the skills intraperitoneal fetal transfusions at the Grace Maternity Hosrequired for IVT are maintained. pital until individuals qualified in the technique of cordocenPROGRAM EFFECTIVENESS tesis and intravascular fetal transfusion (IVT) were available. Consequently, immunized women from Nova Scotia requirThe experience and effectiveness of the Nova Scotia Rh Program from 1964 to 1984 has previously been repotted. 9 TABLE I In 1982, the prevalence ofRh(D) alloimmunizaPROBABLE CAUSE OF RH (D) ALLOIMMUNIZATION tion in pregnancy was 1.5 per 1,000 total bitths. IN NOVA SCOTIA As shown in Figure 1, there has been further Cause 1982-84 1990-1999 decline in this rate over the past 17 years. Between (n 53) (n 67) 1990 and 1999 there were 109,989 bitths in Nova n (%) n (%) Scotia, among which were 73 cases of maternal Rh(D) alloimmunization, for an incidence of 0.7 Occurred before protocol established 9 ( 17.0) 0 (0) per 1,000 total births. Bowman has suggested that Occurred before 28 weeks gestation 3 (5.6) 23 (34.3) the elimination ofRh(D) alloimmunization is Rh immune globulin (RhIG) given, but failed 9 ( 17.0) 23 (34.3) Failure to give indicated RhlG impossible, but that with complete compliance 32 (60.4) 21 (31.4) 9 7 Antepartum with prophylaxis recommendations, combined Postpartum II 3 with Kleihauer-Betke screening for transplacental Post abortion 8 6 haemorrhage, it can be reduced to 0.4 per 1,000 Blood/platelet transfusion 4 I bitths. 14 Over the last three years, 1997-9, this rate Patient refusal 0 2 ofO.4 per thousand births (13 cases in 29,834 Antepartum bleed 0 2 bitths) has been achieved in Nova Scotia. FIGURE I
=
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=
NOVEMBER 2000
TABLE III
TABLE 11
NEONATAL THERAPY FOR SURVIVORS OF INTRAUTERINE FETAL TRANSFUSION: 1964-1999'
OUTCOME OF INTRAUTERINE FETAL TRANSFUSION FOR SEVERE MATERNAL ALLOIMMUNIZATION: 1964-1999'
1964-87 1990-1999 (Intraperitoneal (Intravascular technique) technique) n (%) n (%)
1964-87 1990-1999 (Intraperitoneal (Intravascular technique) technique) n (%) n (%) Fetuses Transfusions Stillbirth Neonatal death Procedure-related death per transfusion Survivors :?36 wks 31-35 wks < 31 wks
124 255 46 (37.1) 16 (12.9) (7.1 ) 62 (50.0) 0 57 (91.9) 5 (8.1 )
28 83 0 2
Survivors No therapy Phototherapy only Direct transfusion Exchange transfusion Direct and exchange transfusion
(0) (7.1 )
(2.4) 26 (92.9) 12 (46.2) 12 (46.2) 2 (7.6)
* Nova Scotia and out-of-province referrals
The timing and probable cause of alloimmunization was identifiable in 67 of the 73 cases between 1990 and 1999 (Table I). Less than one third of the 67 cases (31 %) were due to failure to give indicated RhIG. In two of the 67 cases, patients refused RhIG prophylaxis. There were, therefore, 65 theoretically preventable cases. The expected Rh(D) alloimmunization rate where no prevention policy is used is approximately ten per 1,000 total births. 2,15 Based on this assumption, it is estimated that without prevention there would have been 1,099 cases in Nova Scotia between 1990 and 1999. Therefore, 1,034 (94%) of the expected cases were prevented. Between 1964 and 1999, there were 338 intrauterine transfusions in 152 fetuses. The majority of patients were referred from Nova Scotia and New Brunswick, but there were also some referrals from Prince Edward Island, Newfoundland, and Saint Pierre et Miquelon. The gestational age at the time of transfusion ranged from 21 to 35 weeks. The intraperitoneal method of intrauterine fetal transfusion was used between 1964 and 1987, whereas transfusions performed between 1990 and 1999 utilized the direct intravascular technique. The overall survival following intraperitoneal transfusion was 50 percent compared to a survival rate of 93 percent following intravascular transfusion (Table II). The procedure-related death rate per transfusion decreased from 7.1 percent using the intraperitoneal technique to 2.4 percent when the intravascular method was employed. Approximately one half (46%) of the 26 survivors following intravascular transfusions delivered at 36 weeks gestation or greater. All but two of the infants delivered prematurely during this period were between 31 and 35 weeks gestation. All of the 62 survivors who received intraperitoneal transfusions delivered before 36 weeks gestation, with JOURNAL
