Rh‐prophylaxis in early abortion

In most countries anti-D immunoglobulin G (anti-D IgG) is given to rhesus (Rh)-negative women, although evidence is lacking for the need of this intervention after abortion in early pregnancy. This is especially true for medical abortion, which has been used increasingly in recent years. Mifepristone was approved for medical abortion in France in 1988 under the brand name of Mifegyne. The UK and Sweden followed in 1991 and 1992, respectively, and most other European countries in 2000. So far more than one million women have used this method in Europe alone, and the use is still increasing. The need for the application of immunoglobulin in medical abortion has never been evaluated. The necessity seems questionable when the intervention is performed in early pregnancy and in many cases even before a fetal heart rate can be demonstrated by ultrasound. The Swedish Board of Health and Welfare gave a recommendation against the use of anti-D IgG in early spontaneous or medical abortions in 1997. However, there is still no evidence-based analysis for or against prophylaxis. This leads to regional variations in the treatment of early abortion. This paper reviews publications on this subject with the particular aim of providing a background for recommendations or further research initiatives. A review of this kind could not be found in the literature, and has probably not been done recently. This article is based on: a review of the literature in MedLine on the Rh blood group system, fetomaternal hemorrhage (FMH) and Rh (D)-immunization in relation to spontaneous or induced surgical and medical abortion; further articles found as reference in the above-mentioned publications and recommendations from specialists working in the field; recommendations and references from health authorities, abortion providers and manufacturers of Rh immunoglobulins; personal communication with specialists in gynecology and obstetrics, haematology and embryology. The origin of the hematopoietic stem cells (HSCs) that can be found in the hematopoietic organs of the embryo have long been the subject of controversy. The first recognizable blood cells appear within the wall of the yolk sac at about day 17 postconception. The numbers of erythroid burst-forming units (and granulomacrophage progenitors) within the yolk sac decline between the fourth and fifth week after conception, or 6–7 weeks after the last menstrual period (LMP), as they increase reciprocally in the liver. This suggests that HSCs of the yolk sac migrate to the liver, where they establish nests of proliferating cells that may eventually seed other hematopoietic organs of the embryo, including spleen, lymph nodes, thymus and bone marrow. There is a concomitant switching from embryonic to fetal hemoglobin (Hb F) isoforms (1). The role of the yolk sac as the primary source of blood cells is short lived. Its hematopoietic activity decreases rapidly until 10 weeks postconception (12 weeks LMP), when it finally ceases to produce blood cells. At around the fifth week postconception (7 weeks LMP) the hematopoietic activity of the liver quickly becomes the primary source of red blood cells, a position it holds until the 30th week of gestation. The majority of hemoglobin synthesized during the hepatic phase is Hb F. The fetal spleen also commences production of red blood cells at about 10 weeks LMP and continues throughout the second trimester of pregnancy. Bone cavities begin to form red blood cells at about 20 weeks LMP and rapidly become the sole source of hematopoiesis in humans. Additionally, Hb F is gradually replaced after delivery by adult hemoglobin (Hb A), the latter being produced only in the bone marrow. By the end of the first year after birth, Hb A is the only type of hemoglobin that can be found, although some individuals continue to produce a low level of Hb F (1-3). The Rh blood group system consists of a number of inherited antigens. It is the commonest cause of hemolytic disease of the fetus and the newborn. The presence of anti-D antibodies in an Rh (D)-negative woman causes hemolytic disease in an Rh-positive fetus/newborn. The Rh blood group system is also of major importance for hemolytic transfusion reactions. The Fisher–Race nomenclature assumes the presence of three genetic loci for the antigens, each with possible alleles. Today more than 45 antigens in the Rh system are known. The most important are D, c, C, e and E. There are two Rh genes, RhD and RhCE, located on the short arm of chromosome 1. The genes that control their synthesis are not clearly known. There are three codominant alleles; D, d, C, c, E and e. The entire gene complex is inherited as a unit (haplotype). The resulting antigens are named D, C, c, E and e and are inherited in two sets of three; one set from each parent. The most common sets of antigens are Cde (42%), cde (38%) and cDE (14%). Many variations of the D-antigen expression form a heterogeneous group called weak D (previously Du). All weak D forms are considered to be D-positive because of their ability to produce an antibody response. Rh-antigens are proteins (nonsugar containing, like other antigens) that are associated with large membrane complexes on the red blood cell surface. The number of antigenic sites for a specific red cell depends on the genotype (3-5). About 40–50% of all Rh-positive individuals are homozygous for D, having inherited D from both parents. The others (50–60%) are heterozygous