Rh isoimmunization during pregnancy: antenatal prophylaxis.

Of 3533 Rh-negative women who began a pregnancy without detectable Rh antibodies, 62 (1.8%) demonstrated evidence of Rh isoimmunization during pregnancy or within 3 days after delivery. All denied transfusions as well as abortions or previous pregnancies not followed by the administration of Rh immune globulin. Rh isoimmunization during pregnancy or within 3 days after delivery, which will not be prevented by the administration of Rh immune globulin after delivery, is the most important cause of residual Rh isoimmunization. A clinical trial of antenatal administration of Rh immune globulin, initially at 34 weeks''s and subsequently at 28 and 34 weeks'' gestation, in 1357 Rh-negative pregnant women who were delivered of Rh-positive babies, was effective in preventing the development of Rh isoimmunization during pregnancy or within 3 days after delivery. Antenatal prophylaxis with Rh immune globulin will be necessary if the incidence of Rh isoimmunization is to be reduced to its lowest possible level. Antenatal prophylaxis at 28 weeks'' gestation is now an insured service in Manitoba.     

Rh immunization in Manitoba: progress in prevention and management.

For two decades the perinatal mortality caused by erythroblastosis has been decreasing in Manitoba. The improved management of Rh-immunized pregnancies has lowered the death rate among affected infants from 10.8% to 3.4%, while the prevention of Rh immunization has reduced its incidence from 9.1 to 2.2 per 1000 total births. In its first 6 years and 8 months Manitoba''s antenatal prophylaxis program, in which immunoglobulin is administered to Rh-negative women at 28 weeks'' gestation, reduced the incidence of Rh immunization during pregnancy by 93%. In combination with post-abortion and postpartum prophylaxis the antenatal treatment has provided a protection rate of 98.6% among primigravidas at risk. Further improvements are expected.     

WinRho: Rh immune globulin prepared by ion exchange for intravenous use.

An Rh immune globulin [Rh IgG] for intravenous use, WinRho, has been prepared by the Winnipeg Rh Institute by a modification of the ion-exchange column method of Hoppe and colleagues. When administered to Rh-negative male and nonpregnant female volunteers WinRho was found to be nonpyrogenic, nontoxic, safe and protective against Rh alloimmunization. In a clinical trial with 240 microgram given at about 28 weeks'' gestation and 120 microgram given after delivery to Rh-negative women at risk of Rh immunization WinRho was effective in preventing Rh immunization. Of the 870 women carrying Rh-positive fetuses who were treated with WinRho during pregnancy and were not tested several months after delivery 14 would have shown evidence of Rh immunization by the time of delivery if WinRho had been ineffective; none showed such evidence. Of the 1122 women carrying Rh-positive fetuses who were retested 4 to 6 months after delivery 83 would have shown evidence of Rh immunization at that time if WinRho had been ineffective; only 1 showed such evidence. The efficiency of yield of anti-D with the modified method of production, the fct that it can be given intravenously (a route that causes the patient less discomfort and immediately results in high anti-D levels) and the lower levels of contaminating IgA and IgM make WinRho the preparation of choice for preventing Rh immunization.     

Incidence of Maternal Rh Immunization by ABO Compatible and Incompatible Pregnancies

The incidence of maternal Rh immunization in Rh-negative women following a single ABO compatible Rh-positive pregnancy is about 17%. This incidence was determined by following Rh-negative women through two Rh-incompatible pregnancies and analysing their sera for anti-Rh at the time of delivery of their second observed pregnancy. Maternal Rh immunization occurs almost exclusively after delivery; however, antibodies may not be detectable in the absence of further antigenic stimulation.The incidence of maternal Rh immunization when maternal-foetal ABO incompatibility is also present is 9–13% and 17% for group O and non-group O women respectively. This study emphasizes the need to offer Rh-immune prophylaxis to Rh-negative women having Rh-positive infants whether or not ABO incompatibility exists between the mother and infant.     

Clinical Evaluation of Rh0(D) Immune Globulin (Human) in Canada

—During 1966, clinical trials were conducted in three Canadian centres to determine the safety and efficacy of Rh₀(D) immune globulin (human) in preventing isoimmunization by the Rh₀(D) antigen in Rh-negative women delivering ABO-compatible Rh-positive infants.The candidates were randomly divided into control and treated groups; the treated mothers received an intramuscular injection of 300 μg. of anti-Rh₀(D) within 72 hours of delivery. Follow-up antibody screening tests were conducted on the sera of all patients six to nine months post partum.Of the 175 control patients, 11 or 6.2% became actively immunized to the Rh antigen, whereas complete protection against maternal Rh immunization was observed in the 191 treated patients.     