62 0 (0) 6 (9.7) 4 (6.5) 31 (50.0) 21 (33.8)
26 2 (7.6) 8 (30.8) 8 (30.8) 7 (27.0) I (3.8)
*Nova Scotia and out-of-province referrals
the majority (92%) born between 31 and 35 weeks (Table II). Neonatal therapy for survivors of intrauterine fetal transfusion using both techniques is shown in Table Ill. Neonatal morbidity associated with intrauterine transfusion has improved significantly, with more than one third (39%) requiring no therapy or phototherapy only. There has also been an increase in the percentage of neonates requiring direct transfusion plus or minus phototherapy with a significant decrease in the need for exchange transfusion. CONCLUSION
Since its founding in 1964, the Rh Program of Nova Scotia has been dedicated to three main objectives: education, prevention, and clinical consultation and management. Through the combined efforts of many dedicated individuals, the prevalence of Rh(D) alloimmunization has been reduced by about 95 percent and the outcome of pregnancies complicated by maternal isoimmunization has improved dramatically.
SOGC.
FIGURE 2
RH PROGRAM OF NOVA SCOTIA 30TH ANNIVERSARY MEETING. HALIFAX, SEPTEMBER 1995
James Corston, Fran Irwin, Margaret Parsons, Tony Armson.
NOVEMBER 2000
In September 1995, during the Annual Clinical Meeting of the Atlantic Society of Obstetricians and Gynaecologists, a half day scientific session, Alloimmunization in Pregnancy: Past, Present and Future, was held to mark the 30th anniversary of the Rh Program of Nova Scotia. Jack Bowman, former director of the Winnipeg Rh Laboratory, was invited as guest speaker. Many of the founding members attended this very successful celebration (Figure 2). Now, after 35 years of existence and entering the next century, the Rh Program has achieved a practical and very effective prevention strategy which has almost reduced the prevalance of Rh(D)alloimmunization to the lowest rate possible. There will always remain a small irreducible number of Rh(D) cases, along with the unpreventable non Rh(D) immunized pregnancies. In the last three years, 15 percent of all immunized pregnancies in Nova Scotia were Rh(D) and 85 percent were due to other, non Rh(D) antibodies. The near eradication and improved management of haemolytic disease of the newborn epitomizes all that is best in perinatal medicine. Over the latter half of the 20th century the pathophysiology has been defined, the diagnosis and treatment improved, and the method of its prevention achieved: a triumph of applied scientific and clinical investigation that has almost accomplished, in a sense, the death of a disease. 16
13. Nicolaides KH. Soothill pw. Clewell W. Rodeck CH. Campbell S. Rh disease: intravascular fetal blood transfusion by cordocentesis. Fetal Therapy 1986; I: 185-9. 14. Bowman JM.The prevention of Rh immunization.Transfus Med Rev 1988;2: 129-38. 15. Mollison Plo The Rh blood group system. In: Blood Transfusion in Clinical Medicine. 7th ed. Oxford: Blackwell. 1983:378. 16. Baskett TF. Some 20th century milestones in obstetrics and gynaecology.ln: O'Brien PMS (ed).Yearbook of Obstetrics and Gynaecology. London: RCOG Press. 2000;8: 1-9.
Competing interest: None declared
Surgical Management of an Adnexal Mass Suspicious for Malignancy
REFERENCES I.
