An audit of anti-D sensitisation in Yorkshire
Correspondence: Dr E. McSweeney, Mersey and North Wales Blood Centre, West Derby Street, Liverpool L7 8TW, UK.
Objective To determine the likely factors that contribute to RhD sensitisation.
Design Retrospective study of all new cases of RhD sensitisation occurring between 1988 and 1991.
Setting Leeds Blood Centre, National Blood Service, Yorkshire.
Population One hundred and forty-seven cases of RhD sensitisation from 15 obstetric units within the Yorkshire region, of which 129 (312 pregnancies) could be assessed.
Main outcome measures Identification of potential immunising events and adherence with recommendations on anti-D immunoglobulin administration.
Results Twenty-eight women (22%) had immune anti-D antibodies during their first pregnancy or at delivery and 50 (39%) in their second pregnancy. Overall, 98 potential immunising events were identified in 62 women, excluding delivery; 67 women (52%) had no events, other than delivery. Miscarriages and medical terminations of pregnancy accounted for 81% of all identified events. Iatrogenic failure to adhere to recommendations for the administration of anti-D immunoglobulin occurred in a significant proportion of women who subsequently developed immune anti-D antibodies. Anti-D immunoglobulin failed to protect against immunisation despite adherence to the protocol in 20 events (20%), 13 of which involved miscarriages or termination of pregnancy < 20 weeks of gestation. Potentially, antenatal prophylaxis might have prevented 86% of immunisations that were identified during the first pregnancy.
Conclusions The introduction of antenatal administration of anti-D immunoglobulin could significantly reduce the level of sensitisation in primigravidae, and adherence to recommendations for administration of anti-D immunoglobulin could be improved. Consideration should be given to reviewing the current recommendation that a dose of 250 IU of anti-D immunoglobulin is adequate following termination of pregnancy before a gestational age of 20 weeks.
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Since its introduction in 1969 the use of anti-D immunoglobulin for immunoprophylaxis has played a major role in decreasing the incidence of haemolytic disease of the newborn. The incidence of this disease has fallen from 1:170 births in 1969 to 1500 births in 19881, and the mortality rate has fallen more dramatically, from 1:2000 births in 1953 to 1:65,000 in 1989. This can be attributed to the contribution of immunoprophylaxis plus advances in antenatal care, including intrauterine transfusion and improvements in neonatal care making earlier planned delivery safer.
However, new cases of RhD sensitisation continue to appear. A previous study2 carried out in Yorkshire showed that, despite meticulous immunoprophylaxis after delivery, RhD immunisation occurred in approximately 1% of RhD negative women. There are a number of explanations for the continued development of RhD sensitisation, including failure of administration of anti-D immunoglobulin, failure of protection despite administration of anti-D immunoglobulin, and unrecognised sensitising events, such as occult fetomaternal haemorrhage during the third trimester of pregnancy. We conducted a retrospective study to determine the likely factors that contributed to RhD sensitisation in a consecutive series of 147 cases that occurred during the period 1988 to 1991. Ethics committee approval was obtained before undertaking this study.
At the outset the criteria to be measured were identified, including: 1. the identification of potential immunising events outlined in local and National Blood Transfusion Service guidelined current at the time of the study; 2. adherence to the local blood transfusion service recommendations for antibody screening during pregnancy; 3. adherence to the recommendations for anti-D immunoglobulin administration (ie, was anti-D immunoglobulin given when indicated at the recommended dose and within correct time specification3?); 4. adherence to the recommendations on Kleihauer testing (ie, was a Kleihauer test performed when indicated and was appropriate action taken on the result thereof3–5?).
A research midwife was employed to scrutinise the obstetric notes, identify any potential immunising events and determine if the criteria had been satisfied. For each event identified, the pregnancy in which it occurred and the stage of gestation were noted. The pregnancy and gestational age at which immune anti-D antibodies were first identified were also noted. In this study the term ‘first pregnancy’ is used in the sense of indicating a woman's very first pregnancy (even if this pregnancy was aborted) and not as a woman's first on-going pregnancy.
Blood grouping and red cell antibody screening is recommended for all antenatal women in early pregnancy. In Rh(D) negative women screening is repeated at 34 weeks in the first pregnancy and in subsequent pregnancies at 2–28 weeks and at 34 weeks. Antibody screening is carried out at delivery, and if anti-D antibodies are detected, quantification is perfomed by an autoanalyser technique6. For this study immune anti-D was defined as a sample reactive at least 3+ by the indirect antiglobulin technique and > 1 international unit per millilitre (TU/mL) on quantification.
