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Objectives: To evaluate the prevention of fetomaternal rhesus-D allo-immunization between 2008 and 2010. This evaluation was a part of the continuous medical evaluation (CME) that is compulsory in French hospitals. It was carried out using the tools recommended by the Haute Autorité de santé. We followed the national guidelines for the prevention of fetomaternal rhesus-D allo-immunization as outlined in 2005 by the national French college of Obstetrics and Gynecology., Materials and Methods: We audited 3926 consultations in the first four months of 2008. Based on the results of the audit, actions were implemented to improve care. In 2009, we audited 4021 consultations to look for improvement, and another 3932 consultations in 2010., Results: In 2008, 14% of the patients had an overall optimal prevention. After actions were taken, 44% of patients in 2009 and 58% of patients in 2010 demonstrated optimal prevention (P<0,05). Especially, the prevention of fetomaternal allo-immunization has been explained for 43% of the patients in 2008 and to 90% of them in 2010. And immunoprophylaxia has been prescribed to 70% of the patients in 2008 and to 93% of them in 2010., Conclusion: This CME has resulted in a statistically significant improvement of the prevention of allo-immunization., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

At present, rhesus prophylaxis concerns RhD negative pregnant women, even though 30 to 40% of them are bearing a RhD negative child. Knowing the RhD fetal genotype could change this quite irrational practice of prophylaxis (exposing many more women than needed to blood derived products) without reducing its efficacy. RhD fetal genotype determined on amniotic fluid has an excellent sensitivity. Presence of silent D genes slightly impairs its specificity which remains acceptable. However women have to be informed of possible false positives. Fetal RhD genotyping on maternal blood is more complex. Sensitivity is good from 10 GW and excellent after 15 GW. In case of a first negative result, it is recommended to control fetal RhD on a second sample drawn a few weeks later. Another new perspective for rhesus prophylaxis is the attempt to substitute polyclonal IgG anti-D into human monoclonal IgG anti-D. The main difficulty is to elaborate monoclonal antibodies with a capacity to neutralize RhD positive red blood cells equivalent to those of polyclonal anti-D. A new generation of antibodies is in process and preliminary clinical results are suggesting a possible use of these monoclonal antibodies for future rhesus prophylaxis but long-term follow-up is required to draw further conclusions.

Any prevention policy has a cost. For anti-D immunization, the main questions concern the cost of a change in the prevention policy by the health insurance fund and more globally by the society in general. Furthermore, the analysis must also examine the cost effectiveness of systematic prevention extended to all Rhesus negative women in comparison with targeted prevention or no prevention. Studies published in Great Britain, Canada, and The United States have generally concluded that the raw cost of systematic prevention is high compared with targeted prevention. On the other hand, the cost-effectiveness would favor the systematic approach. These data are difficult to apply to the French situation because health care costs are different and because of the lack of perfectly reliable epidemiological data on the frequency and consequences of severe forms of allo-immunization. Technological advances, particularly concerning genotyping of fetal Rhesus from maternal blood samples, could have an important impact on the cost factor if a systematic approach is adopted.

RhD prophylaxis concerns RhD negative women, who are non-sensitized against D antigen during and at the end of their pregnancy with a RhD positive child. RhD prophylaxis includes targeted prophylaxis (prevention of anti-D immunization after feto-maternal hemorrhage (FMH) induced by prenatal events and delivery) and routine antenatal D prophylaxis (prevention of anti-D immunization resulting from spontaneous FMH in the last trimester of pregnancy). Targeted prophylaxis should be applied regardless of the gestational age and a dose of 100microg anti-D is usually enough (200microg is the lowest dosage currently available in France). However it is recommended to quantify the volume of feto-maternal hemorrhage to avoid administration of a dose of IgG anti-D less than 20microg per ml of fetal red blood cells. Efficacy of prophylaxis relies also on the delay between the sensitizing event and the injection of anti-D, delay should be less than 72 hours. Intravenous administration of anti-D allows immediate neutralization of D positive fetal red blood cells and should be, if possible, preferred to intramuscular administration (IM). After a first injection of anti-D, if repetition of potential sensitizing events occurs, abstention of prophylaxis is possible depending on the previous administrated dose (protection lasts 6 weeks for 200microg and 9 weeks for 300microg) and the amount of feto-maternal hemorrhage. For routine prophylaxis of the third trimester, 300microg of anti-D should be proposed IM at 281+/-GW. Abstention of Rh prophylaxis is possible if the alleged father is certified RhD negative or if the fetal RhD genotype is confirmed negative. At delivery, RhD phenotype of the newborn should be determined even if RhD fetal genotype is known. Maternal blood should be drawn for quantification of feto-maternal transfusion at least 30 min after delivery is completed.