Bowman JM. Dr. Bruce Chown and the Winnipeg Rh Laboratory: from tragedy to triumph. J Soc Obstet Gynaecol Can 1997; 19:59-68. 2. Bowman JM. Chown B. Lewis M. et al. Rh isoimmunization. Manitoba. 1963-75. Can Med Assoc J 1977; 116:282-4. 3. Morton BS. Hemolytic disease of the newborn: management in pregnancy. NS Med Bull 1965; 12:255-8. 4. Liley AW.lntrauterine transfusion of foetus in haemolytic disease. BMJ 1963;2:1107-9. 5. Bowman JM. Friesen RF. Multiple intraperitoneal transfusions of the fetus for erythroblastosis fetalis. N Engl J Med 1964;271 :703-5. 6. Corston JM. Morton BS. Robinson SC.lntrauterine blood transfusion of the fetus. Can Med Assoc J 1964; 91 :815-7. 7. Baskett TF. Bowman JM. Some historical aspects of intrauterine fetal transfusion in Canada.J Soc Obstet Gynaecol Can 1991; 13:53-62. 8. Bowman JM. Chown B. Lewis M. Pollock JM. Rh immunization during pregnancy: antenatal prophylaxis. Can Med Assoc J 1978; I 18:623-6. 9. BaskettTF, Parsons ML. Peddle. LJ.The experience and effectiveness of the Nova Scotia Rh Program. 1964-84. Can Med Assoc J 1986: 134: 1259-61. 10. Baskett TF, Parsons ML. Prevention of Rh(D) alloimmunization: a cost-benefit analysis. Can Med Assoc J 1990; 142:337-9. I I. Rodeck CH. Holman CA, Karnicki J. Kemp JR.Whitmore DN. Austin MA. Direct intravascular fetal blood transfusion by fetoscopy in severe rhesus isoimmunisation. Lancet 1981; I :652-3. 12. Berkowitz RL. Chitkara U. Goldberg JD. Wilkins I. Chervenak FA. Intrauterine intravascular transfusions for severe red blood cell isoimmunization: ultrasound guided percutaneous approach. Am J Obstet Gynecol 1986; 155:574-7.
JOURNAL SOGC
This issue of the Journal saGe includes a Self-Directed Learning Module on the surgical management of an adnexal mass suspicious for malignancy. This module qualifies for credits under Section 2 of the Maintenance of Certification Programme of the Royal College of Physicians and Surgeons of Canada.
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JA, WYETH-AYERST
®~W CANADA INC
NOVEMBER 2000
1964-2000 B.Anthony Armson, MD Margaret L. Parsons, BN Thomas F. Baskett, MB
Abstract: the Rh Program of Nova Scotia was established in 1964, modelled on the Manitoba example. The history, evolution and results of the first 35 years are presented. During the life of the program the incidence of Rh(D) alloimmunization in Nova Scotia has fallen from ten to 0.4 per thousand births. Fetal survival in severe cases is 93 percent.
Department of Obstetrics and Gynaecology Dalhousie University Halifax NS
Resume : le programme d'allo-immunisation anti-D de la Nouvelle-Ecosse a ete etabli en 1964 it partir du modele du Manitoba. Cet article presente I'historique, I'evolution et les resultats des 35 premieres annees. Depuis que ce programme existe, I'incidence d'alloimmunisation freto-maternelle en Nouvelle-Ecosse est passee de dix it 0,4 pour 1000 naissances. Le taux de survie des cas graves est de 93 pour cent.
J Soc
Obstet Gynaecol Can 2000;22( I 1):954-8
HISTORY OF THE PROGRAM
Key Words History of medicine, Rh alloimmunization Received on March 21. 2000. Revised and accepted on June 26, 2000.