One hundred and forty-seven cases of RhD sensitisation from 15 obstetric units were identified for the period 1988–1991. Data regarding previous pregnancies or previous antenatal antibody screening were not available in 18 cases, leaving 129 (312 pregnancies) for assessment. Immune anti-D was initially detected during the first pregnancy in 28 women (22% of all cases), second pregnancy in 50 women (39%), third pregnancy in 36 women (28%), fourth pregnancy in nine women (7%), and fifth or subsequent pregnancy in six women (4%).
Only 4 of 28 women (14%) in their first pregnancy had developed immune anti-D by 28 weeks. Thus 86% of immunisations occurring during first pregnancy might have been prevented by antenatal prophylaxis administered at 28 and 34 weeks. A potential immunising event was identified in only five cases (18%): threatened abortion in four and an antepartum haemorrhage in one.
Sixteen of 50 women (32%) in their second pregnancy had detectable anti-D at booking, seven of whom had experienced potential immunising events during the first pregnancy. Fifty-six percent of women had no identifiable immunising events other than their first delivery. Twenty-four events were identified in 22 women; 17 of these events occurred during the first pregnancy and seven during the second. Many events occurred in early pregnancy; in some of these the women did not at that time present to their general practitioners.
Eleven of the 36 women (31%) in their third pregnancy had no identifiable events other than previous delivery. In 25 women there were 37 potential immunising events identified, of which 17 occurred during the first pregnancy, 17 during the second and 3 during the third pregnancy. Miscarriage and termination of pregnancy accounted for 31 of the 37 events (84%). Ectopic pregnancy was noted as the probable immunising event in two cases, and in neither case was anti-D immunoglobulin given.
Immune anti-D was detected initially during the fourth or subsequent pregnancy in 15 women (11%), in two of whom this was the second RhD positive pregnancy. Five women (34%) had no identifiable events during any of their pregnancies other than delivery. Excluding deliveries, 32 potential immunising events occurred in 10 women. Four women had been included in a previous Yorkshire Antenatal Prophylaxis Trial2.
The blood transfusion service antibody screening protocol was not followed on 71 occasions: on 33 occasions the 26–28 week sample was omitted, on 12 occasions the 34 week sample was omitted, and on 26 occasions the post-delivery sample was not tested.
Ninety-eight antenatal events were identified in 62 women, and 67 women (52%) had no identifiable event other than delivery. Of the 98 identified antenatal events full information was available for 58 which were managed in NHS hospital settings. Of the 40 events in which full information was not available, 13 terminations of pregnancy had taken place in private clinics, the notes of which were not available to us. One termination had been performed in an NHS hospital, but the notes were missing. Twenty-six miscarriages had occurred early in pregnancy before booking at NHS hospital antenatal clinics, and so the hospital notes did not clarify whether the recommendations of the blood transfusion service were followed. Data relating to the adherence rates in specific events is shown in Table 1. The protocol was followed in 30 events (52%).
Table 1. Potentially immunising events occurring during pregnancy. TOP = termination of pregnancy.
|External cephalic version||2||2†||0||0|
In the 28 events (48%) the recommendations were not followed, anti-D Ig was not given on 22 occasions, 17 of which occurred < 20 weeks of gestation. On one occasion an incorrect dose was given (250 IU anti-D Ig following an intrauterine death at 28 weeks). When given, anti-D Ig was given within 72 hours of an identified event on all occasions. A Kleihauer test was not carried out on 11 occasions, in five of which anti-D Ig was also omitted and on one occasion an incorrect dose was given (Table 2). The majority of cases in which the blood transfusion service recommendations were not followed occurred in NHS hospital settings.
Table 2. Failure to comply with blood transfusion service protocol. K = Kleihauer; TOP = termination of pregnancy.
Terminations of pregnancy occurred as potential immunising events on 24 occasions in 21 women, 18 of which related to the first pregnancy, four the second, one the third and one the sixth. Six women who terminated their first pregnancy were found to have immune anti-D antibodies during their second pregnancy, in five of whom there were no other immunising events; complete information was available for two of these women who each received 250 IU of anti-D immunoglobulin as per protocol. Neither woman had any identifiable immune events other than the termination itself. In one case the second pregnancy was RhD negative.