Background: In France, anti-Rh prophylaxis is currently based on systematic postnatal prevention which has validated efficacy (relative risk=0.04 versus placebo), associated with targeted antenatal prevention in the event of situations raising a risk of fetomaternal hemorrhage. In most industrialized countries, a systematic prevention policy is applied with immunoglobulin injections for the above cited situations and during the third trimester to cover the risk of spontaneous occult fetomaternal hemorrhage occurring at the end of pregnancy., Objective: Compare the efficacy of two strategies for antenatal prevention., Material and Methods: Review of the literature of published comparative studies. Eleven studies were retained (two randomized trials, seven comparative studies, one before-after study, one population-based study) including more than 30,000 treated patients., Results: Globally, immunization rate was to the order of 1.5% (1.2-1.9%) for targeted prevention limited to situations at risk and to the order of 0.2% (0-0.9%), all parities included, for systematic antenatal prevention. Comparative analyses have reported significant odds ratios of 0.20 and 0.37 in all subgroups., Conclusion: Despite the heterogeneous nature of the published studies, available data are in favor of systematic prevention: either with a 300g dose at 28GW or 100g at 28GW and 34GW complementary to the postnatal prevention. Few data are available on the real perinatal benefit of systematic prevention.

Anti-D prophylaxis should be proposed to all RhD negative non-sensitized pregnant women, after delivering an information concerning both Rhesus disease and anti-D immunoglobulins. This information must be delivered as a written document and the patient's oral consent is required before administration of the anti-D immunoglobulins. Anti-D immunoglobulins currently used in France for prophylaxis are extracted from plasma of hyperimmunized paid donors. Even if all the conditions of viral safety are fulfilled in the preparation of anti-D immunoglobulins, they remain blood derived products. As such, prescription of anti-D immunoglobulins should follow legal rules concerning tracability and information. Refusal of rhesus prophylaxis can occur but should be transcribed and motivated in the patient's chart. Administration of anti-D immunoglobulins is usually well tolerated. Reactions to hemolysis of fetal Rhesus positive red cells can occur but remain rare and linked to important foeto-maternal hemorrhage. They can be easily prevented or treated by anti-inflammatory drugs. Patients can be vaccinated against rubella in the post-partum period even though they will receive a concomitant prophylaxis with Rh immunoglobulin. Persistence of passive anti-D in maternal circulation after injection lasts several weeks or months and could have various consequences. In the mother: it can interfere with diagnosis of active anti-D immunization. In most cases, it may be possible to differentiate passive and immune anti-D. When reliable information concerning date and dosage of antenatal anti-D prophylaxis are available. In the newborn: anti-D immunoglobulins can pass through the placenta and enter the fetal circulation, coat the D positive fetal red cells and give positive DAT. Positive DAT is reported in 5 to 15% of the newborns following rhesus prophylaxis in the third trimester but with no report of anemia or jaundice. In absence of ABO incompatibility, no additional investigation is needed in these newborns.