In the early 1960's, the incidence of Rh(D) alloimmunization was approximately ten per 1,000 births. Before the development of intrauterine fetal transfusion and prevention protocols, the perinatal mortality associated with Rh(D) alloimmunization in Nova Scotia was among the highest in Canada. In 1963, a group of obstetricians and paediatricians from Halifax met to discuss this situation and review the available literature on treatment and prevention of maternal alloimmunization. With the support of the Nova Scotia Department of Health, Bruce Morton from the Department of Paediatrics visited Winnipeg to study the Manitoba Rh Program, at that time under the direction of Bruce Chown. I The Neonatal Jaundice Committee was formed in January 1964 under the auspices of the Nova Scotia Medical Society through the Standing Committee of Child Health. A project funded by a federal-provincial grant was initiated to study the latest methods of management of Rh(D) alloimmunization and to disseminate available information to physicians in Nova Scotia in an effort to improve survival rates. With the assistance and support of the postgraduate office of the Dalhousie Medical School, teams of obstetricians and paediatricians travelled throughout the province of Nova Scotia discussing the problem of neonatal jaundice with branch medical societies. Following a number oflively and controversial discussions regarding the management of haemolytic disease in pregnancy, the decision was made to establish a standing committee. Thus, the Medical Society of Nova Scotia established its Rh Program in June 1964, with the Committee on Fetal-Maternal Incompatibility. The primary function of this committee of obstetricians and paediatricians, modelled on the Manitoba example,2 was to evaluate and discuss all cases of maternal Rh(D) alloimmunization and provide management recommendations for referring physicians;' James Corston of the Department of Obstetrics and Gynaecology was the first chair of the Committee, and Bruce Morton became medical director of the Program. Other members of the Committee were Irving Perlin and Ethel Pereira (Obstetrics and Gynaecology), and Robert Grant (Paediatrics). The Committee subsequently became known as the Rh Committee of the Medical Society of Nova Scotia, and since that time has continued to meet on a weekly basis to discuss the optimum management of pregnancies complicated by alloimmunization. In October 1963, William Liley of Auckland, New Zealand reported the first cases of intrauterine fetal transfusion. 4 Using this technique, the first successful intrauterine fetal JOURNAL SOGe
NOVEMBER 2000
transfusion in Canada was performed in Winnipeg in February 1964 by Rhinehart Friesen and Jack Bowman. s The first intraperitoneal fetal transfusion in Halifax was performed by James Corston on June 14, 1964, at 31 weeks gestation. 6 The infant was subsequently delivered at 35 weeks gestation and survived following three exchange transfusions. This important milestone in the management of maternal isoimmunization in Nova Scotia was summarized by Corston who wrote: 7 The publication by William Liley in the British Medical Journal in November, 1963, of his method of intrauterine transfusion was indeed a great stimulus to those of us in the disciplines of obstetrics and paediatrics. The heart rending histories of repeated deaths in utero and in the neonatal period left us feeling helpless. We had established a very keen Rh Committee at Dalhousie and, therefore, when Liley's paper appeared we seized upon it with enthusiasm. Five months later a suitable case was referred to us and she was successfully treated by means of intrauterine transfusion. My feelings on the day of the transfusion, June 14, 1964, ranged from apprehension, in case our manoeuvre might kill the fetus in utero,
to
a feeling of great satisfaction when all went well
and the baby survived.
