Routine Antenatal Prophylaxis Research Articles

Terminating Routine Cord Blood RhD Typing of the Newborns to Guide Postnatal Anti-D Immunoglobulin Prophylaxis Based on the Results of Fetal RHD Genotyping

Introduction: Targeted routine antenatal prophylaxis with anti-D immunoglobulin (Ig) only to RhD-negative pregnant women who carry RhD-positive fetuses (determined by fetal RHD genotyping) has reduced D-alloimmunization significantly when administered in addition to postnatal prophylaxis. Achieving high analysis sensitivity and few false-negative fetal RHD results will make RhD typing of the newborn redundant. Postnatal prophylaxis can then be given based on the result of fetal RHD genotyping. Terminating routine RhD typing of the newborns in cord blood will streamline maternity care. Accordingly, we compared the results of fetal RHD genotyping with RhD typing of the newborns. Methods: Fetal RHD genotyping was performed, and antenatal anti-D Ig was administered at gestational week 24 and 28, respectively. Data for 2017–2020 are reported. Results: Ten laboratories reported 18,536 fetal RHD genotypings, and 16,378 RhD typing results of newborns. We found 46 false-positive (0.28%) and seven false-negative (0.04%) results. Sensitivity of the assays was 99.93%, while specificity was 99.24%. Conclusion: Few false-negative results support the good analysis quality of fetal RHD genotyping. Routine cord blood RhD typing will therefore be discontinued nationwide and postnatal anti-D Ig will now be given based on the result of fetal RHD genotyping.

Diagnostic Accuracy of Routine Antenatal Determination of Fetal RHD Status Across Gestation

The RhD (RH1) antigen of the rhesus system is the most commonly implicated antigen for hemolytic disease of the fetus. Postnatal prophylaxis with anti-RhD immunoglobulin in RhD− women with an RhD+ child has been shown to reduce the risk of becoming alloimmunized. Subsequent introduction of routine antenatal prophylaxis with anti-RhD immunoglobulin in the third trimester for all RhD− women is now standard in many countries. Cell-free fetal DNA in maternal plasma can be tested for the presence or absence of the RHD gene, essentially screening for fetal Rh status. This prospective, multicenter cohort study was performed to determine the diagnostic accuracy of RHD genotyping in RhD− parturients and the optimal gestation for implementation into practice. From 2009 to 2012, consenting parturients had blood samples obtained at their initial appointment, at Down syndrome screening (11–21 weeks’ gestation), and at routine anomaly scanning (18–23 weeks’ gestation). At the third trimester visit (∼28 weeks), women were given the results of molecular testing, and an additional blood sample was obtained to confirm fetal RHD status. When this testing confirmed that the fetus was RHD−, women were allowed to opt out of receiving anti-RhD immunoglobulin. All women predicted to be carrying an RhD+ baby, or if the genotyping result was inconclusive, were offered anti-RhD immunoglobulin. All women who had a sensitizing event at less than 28 weeks were also offered anti-RhD immunoglobulin. RhD typing on cord blood samples was performed using routine serologic methods. Genotyping results were interpreted as RHD+, RHD−, or inconclusive. The final analysis included 2288 women and 4913 fetal genotype results with 4 analyses or less per parturient. Genotyping results were inconclusive for 393 samples (8.0%; 95% confidence interval, 7.3%–8.8%). Based on cord blood analyses, 2023 samples were from RhD− babies, of which 18 had been falsely predicted antenatally to be genotypically RHD+, and 85 were inconclusive; 2890 were RhD+, of which 308 were inconclusive on fetal RHD genotyping, and 19 were falsely predicted to be genotypically RHD−. The odds of correctly identifying RHD+ and RHD− fetuses increased significantly with gestational age, with low levels of false-negative results after 11 weeks’ gestation. At less than 11, 11 to 13, 14 to 17, 18 to 23, and more than 23 weeks, the sensitivities for detecting fetal RHD positivity were 96.85% (94.95%–98.05%), 99.83% (99.06%–99.97%), 99.67% (98.17%–99.94%), 99.82% (98.96%–99.97%), and 100% (99.59%–100%). At less than 11 weeks, 16 (1.9%) of 865 babies tested were falsely predicted to be RHD−. Massive throughput fetal RHD genotyping can be performed as soon as possible at 11 weeks or more. After 11 weeks, the incidence of false-negative results was considerably lower and did not decrease between 11 and 24 weeks, in agreement with evidence that concentrations of cell-free fetal DNA increase only minimally at 10 to 20 weeks’ gestation. The small number of false RHD− results after 11 weeks would lead to a small increase in the risk of alloimmunization. The tradeoffs between treating fewer women with antepartum immunoglobulin versus a few women becoming alloimmunized need to be considered carefully.