Miscarriage-threatened, complete, incomplete or missed-accounted for 55 identifiable events in 39 women. Miscarriage and termination of pregnancy together accounted for 79 of the 98 identified events (81%); of these, the blood transfusion service recommendations were followed in 17 events (22%), not followed in 22 events (28%), and in 40 events (51%) data were not available (Tables 1 and 2). Anti-D Ig was not given on two occasions each of external cephalic version and ectopic pregnancy, as these were not specified in the blood transfusion service recommendations current at that time.
Of 161 deliveries, 129 babies were RhD positive (80%), 31 RhD negative (19%), and there was one failure to determine the Rh type of the baby as it was not realised that the mother was RhD negative. This woman did not have a Kleihauer test and did not receive anti-D Ig.
On 1 of 129 occasions (0.8%) a Kleihauer test was omitted after delivery. On three occasions (2%) a Kleihauer test was performed, but an inadequate dose of anti-D Ig was given. On one occasion a follow up Kleihauer test was not performed following 3000 IU anti-D Ig. Anti-D Ig was administered in all cases within 72 hours of delivery.
Recently there has been much debate regarding the measures that need to be addressed to prevent RhD iso-immunisation7–13. The aim of this study was to determine the likely factors that contribute to RhD sensitisation in our region. The two commonest identifiable events, excluding delivery, were miscarriage and termination of pregnancy. Taken together, they accounted for 79 of the 98 identified events (81%).
We found a significant level of noncompliance with published recommendations in relation to routine screening for antibodies, administration of anti-D immunoglobulin and Kleihauer testing. Failure to carry out a 28–34 week antibody screening could result in delayed identification of an isoimmunised woman who may be carrying a RhD positive fetus. Failure to carry out an antibody screening after delivery could result both in unnecessary administration of anti-D Ig after delivery and lack of awareness of the mother's immunised state with respect to future pregnancies.
A number of events were managed outside of the hospital setting and were thus not documented in hospital casenotes. Many of these events occurred in early pregnancy, before booking at the hospital antenatal clinic. However, of the 58 events for which data are available, the recommendations were not followed on 28 occasions (48%).
We conclude that in order to prevent RhD sensitisation in future more stringent adherence to published recommendations for anti-D immunoglobulin administration is needed including Kleihauer testing. This can be achieved by educational programmes that include all medical and nursing staff involved in the management of RhD negative pregnant women.
It was noted that anti-D Ig was not given following external cephalic version on two occasions and after ectopic pregnancy on two occasions. These circumstances were not specified in the blood transfusion service recommendations between 1988 and 1991. However, recommendations state that anti-D Ig should be given in these situations.
Apparent failure of protection is a less common, though nonetheless important, factor in RhD sensitisation (ie, the occurrence of sensitisation despite the administration of an apparently appropriate dose of anti-D immunoglobulin). Failure of protection occurred in 20 of the 98 events (20%). Seventeen of these 20 events had occurred at < 20 weeks of gestation, thus 250 IU of anti-D immunoglobulin had been administered, as per published recommendations. Two cases are of particular interest. Both involved termination of first pregnancy at < 20 weeks of gestation. In both immune anti-D was detected during the second pregnancy. As neither woman had experienced any identifiable immunising events other than the termination itself, this suggests that 250 IU of anti-D immunoglobulin may not be an adequate dose to prevent immunisations in this setting. Further research is required.
A previous Yorkshire trial of antenatal prophylaxis in primigravidae showed a significant reduction in the incidence of RhD sensitisation2. Our present results indicate that at least 86% of RhD immunisations which occur during the first pregnancy are potentially preventable by antenatal prophylaxis, as only four of the 28 cases (14%) who were immunised during the first pregnancy were immune by 28 weeks.
Our results show that to prevent further RhD immunisations occurring increased compliance with published recommendations for the administration of anti-D immunoglobulin is needed and further research undertaken to determine the dose of anti-D immunoglobulin that should be administered following potentially immunising events during the first 20 weeks of pregnancy, particularly following termination of pregnancy and miscarriage. Routine antenatal prophylaxis in the third trimester has been advocated by other workers'. Our data confirm that this would reduce the level of sensistisation in primigravidae; however, such an approach would need to be combined with the measures outlined above if maximum benefit is to be achievcd.