Patient files were maintained by obstetrical residents until a permanent office for the Program was established at the Grace Maternity Hospital in 1967. Fran Irwin, herself an Rh negative mother with a history of perinatal loss due to haemolytic disease, was hired as secretary to and coordinator of the Program. Her dedication and compassion for the women whose pregnancies were complicated by alloimmunization provided the essential framework for the success of the Program. With the introduction of prevention strategies in 1968, volunteers with high anti-D antibody titres in previous pregnancies were persuaded by Irwin to donate blood on a weekly basis at the Grace Maternity Hospital. Whole blood obtained from twelve such women, including Irwin herself, was taken to the pathology laboratory for plasmaphoresis and, following plasma extraction, the packed red blood cells were returned to the donors later in the day by transfusion. The plasma was sent to the Connaught Laboratory in Toronto for preparation of Rh immune globulin (RhIG) which was subsequently returned to Halifax and distributed to hospitals throughout the province to be made available to all Rh negative women in Nova Scotia. The first postpartum RhIG injection in Nova Scotia was administered in June 1968 after involvement in a multicentre Canadian trial to evaluate the efficacy of postpartum RhIG prophylaxis. A news release by the Halifax Chronicle Herald announced the availability ofRhIG free of charge to all Rh negative women and the cooperation of physicians and nurses throughout Nova Scotia was sought. Periodically, Nova Scotia physicians were sent clinical updates regarding the prevention of Rh disease, and a reminder to ensure that Rh testing was done on all pregnant women. In 1968, Robert Grant assumed the position of co-director with Bruce Morton, and later became medical director of the JOURNAL SOGe
Rh Program until 1979. Grant worked tirelessly to obtain government funding and sustained the administrative success of the Program. In 1971, RhIG was made available to Rh negative women following miscarriage or ectopic pregnancy. Blood group and antibody testing was advocated for all women at the first prenatal visit to ensure that RhIG was provided in the event of early pregnancy loss. Ultrasonic placental localization before amniocentesis was introduced in an effort to reduce the procedure-related sensitization rate. Postpartum Kleihauer-Betke testing was recommended in 1972; and in that year, five patients required more than the standard 300 ]lg dosage of Rh immune globulin on the basis of this testing. Since the 1970's, the indications for RhIG prophylaxis were expanded to include any procedure or event that increased the risk of feto-maternal bleed, such as: amniocentesis, cordocentesis, external cephalic version, antepartum bleed or platelet transfusion. Other individuals who played significant roles in the early years of the Rh Committee were Douglas Cudmore, Murray Davis, Rudolph Ozere, S.c. Robinson, Kenneth Scott, Pius Sigsworth, and Donald Smith. Leo Peddle became medical director in 1979. He had been involved as an Rh Fellow in the Winnipeg Rh Laboratory with Bowman and in the early work on antenatal prophylaxis. 8 Based on this work, Peddle advocated administration ofRhIG at 28 weeks to all Rh negative women. 1 The first such injection in Nova Scotia was given in January 1979. In addition to receiving copies of Red Cross blood group and antibody reports for Rh negative and Rh positive women with antibodies, the Rh Program office began to receive maternal antibody tests for all Rh negative women. Attending physicians were sent letters to remind them to administer RhIG at 28 weeks gestation in these women. Reports of antepartum injections were then sent to and recorded by the Rh Program office, a practice which continues to the present day. In addition, monthly antibody screening for all Rh negative pregnant women was recommended, changing in 1997 to the first antenatal visit, 28 weeks and delivery. In 1981, following 14 years of dedicated service to the Rh Program, Fran Irwin retired as secretary and coordinator. Margaret Parsons was hired as nurse coordinator and continues to function in that role. In 1983, when Peddle became Head of the University Department of Obstetrics and Gynaecology at Dalhousie, Tom Baskett was appointed medical director of the Rh Program. Baskett documented the first twenty years of experience and effectiveness of the Nova Scotia Rh Program from 1964 to 1984,9 demonstrating the improvement in survival of fetuses requiring intrauterine transfusion and the significant reduction in the incidence of Rh(D) alloimmunization during this period. Baskett and Parsons subsequently examined the costeffectiveness of the Rh Program by comparing the cost of prevention with the cost of health care services required for women with severe Rh(D) alloimmunization treated from NOVEMBER 2000