The experience and effectiveness of the Nova Scotia Rh program, 1964-84.

A program to reduce the incidence of erythroblastosis fetalis was started in Nova Scotia in 1964. Up to the end of 1984, 120 fetuses received 247 intrauterine transfusions. The survival rate was 45.6% in the first 10 years of the program and 66.7% in the next 11 years. For fetuses at or over 26 weeks'' gestation the figures were 51.5% and 73.7% respectively. Postpartum prevention was started in 1968, with administration of Rh immune globulin (RhIG) to Rh-negative unimmunized women within 72 hours after the birth of an Rh-positive infant. Antepartum prevention, started in 1979, consisted of administration of RhIG at 28 weeks'' gestation to Rh-negative unimmunized women. The effectiveness of the prevention program was evaluated by enumerating the known cases of Rh(D) alloimmunization in the province from 1982 to 1984: 55 cases were identified, a rate of 1.5 per 1000 births instead of the expected rate of about 10 per 1000.     

Prevention of Rh Hemolytic Disease of the Newborn

Rh_o(D)-Immune Globulin was given to 322 Rh-negative women delivered of ABO-compatible, Rh-positive infants with no apparent failures to suppress Rh sensitization. In contrast, 32 of 305 mothers of a control group made Rh antibody during the six months following delivery. In subsequent pregnancies, 69 women administered RhoGAM had no evidence of isoimmunization after delivery while six of forty mothers of the control study produced anti-Rh. RhoGAM, given within 72 hours of delivery in the amounts employed, was effective for suppression of Rh immunization.     

Compliance with postpartum Rh isoimmunization prophylaxis in Alberta

A retrospective review of obstetric records for 1979 in two major Calgary hospitals was undertaken to determine the rate of compliance with postpartum Rh isoimmunization prophylaxis in Alberta. The charts of 4528 women ranging in age from 13 to 46 years were reviewed. The prevalence rate of Rh negativity was found to be 16%. Of the 710 Rh-negative women 490 (69%) were eligible to receive Rh immune globulin (RhIG); that is, they had no anti-D antibodies, and the baby/fetus was Rh-positive or Rh-unknown. RhIG had been administered to 93.6% of the eligible women; the compliance rate ranged from 66.7% for obstetric emergencies (i.e., spontaneous abortion, antepartum or early-pregnancy hemorrhage, or ectopic pregnancy) to 98.2% for postpartum diagnoses. In more than half (54.7%) of the women who underwent amniocentesis Rh type was not determined; the implications of this finding are discussed. Although poor compliance with postpartum RhIG administration is not a reason for withholding antepartum administration of RhIG, maximum compliance with the more cost-effective programs should be attained before antepartum programs are fully implemented.     

Rh isoimmunization,Manitoba, 1963-75.

The number of Rh-isoimmunized pregnancies in Manitoba has been reduced from 223 and 228 in the years ending Oct. 31, 1963 and 1964 to 60 and 62 in the years ending Oct. 31, 1974 and 1975. The number per 1000 total births in the same years has decreased from 10.0 and 10.6 to 3.4 and 3.5 Perinatal mortality rates in those years decreased from 13.8 amd 15.7% to 0 and 2.2%, respectively. The number of perinatal deaths has been reduced from 55 in the first 2 years reported to 1 in the last 2 years. Among the 121 isoimmunized women pregnant in the 2-year period ending Oct. 31, 1975, isoimmunization was due to failure to give Rh immune globulin after delivery in 33 and failure to give it during pregnancy in 48. Of the remaining 40, 37 were immunized before Rh immune globulin became available. Complete prevention of Rh isoimmunization and therefore of all perinatal deaths from Rh erythroblastosis can only be achieved through universal Rh testing prenatally and immediately after delivery, and institution of an antenatal Rh prophylaxis program.     

Efficacy and long term effects of antenatal prophylaxis with anti-D immunoglobulin.