BCSH guideline for the use of anti-D immunoglobulin for the prevention of haemolytic disease of the fetus and newborn.

BCSH guideline for the use of anti-D immunoglobulin for the prevention of haemolytic disease of the fetus and newborn.

Relevance of new recommendations on routine antenatal prevention of rhesus immunization: An appraisal based on a retrospective analysis of all cases observed in two French administrative areas of 3 million inhabitants

Objective To assess the potential impact of new guidelines recommending routine antenatal prophylaxis at 28 weeks of pregnancy on incidence, consequences and cost of rhesus immunization. Study design All rhesus immunizations of 224,500 ongoing pregnancies in two neighbouring administrative areas in France between 2000 and 2006 were enrolled in this retrospective study. To determine the aetiology of immunization and to specify when sensitization occurred, we searched sensitizing events between the last negative and the first positive red-cell antibody test results. Perinatal consequences and costing were also analyzed. Results From 138 rhesus negative women bearing anti-D antibodies, none had received routine prophylaxis at 28 weeks. 37% were primary immunizations and 63% were reactivating former immunization. 63% sensitizations occurred after unprovoked foetal-maternal haemorrhage, mostly after 28 weeks (54%). Twenty-five (18.1%) sensitizations resulted from inappropriate management of existing prophylaxis. Immigrants with previously acquired antibodies accounted for 10% of cases. There was no foetal demise and none born before 28 weeks among our 140 babies. Only 25% required intensive care, mostly those born to mothers reactivating immunization, with an overall good perinatal outcome. Systematic 28-week prophylaxis would have cost about €2.5 million to reduce overall cost of immunizations by €0.6 million. Conclusions The incidence of rhesus immunization in our population was low at 0.41‰. Routine antenatal prophylaxis could have avoided 54% of these immunizations but expected perinatal benefits are low, as newborns with the worst issue were born to mothers with unavoidable immunizations. Therefore the cost-effectiveness of this strategy is doubtful.

RhD Prophylaxis in Australia: 1966 and Beyond

In the late 1960s clinical trials showed that the incidence of Rh D immunisation of Rh negative women could be dramatically reduced by the administration of Rh D immunoglobulin (Ig) after delivery. In 1968 Australia became the first country to be self sufficient in Rh D Ig with the introduction of the Rh programme. Despite appropriate use of Rh D Ig 1–2% of Rh negative women still became immunised. Studies subsequently showed that immunisation rates could be further reduced by prophylactic administration of Rh D Ig during pregnancy. Routine antenatal prophylaxis has been practiced in Canada and USA for more than 20 years. The first NHMRC Clinical Practice Guidelines on the use of Rh D Ig were issued in 1999. These acknowledged that routine antenatal prophylaxis was best practice, however could not be recommended due to supply constraints. Subsequent initiatives included the licensing of the 250 IU dose of Rh D Ig, expansion of plasma collection and importation of product. Staged introduction of routine antenatal prophylaxis began in late 2002 with introduction of prophylaxis for primigravidae. Stage 2, which provides antenatal prophylaxis for all Rh D negative women, is to be implemented by 1 January 2005. Stage 3 will see cessation of the need for use of imported product. A Joint Consultative Committee of involved specialties is helping to ensure consultation and communication for the implementation process. The possibility of developing a laboratory Rh D Ig which could be produced in unlimited quantities, in a standardised formulation with no reliance on human derived sources has been entertained for many years. Results of trials of possible options have been intermittently published. However, it is likely that the ‘liquid gold’ anti D plasma donated by our amazing volunteers will be needed for many years to come.