ing intrauterine fetal transfusion were sent to Winnipeg for direct intravascular transfusion INCIDENCE OF RH(D) ALLOIMMUNIZATION until 1990 when the procedure became availIN NOVA SCOTIA 1982-1999 able in Halifax. Rate of new alloimmunized pregnancies per 1,000 total births (500+ g) In April 1988, the Rh Committee became a 1.6.-------------------------,1.6 sub-programme within the Reproductive Care Program (RCP) of Nova Scotia, while continu1.4 I----''''--~------------------i 1.4 ing to be endorsed by the Medical Society of Nova Scotia. The Rh Committee now became 1 . 2 1 - - - - - \ - - - - - - - - - - - - - - - - - - - - \ 1.2 officially known as the Rh Program of Nova Scocia. A computer data base was established. Tony Armson became Medical Director of 0.8 1--------"--..,....--f--+--......,.-----7'---~-__j 0.8 the Program in 1990. In 1995, he was suc0.6 I - - - - - - - - - - \ - - - / - - + - - + - - - - - \ - _ _ j 0.6 ceeded by Michiel Van den Hof, who continues in that position. Armson, Robert Liston, 0:4 / - - - - - - - - - - - " - - - - - - ' f I . . - - - - - + - - - f ! 0.4 and Van den Hof all gained experience with cordocentesis and this diagnostic procedure, 0.2/---------------------;-.,'-10.2 along with intravascular fetal transfusion, O~-------------------~O became available in Halifax. The first intravas82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 cular fetal transfusion in Halifax was performed at 25 weeks gestation on April 27, 1990 by Armson and Van den Hof. Three further 1982 to 1986.10 Neonatal intensive care accounted for 80 perintravascular transfusions culminated in the delivery of a live cent of the additional health care expenses, with 66 percent of female infant at 36 weeks gestation. Since that time, intravascular fetal transfusion has been available for the management the cost related to extra hospital days needed for such care. The cost per case prevented ($1,495) was 2.7 times less than the of the approximately three severely immunized women per year cost per case treated ($3,986), with an annual cost saving of from Nova Scotia, New Brunswick, and Prince Edward Island. approximately $340,000 per year. 10 The number ofIVTs performed from 1990 to 1992 was 36 in Following several reports of direct intravascular blood trans12 fetuses, and from 1997 to 1999 there were 25 in six fetuses. fusion by fetoscopy and cordocentesis, 11-13 the Rh Committee Although the numbers are small and falling, other indications made the decision in 1987 to discontinue performing for cordocentesis, one to two per month, ensure that the skills intraperitoneal fetal transfusions at the Grace Maternity Hosrequired for IVT are maintained. pital until individuals qualified in the technique of cordocenPROGRAM EFFECTIVENESS tesis and intravascular fetal transfusion (IVT) were available. Consequently, immunized women from Nova Scotia requirThe experience and effectiveness of the Nova Scotia Rh Program from 1964 to 1984 has previously been repotted. 9 TABLE I In 1982, the prevalence ofRh(D) alloimmunizaPROBABLE CAUSE OF RH (D) ALLOIMMUNIZATION tion in pregnancy was 1.5 per 1,000 total bitths. IN NOVA SCOTIA As shown in Figure 1, there has been further Cause 1982-84 1990-1999 decline in this rate over the past 17 years. Between (n 53) (n 67) 1990 and 1999 there were 109,989 bitths in Nova n (%) n (%) Scotia, among which were 73 cases of maternal Rh(D) alloimmunization, for an incidence of 0.7 Occurred before protocol established 9 ( 17.0) 0 (0) per 1,000 total births. Bowman has suggested that Occurred before 28 weeks gestation 3 (5.6) 23 (34.3) the elimination ofRh(D) alloimmunization is Rh immune globulin (RhIG) given, but failed 9 ( 17.0) 23 (34.3) Failure to give indicated RhlG impossible, but that with complete compliance 32 (60.4) 21 (31.4) 9 7 Antepartum with prophylaxis recommendations, combined Postpartum II 3 with Kleihauer-Betke screening for transplacental Post abortion 8 6 haemorrhage, it can be reduced to 0.4 per 1,000 Blood/platelet transfusion 4 I bitths. 14 Over the last three years, 1997-9, this rate Patient refusal 0 2 ofO.4 per thousand births (13 cases in 29,834 Antepartum bleed 0 2 bitths) has been achieved in Nova Scotia. FIGURE I