OBJECTIVE--To measure the safety and efficacy of antenatal treatment with anti-D immunoglobulin. DESIGN--Open study with historical controls. SETTING--Multicentre study in 17 hospitals in West Yorkshire. PATIENTS--1238 Rh negative women who delivered Rh positive infants after 34 weeks in their first pregnancy in 1980-1 (group 1) and 2000 similar primigravidas from 1978-9 (group 2). Obstetric data were collected for 616 women in group 1 who had a subsequent pregnancy, 536 similar women in group 2, and 410 Rh positive but otherwise similar primigravidas who delivered in the same hospitals in 1978-81 (group C). INTERVENTIONS--Anti-D immunoglobulin 100 micrograms intramuscularly was given at 28 and 34 weeks to the mothers in their first pregnancy who delivered in 1980-1. END POINTS--Detection of anti-D antibody in the first or any subsequent pregnancy in groups 1 and 2. For all three groups having subsequent pregnancies gestation at delivery, birth weight, fetal survival at one month, pre-eclampsia defined as blood pressure greater than 140/90 on two occasions more than 12 hours apart, and proteinuria greater than 0.25 milligram. MEASUREMENTS AND MAIN RESULTS--Antenatal immunisation to Rh(D) occurred in six mothers in group 1 and 32 group 2. Most immunisations occurred in the first or second pregnancy. The rates of abortion, gestation at delivery, birth weight, and fetal survival were not significantly different among the three groups. The incidence of pre-eclampsia was lower in mothers given antenatal anti-D immunoglobulin, but the difference was not significant. CONCLUSIONS--Antenatal prophylaxis with anti-D immunoglobulin is effective, and the effect of giving it in the first pregnancy persists into at least the second pregnancy. It seems to be safe for the fetus in the index and subsequent pregnancies.     

An error in Rh testing in pregnancy.

Anti-D (anti-Rho) in the blood of two Rh-negative pregnant women was believed to be due to active immunization. In the first case, however, antibodies were no longer detectable 2 weeks later. In the second case they disappeared by the end of 31 weeks. It was discovered that both women had been given immune globulin (human) because of exposure to rubella. The globulin given to the first woman probably contained about 0.1 mug of anti-D per ml; that given to the second probably contained about 0.6 mug of anti-D per ml. Both babies were O Rh-positive. Both women were given Rh immune globulin after delivery. Both have completed a further pregnancy and no anti-D has been found on many tests. In tests carried out in 1971 all samples of immune globulin (human) examined contained anti-D, but usually in inconsequential trace amounts.     

THE WORK OF AN Rh COMMITTEE—Experiences in a Private General Hospital

An Rh committee was formed at Saint John''s Hospital in Santa Monica to provide preadmission consultation on all potential Rh and ABO problems and to maintain a file of information on Rh-negative patients in the delivery room. It is urged that no patient go to the delivery room without the known Rh-ABO type as part of the labor record. All obstetrical patients at the hospital are given “obstetrical information cards” for use as a memorandum on the labor record. A pink card identifies the Rh-negative patient.The program keeps the staff “Rh-conscious” and has improved teamwork among the obstetricians, pediatricians, nurses and the laboratory.     

Prevention of Rh-haemolytic Disease: Final Results of the “High-risk” Clinical Trial: A COMBINED STUDY FROM CENTRES IN ENGLAND AND BALTIMORE

The final results are reported of a trial of about 1,000 μg of anti-D gammaglobulin given intramuscularly to a selected high-risk group of Rh-negative primiparae just delivered of an ABO-compatible Rh-positive baby, the aim being to prevent them becoming immunized to Rh. Six months after delivery only 1 out of 173 treated mothers had been immunized as against 38 out of 176 controls. The crucial test of the prophylactic therapy depends on the presence or otherwise of anti-D at the end of a second Rh-positive pregnancy. Of 86 treated mothers two had antibodies at this time compared with 20 out of 65 controls.The results show a high degree of protection in this group of mothers.     

Crossmatch difficulties following the prophylactic use of Rh immune globulin.

With increasing demand for platelet transfusion the need to use platelets from Rh-positive persons for Rh-negative individuals often arises. The administration of Rho(D) immune globulin (human) in this situation has been recommended, but may cause serologic difficulties owing to the recipient''s passive acquisition of antibodies other than anti-D.     