Clinical validation of routine antenatal anti-D prophylaxis questions the modelling predictions adopted by NICE for Rhesus D sensitisation rates: Results of a longitudinal study

Objective To compare the rates of Rh(D) sensitisations with a policy of restricted routine antenatal anti-D prophylaxis (first pregnancy only) with the rates predicted with universal routine antenatal anti-D prophylaxis (all pregnancies). Study design A retrospective longitudinal observational study involving 15,500 confinements in Rhesus D negative (Rh(D)−ve) women between 1990 and 2003 in a single health district was conducted. All Rh(D) sensitised pregnancies were identified and evidence for routine antenatal anti-D prophylaxis administration during the first pregnancy was investigated. The rate of Rh(D) sensitisations following a policy of restricted prophylaxis was compared with that predicted with mathematical modelling following universal prophylaxis. Results There were 50 newly sensitised and 37 previously sensitised pregnancies among 15,596 Rh(D)−ve women. For the calculated 13,575 Rh(D)−ve women whose first confinement was in Oxford and who were eligible for restricted prophylaxis, there were 30 new and 26 previously sensitised pregnancies. Of these 30 new sensitisations, 10 were nulliparae, 12 parity 1, and eight parity 2 or greater (third or later continuing pregnancy); only one of these latter eight women had received routine prophylaxis, four had delivered their first baby before the programme was introduced, and in three documentary evidence could not be confirmed that prophylaxis had been given. There was no difference between a policy of restricted and universal routine antenatal anti-D prophylaxis in the sensitisation rates for women during their third or subsequent pregnancy. Conclusions This study has shown that restricted routine antenatal prophylaxis provides continuing protection for subsequent pregnancies although the mechanism for this is unclear. These results challenge the wisdom and expense of a policy of universal prophylaxis and prompt a need for further similar analyses to test the appropriateness of the NICE guideline.

Compliance with routine antenatal rhesus D prophylaxis and the impact on sensitisations: observations over 14 years

Documented routine antenatal anti-D prophylaxis was given to 90% and 81-87% of eligible women at 28 and 34 weeks of gestation, respectively, during the early 1990s and early 2000s. With increasing experience and education, a significant improvement in the timing of the first (OR 0.26, 95% CI 0.16-0.41: P < 0.0001) and second injections (OR 0.40, 95% CI 0.26-0.61: P < 0.0001) occurred during the latter period. Despite these improvements, there was no reduction in the sensitisation rate at 0.4%. However, this low rate occurred despite significant proportions of women delivering more than 42 days after the second injection. Fifteen of the 16 sensitised women had received routine antenatal prophylaxis.

General obstetrics: The kinetics of routine antenatal prophylactic intramuscular injections of polyclonal anti‐D immunoglobulin

To observe the pharmacokinetics of intramuscular anti-D immunoglobulin (IgG) given for routine antenatal prophylaxis. Prospective observational study. Maternity unit and antenatal serology laboratory in a district teaching hospital. Forty-five rhesus-D-negative pregnant women not sensitised to RhD. Serial serum quantitations of anti-D IgG following the intramuscular injections of anti-D IgG 100 microg (500 IU) at 28 and 34 weeks of gestation. Anti-D IgG concentrations were assayed with the RFA-300 continuous flow analyser. The kinetic profile and duration of detectable anti-D IgG in maternal serum following the first and second injections of anti-D IgG. For the 43 women in whom serial data were collected, there were no detectable differences between pregnancies with an RhD-positive (26) or -negative (17) fetus. Maximum IgG concentrations were detected two to five days following the first anti-D IgG injection and ranged between 0 and 28 ng/mL. Only 30% of women still undelivered at 40 weeks of gestation had detectable IgG at 2 ng/mL or greater. There was a significant relationship between higher maximum values and low maternal surface body area (R2 = 0.204, P = 0.002), but this did not influence duration of persistent IgG. Using previously published data, 70% women are not adequately protected with anti-D IgG 12 weeks after the first prophylactic injection. Despite this, previous clinical results suggest that the antenatal prophylaxis schedule used provides adequate protection and that the recommendation for the lowest concentration of protective anti-D IgG antibody levels currently in use is probably overestimated.

Editor's Choice

Editor's Choice

Monoclonal anti-D for immunoprophylaxis.