=
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=
NOVEMBER 2000
TABLE III
TABLE 11
NEONATAL THERAPY FOR SURVIVORS OF INTRAUTERINE FETAL TRANSFUSION: 1964-1999'
OUTCOME OF INTRAUTERINE FETAL TRANSFUSION FOR SEVERE MATERNAL ALLOIMMUNIZATION: 1964-1999'
1964-87 1990-1999 (Intraperitoneal (Intravascular technique) technique) n (%) n (%)
1964-87 1990-1999 (Intraperitoneal (Intravascular technique) technique) n (%) n (%) Fetuses Transfusions Stillbirth Neonatal death Procedure-related death per transfusion Survivors :?36 wks 31-35 wks < 31 wks
124 255 46 (37.1) 16 (12.9) (7.1 ) 62 (50.0) 0 57 (91.9) 5 (8.1 )
28 83 0 2
Survivors No therapy Phototherapy only Direct transfusion Exchange transfusion Direct and exchange transfusion
(0) (7.1 )
(2.4) 26 (92.9) 12 (46.2) 12 (46.2) 2 (7.6)
* Nova Scotia and out-of-province referrals
The timing and probable cause of alloimmunization was identifiable in 67 of the 73 cases between 1990 and 1999 (Table I). Less than one third of the 67 cases (31 %) were due to failure to give indicated RhIG. In two of the 67 cases, patients refused RhIG prophylaxis. There were, therefore, 65 theoretically preventable cases. The expected Rh(D) alloimmunization rate where no prevention policy is used is approximately ten per 1,000 total births. 2,15 Based on this assumption, it is estimated that without prevention there would have been 1,099 cases in Nova Scotia between 1990 and 1999. Therefore, 1,034 (94%) of the expected cases were prevented. Between 1964 and 1999, there were 338 intrauterine transfusions in 152 fetuses. The majority of patients were referred from Nova Scotia and New Brunswick, but there were also some referrals from Prince Edward Island, Newfoundland, and Saint Pierre et Miquelon. The gestational age at the time of transfusion ranged from 21 to 35 weeks. The intraperitoneal method of intrauterine fetal transfusion was used between 1964 and 1987, whereas transfusions performed between 1990 and 1999 utilized the direct intravascular technique. The overall survival following intraperitoneal transfusion was 50 percent compared to a survival rate of 93 percent following intravascular transfusion (Table II). The procedure-related death rate per transfusion decreased from 7.1 percent using the intraperitoneal technique to 2.4 percent when the intravascular method was employed. Approximately one half (46%) of the 26 survivors following intravascular transfusions delivered at 36 weeks gestation or greater. All but two of the infants delivered prematurely during this period were between 31 and 35 weeks gestation. All of the 62 survivors who received intraperitoneal transfusions delivered before 36 weeks gestation, with JOURNAL
62 0 (0) 6 (9.7) 4 (6.5) 31 (50.0) 21 (33.8)
26 2 (7.6) 8 (30.8) 8 (30.8) 7 (27.0) I (3.8)
*Nova Scotia and out-of-province referrals
the majority (92%) born between 31 and 35 weeks (Table II). Neonatal therapy for survivors of intrauterine fetal transfusion using both techniques is shown in Table Ill. Neonatal morbidity associated with intrauterine transfusion has improved significantly, with more than one third (39%) requiring no therapy or phototherapy only. There has also been an increase in the percentage of neonates requiring direct transfusion plus or minus phototherapy with a significant decrease in the need for exchange transfusion. CONCLUSION
Since its founding in 1964, the Rh Program of Nova Scotia has been dedicated to three main objectives: education, prevention, and clinical consultation and management. Through the combined efforts of many dedicated individuals, the prevalence of Rh(D) alloimmunization has been reduced by about 95 percent and the outcome of pregnancies complicated by maternal isoimmunization has improved dramatically.
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FIGURE 2
RH PROGRAM OF NOVA SCOTIA 30TH ANNIVERSARY MEETING. HALIFAX, SEPTEMBER 1995
James Corston, Fran Irwin, Margaret Parsons, Tony Armson.