Prevention of Rh-haemolytic Disease: Results of the Liverpool “Low-risk” Clinical Trial

A clinical trial is reported in which Rh-negative primiparae, just delivered of an Rh-positive ABO-compatible infant and in whom fetal cell counts after delivery suggested less than 0·2 ml of circulating fetal blood, were treated with about 200 μg of anti-D gammaglobulin. Three (0·36%) out of 844 women thus treated developed anti-D in the subsequent six months; this is 10% of the incidence in untreated controls. Three (1·8%) out of 171 treated mothers had anti-D at the end of the second Rh-positive pregnancy, and this is 18% of the incidence in controls.Possible reasons for the occasional failure of the treatment are discussed and the results of this trial are compared with those of a previous trial in which 1,000 μg or more of anti-D was given to a different group of mothers. The combined results of the two trials lead to the conclusion that the passive administration of anti-D gammaglobulin after delivery affords in this population of Rh-negative women a 95% protection rate in the postdelivery period and an 89% protection rate by the end of the subsequent pregnancy.     

Rh-immunization by Pregnancy: Results of a Survey and Their Relevance to Prophylactic Therapy

A series of Rh-negative primiparae has been studied in order to gain further insight into the process of immunization by pregnancy. The distribution of foetal cell counts in blood samples taken after delivery was determined for 2,029 mothers giving birth to ABO-compatible babies and for 417 mothers with ABO-incompatible babies.A total of 760 mothers were tested for the development of Rh antibodies six months after the delivery of an ABO-compatible Rh-positive baby and 236 were further followed up through a second Rh-positive pregnancy. The incidence of anti-D six months after delivery is estimated to be 8.5%, and there is evidence of a direct relation between the count of foetal cells after delivery and the risk of developing antibodies. A further 8.5% of mothers were estimated to develop anti-D by the end of the second pregnancy, and it is postulated that these individuals had been primed by the first pregnancy. There is some evidence that the larger stimuli of Rh-positive blood in the first pregnancy are more likely to result in overt antibody formation, while the smaller stimuli are more likely to prime, antibodies not being detected until a second stimulus occurs during the second pregnancy.These findings are relevant to the programme for preventing Rh-immunization by injecting anti-D gammaglobulin.     

Association between Foeto-maternal Bleeding and Hypertension in Pregnancy

A blind prospective survey of foeto-maternal bleeding in 200 primiparous pregnancies was carried out in an investigation of a possible association between foeto-maternal bleeding and hypertension in pregnancy. Evidence of foeto-maternal bleeding was found in 61% of 36 hypertensive pregnancies, and in 51% of 160 normotensive pregnancies, a difference which is not statistically significant.Significant differences between the hypertensive and the normotensive groups were found when foeto-maternal bleeding was related to gestation. In pregnancies that became hypertensive more foetal cells were found in the maternal circulation before week 36 than in normotensive pregnancies. In patients with oedema of the abdominal wall during pregnancy the incidence of foeto-maternal bleeding was significantly increased.These findings seem to explain why pre-eclamptic toxaemia is a significant predisposing factor in women who later develop Rh antibodies. It is recommended that anti-D gammaglobulin should be offered to all Rh-negative women with Rh-positive infants following a hypertensive pregnancy. Consideration should also be given to the question of administering anti-D gammaglobulin during Rh-negative hypertensive pregnancies if this procedure is proved to be both safe to mother and foetus and effective.The results provide contributory evidence that the placental vascular changes in toxaemic pregnancies precede the clinical signs and are not the result of hypertension.     

Rhesus Isoimmunization after Abortion

Out of 177 Rh(D)-negative patients studied, 96 were successfully followed-up after spontaneous or therapeutic abortion. Rh antibodies were detected by the indirect Coombs test in two patients and by an enzyme technique only in a further seven, an overall incidence of 9·4%.The prophylactic use of anti-D immunoglobulin is now recommended for Rh-negative non-immunized patients undergoing abortion, but the dose could be less than 75 μg. The Kleihauer test was of no value in predicting the risk of isoimmunization.     

Reduced severity of Rh-haemolytic disease after anti-D immunoglobulin.

A total of 2459 Rh-negative women who received anti-D immunoglobulin after a Rh-positive pregnancy were followed up in at least one subsequent pregnancy. There was a failure of protection rate of 1-6%. Follow-up of 53 subsequent infants of mother in whom protection had failed showed that the infants were less severely affected than would have been expected. This was confirmed by a comparative statistical analysis of the present series and a series of first affected cases before anti-D immunoglobulin was available, using the antibody titre during pregnancy and the haemoglobin levels at delivery.