Routine antenatal prophylaxis with anti-D has become accepted as desirable, but concerns have been expressed about the adequacies of supply and safety of polyclonal anti-D. Human monoclonal anti-D has been produced using Epstein-Barr virus (EBV)-transformed peripheral B cells, sometimes coupled with fusions to myeloma cell lines. More recently, molecular biology techniques have been used to produce human monoclonal anti-D in a variety of different ways. Many monoclonal antibodies (mAbs) have been characterized for fine specificity and in vitro functional activity in International Workshops. Two mAbs have been shown to cause red cell clearance and immunosuppression in male volunteers. Considerations for the future development of monoclonal anti-D for prophylactic use are reviewed.

Management of women who are Rhesus D negative in Northern Ireland

In 1998, all 15 maternity hospitals in Northern Ireland participated in a retrospective survey of the management of pregnant women who were Rhesus D (RhD) negative. This area of clinical practice was chosen for study in the knowledge that a policy of routine antenatal prophylaxis had been proposed at the RCP/RCOG Consensus Conference, and that a change in current clinical practice was likely to follow. It was therefore felt prudent to survey critically current practice in order to collect baseline data before the introduction of new guidelines. Data were analysed on 3274 RhD negative women. The findings from this study show that current management of women who are RhD negative is suboptimal. In particular, there is poor adherence to the guidelines relating to the management of potentially sensitising events in pregnancy. Testing to assess the size of a feto-maternal bleed was often omitted, and it was therefore impossible to ascertain whether an appropriate dose of anti-D immunoglobulin had been administered. Recent publications have also identified this as an area of concern. Trauma during pregnancy was often not managed appropriately, as a potentially sensitising event. Better compliance with the current guidelines was noted when management after delivery was considered. The reasons for this apparent inconsistency should be addressed. New guidelines, recommending the use of routine antenatal prophylaxis to all women who are RhD negative, have recently been published. Providers of antenatal care will need to address this issue within the context of their own practice environment. In doing so they should be mindful of current deficits in guideline compliance which may need to be remedied, to avoid building new practices upon fragile foundations.

EDITORIAL INTRODUCTION

It is 20 years since the last international gathering of experts to discuss anti-D prophylaxis (McMaster Conference 1977)1 and since then relatively little has changed with respect to the incidence of failures of anti-D prophylaxis which remain constant in the region of 1-2%. On the other hand, major advances have occurred in the monitoring and management of affected fetuses in uteru, and in neonatal intensive care. This has resulted in a very significant reduction in reported mortality associated with RhD haemolytic disease to the extent that it is not perceived as a problem any more. However, it has long been advocated that there is significant under reporting of mortality, and there is greater appreciation of the impact of morbidity, and the resources consumed by monitoring and caring for alloimmunised women and their babies. In the UK, routine antenatal prophylaxis has been resisted on the grounds of lack of demonstrable cost-effectiveness in the UK healthcare setting, and concerns about meeting the demands for the additional anti-D required. The latter is a concern worldwide as anti-D plasma supply from donors is a finite resource, and there have been concerns about the ethics and safety of deliberate immunisation of RhD-negative volunteers. The possible early introduction of monoclonal anti-D proved to be a false dawn, and some countries have difficulties in maintaining self-sufficiency in anti-D plasma because of premature closure or reduction of anti-D immunisation programmes. It therefore seemed timely to have a conference of interested parties to debate these issues, and to attempt to come to a consensus. The consensus framework used by the Royal College of Physicians of Edinburgh was chosen as the vehicle for a 2-day conference (held jointly with the Royal College of Obstetricians and Gynaecologists) addressing a number of specific issues. The details of the questions to be addressed, and the consensus methodology are given in a paper in this supplement, and the evidence presented to the panel is also published. This consists of the three background papers prepared in advance and the abstracts of the oral and poster presentations. The final consensus statement is published in full, together with a personal view from a panel member. One specific objective of the Conference was to obtain a definitive statement on the position of antenatal anti-D prophylaxis in the UK, either for, or against. The session in the programme dealing with this topic was therefore chosen to be addressed with speakers chosen to speak for and against, with the opportunity for each to cross-examine the other in public, and for the panel and audience to judge the weight of evidence. This proved to be a successful format for summarising the issues for and against. Finally, and importantly, the conference presentation and statement produced by the panel provided the UK Committee of experts charged with revising and updating the 1991 UK Guidelines on Anti-D Prophylaxis with essential information to complete their task. These revised recommendations are awaited shortly.