NOVEMBER 2000
In September 1995, during the Annual Clinical Meeting of the Atlantic Society of Obstetricians and Gynaecologists, a half day scientific session, Alloimmunization in Pregnancy: Past, Present and Future, was held to mark the 30th anniversary of the Rh Program of Nova Scotia. Jack Bowman, former director of the Winnipeg Rh Laboratory, was invited as guest speaker. Many of the founding members attended this very successful celebration (Figure 2). Now, after 35 years of existence and entering the next century, the Rh Program has achieved a practical and very effective prevention strategy which has almost reduced the prevalance of Rh(D)alloimmunization to the lowest rate possible. There will always remain a small irreducible number of Rh(D) cases, along with the unpreventable non Rh(D) immunized pregnancies. In the last three years, 15 percent of all immunized pregnancies in Nova Scotia were Rh(D) and 85 percent were due to other, non Rh(D) antibodies. The near eradication and improved management of haemolytic disease of the newborn epitomizes all that is best in perinatal medicine. Over the latter half of the 20th century the pathophysiology has been defined, the diagnosis and treatment improved, and the method of its prevention achieved: a triumph of applied scientific and clinical investigation that has almost accomplished, in a sense, the death of a disease. 16
13. Nicolaides KH. Soothill pw. Clewell W. Rodeck CH. Campbell S. Rh disease: intravascular fetal blood transfusion by cordocentesis. Fetal Therapy 1986; I: 185-9. 14. Bowman JM.The prevention of Rh immunization.Transfus Med Rev 1988;2: 129-38. 15. Mollison Plo The Rh blood group system. In: Blood Transfusion in Clinical Medicine. 7th ed. Oxford: Blackwell. 1983:378. 16. Baskett TF. Some 20th century milestones in obstetrics and gynaecology.ln: O'Brien PMS (ed).Yearbook of Obstetrics and Gynaecology. London: RCOG Press. 2000;8: 1-9.
Competing interest: None declared
Surgical Management of an Adnexal Mass Suspicious for Malignancy
REFERENCES I.
Bowman JM. Dr. Bruce Chown and the Winnipeg Rh Laboratory: from tragedy to triumph. J Soc Obstet Gynaecol Can 1997; 19:59-68. 2. Bowman JM. Chown B. Lewis M. et al. Rh isoimmunization. Manitoba. 1963-75. Can Med Assoc J 1977; 116:282-4. 3. Morton BS. Hemolytic disease of the newborn: management in pregnancy. NS Med Bull 1965; 12:255-8. 4. Liley AW.lntrauterine transfusion of foetus in haemolytic disease. BMJ 1963;2:1107-9. 5. Bowman JM. Friesen RF. Multiple intraperitoneal transfusions of the fetus for erythroblastosis fetalis. N Engl J Med 1964;271 :703-5. 6. Corston JM. Morton BS. Robinson SC.lntrauterine blood transfusion of the fetus. Can Med Assoc J 1964; 91 :815-7. 7. Baskett TF. Bowman JM. Some historical aspects of intrauterine fetal transfusion in Canada.J Soc Obstet Gynaecol Can 1991; 13:53-62. 8. Bowman JM. Chown B. Lewis M. Pollock JM. Rh immunization during pregnancy: antenatal prophylaxis. Can Med Assoc J 1978; I 18:623-6. 9. BaskettTF, Parsons ML. Peddle. LJ.The experience and effectiveness of the Nova Scotia Rh Program. 1964-84. Can Med Assoc J 1986: 134: 1259-61. 10. Baskett TF, Parsons ML. Prevention of Rh(D) alloimmunization: a cost-benefit analysis. Can Med Assoc J 1990; 142:337-9. I I. Rodeck CH. Holman CA, Karnicki J. Kemp JR.Whitmore DN. Austin MA. Direct intravascular fetal blood transfusion by fetoscopy in severe rhesus isoimmunisation. Lancet 1981; I :652-3. 12. Berkowitz RL. Chitkara U. Goldberg JD. Wilkins I. Chervenak FA. Intrauterine intravascular transfusions for severe red blood cell isoimmunization: ultrasound guided percutaneous approach. Am J Obstet Gynecol 1986; 155:574-7.
JOURNAL SOGC
This issue of the Journal saGe includes a Self-Directed Learning Module on the surgical management of an adnexal mass suspicious for malignancy. This module qualifies for credits under Section 2 of the Maintenance of Certification Programme of the Royal College of Physicians and Surgeons of Canada.
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