The number of women exposed to a risk of anti-D allo-immunization who require care depends on the number of pregnancies, the distribution of blood groups in the Rhesus D system, and the number of allo-immunization risk situations as well as the chosen prevention protocol. In 2004, there were 790,000 pregnancies in metropolitan France. The total number of conceptions (adding abortions, voluntary interruptions, ectopic pregnancies and in utero fetal deaths) would be to the order of 1,100,000 to 1,200,000. Since 15% of the French population is RhD-negative, 15% of pregnant women or women who have delivered are RhD-negative, which would correspond to 160,000 to 180,000 women exposed to a risk of anti-D allo-immunization. Two strategies could be evaluated: prevention targeting risk factors and systematic prevention from 28 weeks gestation. Both strategies involve treatment with anti-D anti-globulins to RhD-negative women with an RhD-positive newborn. Targeted prevention would involve 160,000 to 190,000 doses for 130,000 to 150,000 women. The systematic approach would consist in 300,000 to 340,000 doses for 250,000 to 280,000 women. This number could be lowered by reserving treatment for women with a RhD-positive partner (210,000 to 230,000 doses for 260,000 to 290,000 women), but this would require a precise contract between the physician and the woman. Another way to reduce the number of doses would be to determine the Rh group of the fetus either by ovular samples or by genotyping on maternal blood. This would give about 200,000 to 220,000 doses for 240,000 to 270,000 women. In light of the literature, the systematic protocol would probably reduce the number of immunized women, the current estimation being 700 women still immunized in France and the goal being a reduction to a residual 200. The number of infants at risk of in utero maternal allo-immunization (fetal death, anasark, anemia) or after birth (jaundice, severe anemia) is not known in France and could be the cause of a few deaths with involvement of about a hundred children. In light of experience in other countries, the systematic protocol would enable avoiding a certain number of these deaths.

Objectives: To evaluate the predictive value of RHD fetal genotype in maternal plasma of Rh D negative mothers after 10 weeks of gestation in a clinical use., Material and Method: Prospective, comparative study between fetal RHD genotyping in maternal plasma, with amplification of exons 4,5,10 of the RHD gene, by real-time multiplex PCR, and Rh D serology at birth, in 218 pregnancy and their 223 babies, between November 2002 and 2004., Results: Combining the amplification of three exons, the concordance rate of fetal Rh D genotyping in maternal plasma and baby phenotyping at delivery was 100%. Four women whose the babies were Rh D negative were positive for RHD exon 10 during pregnancy. This positivity was, in three cases, correlated with the presence of RHDpsi pseudogene and in last case, with a haplotype Cdes (r's). RHD genotyping was performed for five twin pregnancies., Conclusion: Multiplex PCR using maternal plasma provides perfect prenatal prediction of fetal RHD gene. These results confirm that this non invasive procedure is the preferred method for assessing Rh D fetal status in Rh negative mothers. Using this method for two years in routine practice has led us to modify our management scheme for sensitized Rh D-negative pregnant women.

1,969 non immunized rhesus negative primiparous women were followed up in 23 maternity units in the geographical region of Paris. 1,882 could be retained to study antepartum protection and 1,884 to study transplacental passage of fetal blood cells. Two groups were defined according to whether they were born in even or uneven years, so that: 955 were the "control" group who delivered 590 rhesus D positive infants, and 927 were the "treated" group who delivered 599 rhesus D positive infants. The "control" group were used as controls at the 28th and 34th weeks of pregnancy, while the "treated" group received two injections of anti-D immunoglobulin given on the same dates after taking the necessary tests. Immunological testing at the time of the delivery and after the delivery showed that 7 women had become Rh D immunized in the "control" group whereas only one in the "treated" group. This difference, which is statistically significant, confirms the results of other authors about the efficiency of antepartum rhesus disease prevention. The incidence of immunisation during or immediately after the first pregnancy in women who had no previous story of blood transfusions or of terminations of pregnancy is 1.11%, which is a figure relatively low as compared with studies of series carried out in North America, but close to those carried out in other European centres. When primipara of all categories are lumped together the frequency rises to 1.5%. A study of the passage of fetal red blood cells into the maternal circulation shows that at the 29th week of pregnancy out of 1,884 cases there were 5.5% positive kleihauer tests, without a large volume of blood being detected and at the 34th week of pregnancy when 957 tests were carried out, 7% were positive with one of them being of a massive transfusion of blood from the fetus to the mother, which was life-threatening for the fetus. It may be that the incidence had been under-estimated and that the positive results in the two groups, control and treated, show that there is a statistically significant difference that demonstrates that antepartum treatment in the trial has eliminated a worthwhile percentage of positive kleihauer tests which arose from the transfusion of small quantities of blood.(ABSTRACT TRUNCATED AT 400 WORDS)