Rate of RhD sensitisation before and after implementation of a community based antenatal prophylaxis programme

Despite published guidelines in the United Kingdom for the administration of anti-D immunoglobulin to pregnant women at risk of sensitisation to RhD,1 maternal sensitisation is still between 1% and 1.5%.2...

Prolonged bedrest during pregnancy: does the risk of deep vein thrombosis warrant the use of routine heparin prophylaxis?

This is the first study to assess the risk of clinically apparent DVT in pregnant women placed in the hospital at prolonged bedrest. The outcome is discussed with reference to the risks associated with heparin. Information, including delivery data, length of hospital stay, and discharge diagnoses were extracted from a prospectively collected computerized data bank of all deliveries that occurred over a 5.5-year period at Long Beach Memorial Women's Hospital in Long Beach, California, and at St. Joseph's Hospital in Milwaukee, Wisconsin. One group consisted of all pregnant women who had been hospitalized at prolonged antepartum bedrest, as defined by 3 weeks or more. The other group consisted of the remaining population of women whose deliveries occurred during the same time period. There were 48,525 deliveries during the study period, and 266 (0.5%) women were hospitalized at prolonged antepartum bedrest. The mean number of days in the hospital for these women was 34.6 +/- 14 (range 21-82 days). Of these women, one received prophylactic heparin for a prior history of DVT. There were no cases of DVT in the 265 women who did not receive heparin, risk = 0.0 (CI = 0.00-0.99). Of these 265 women, 234 were hospitalized up to the day of delivery. Of these 234 women, 154 (65.8%) underwent cesarean section and no case of DVT occurred in the postoperative period, risk = 0.0 (CI = 0.0-1.7). Out of the remaining 48,259 women who were not hospitalized at prolonged bedrest, there were 18 cases of clinically apparent DVT, and the longest antepartum hospitalization was 4 days. A conservative risk of complications with prophylactic heparin therapy is 1.0% or greater. Although the risk of DVT in pregnant women hospitalized at prolonged bedrest is not zero, our study indicates that it is very low (< 1.0%). Whereas a risk of DVT of at least 1.0% could warrant heparin prophylaxis, even with 265 patients at prolonged bedrest and 48,525 controls, this risk could not be demonstrated. Using a power analysis with an alpha of 0.05 and a power of 80% to demonstrate this risk, one would need 247 cases and approximately 49,000 controls, which were clearly achieved in this study. In view of the risks associated with heparin, routine antenatal prophylaxis is not recommended unless other risk factors for DVT are present.

Preventing Rhesus D haemolytic disease of the newborn by giving anti-D immunoglobulin: are the guidelines being adequately followed?

To ascertain whether anti-D immunoglobulin is being administered to Rhesus D negative women in accordance with the 1991 recommendations for its use to cover all events which may result in fetomaternal haemorrhage. The notes of women delivered in 1994 were examined for compliance with the 1991 recommendations. Seven maternity units using a central antenatal screening service. Nine hundred and twenty-two Rhesus D negative women delivered in these seven hospitals. The prescription, dosage and indications for administration of anti-D immunoglobulin to women during pregnancy and in the puerperium. Postnatal anti-D immunoglobulin was given in appropriate doses to more than 95% of women who required it. Omissions mainly arose from confusion among women who recently had received antenatal treatment with anti-D immunoglobulin. The 1991 recommendations for antenatal administration were less closely followed. Abdominal trauma was covered in only 20% of cases. An inadequate dosage of 250 i.u. was given to 25 women for antepartum haemorrhage after 20 weeks of gestation. The purpose of the Kleihauer test was sometimes poorly understood, with a 'negative' result interpreted as a reason not to give anti-D immunoglobulin. Closer adherence to the 1991 recommendations might further reduce the incidence of Rhesus D immunisation below the current 1%. It is suggested that more careful application of the recommendations should be evaluated before considering either routine antenatal prophylaxis, or the European recommendation of a larger dose (1000-1500 i.u.), both of which would increase the requirements for this limited resource.