for D, having inherited a D-containing set from one parent and a non-D set from the other parent. A child from homozygous Rh-positive parents can only be Rh-positive. A child from a heterozygous Rh-positive couple on the other side can be Rh-positive or Rh-negative. Only an Rh-positive fetus or a blood transfusion of Rh-positive blood is able to cause Rh-immunization in an Rh-negative woman. The antibodies produced by a woman affect only an Rh-positive fetus (3). The presence or absence of the D-antigen denotes an Rh-positive or an Rh-negative individual and for most clinical purposes, people are classified as Rh-positive or Rh-negative by testing their red cells with anti-D antiserum. Because no antiserum specific for d has been found, d in the blood group classification signifies the absence of a not the first woman has blood group and Rh in there is no of blood In all Rh-negative women are for the presence of anti-D This is done by the for the of IgG A the presence of antibodies of with Rh-positive red cells, and of (3). In of an induced abortion antibodies are not is a and is around from in to in probably Rh-positive at one by genes with genes, a of are as as of and of are Rh-negative. than of and are Rh-negative. Rh-negative women have a of being with an Rh-positive between an Rh-negative and an Rh-positive fetus can be found in of all in Europe The D-antigen is The other Rh-antigens are for than D are of Rh-negative people antibodies of anti-D to Rh-positive red cells (3). of Rh-positive blood may be to produce In one of cases with 10 of Rh-positive blood (3). In other of cases after one of Rh-positive red cells and with of of Rh-positive red cells (3). A may after to of Rh-positive red cells. About of Rh-negative people are never even when to large of Rh-positive blood in the fetus is to the fetal red cells are in the and only in have a of and the blood group A It has been that group A between and against of the blood group against primary it no against the have also that an Rh-positive that an Rh-immunization in the is more than The of to was found to be to The primary response. The primary In Rh-immunization of the first antibodies as early as weeks after it to weeks before a The primary is weak and in not the IgG between weeks to after IgG anti-D the and leads to of Rh-positive fetal red cells The response. the primary has a to Rh-positive red cells leads to a increase in which are IgG in All further may produce even of the between are both antibody and of the antibody for the be and the of Rh The antibody decreases a Because of the only are at for hemolytic disease of the and the fetus The of IgG is an and only from the to the fetus and only the IgG is the only immunoglobulin able to the on the membrane of the The of the IgG produced and the in may the in the of fetal The of anti-D antibody with leads to the of Rh-positive red cells. This is not a and most red blood cells are in the may also to the D-antigen can be by of anti-D IgG before or after to Rh-positive red cells. an of there are three of for the anti-D and and by of cells the of to Rh-positive red cells was first for use in and has to D-antigen is given in at the before has However, it be that anti-D IgG not against of other which may also cause hemolytic disease of the fetus and the newborn. IgG is by from by or with of anti-D IgG The is and by IgG is in and is as an the or in the The of this anti-D IgG is have that the of a of anti-D IgG to Rh-negative women within of delivery the for Rh-immunization by about the woman has not been The the between anti-D IgG and the it be The rate of Rh-immunization at after delivery with application of anti-D IgG is than to an in the of Rh-immunization in women after the first Rh-positive and pregnancy The recommendation and for delivery at is to anti-D IgG to the is Rh-negative and the fetus is found to be Rh-positive or in the of the fetus is This has been under for many years. of of anti-D IgG is considered to against the transfusion of fetal blood or blood cells. However, of women have an of than at delivery A is the of in anti-D The of this is to be between and It is this is of clinical However, IgG from the to the fetus There is also about the of anti-D IgG and there is a in some of the some in the during the first hemorrhage could be The the and of anti-D In countries anti-D IgG is not However, the number of Rh-negative women is in most of the Europe and although women are at of with a Rh-positive The of of and the of anti-D IgG is as to are about the of disease from blood has to the that no from the UK be used for the of blood including anti-D IgG IgG has to be which be considered as a in some of the The for one of anti-D IgG is of pregnancy to the It has been that more than of the fetal blood is in the is this of blood the with the for The of fetal blood at weeks LMP is to be This is based on a that fetal blood of or at an the blood at weeks be than However, the blood in a fetus than weeks has not been or could be found on this It is that Rh-immunization in an Rh-negative woman is to with an Rh-positive or with Rh-positive It has been that early and abortion can cause an as fetal red blood cells or Rh-antigens from red cells the in the during abortion. In this it is important to establish the of fetal at which blood group antigens are found Rh-antigens on the red blood cells of a after or after LMP The embryo was found in a with was because of a The embryo a yolk sac and was within of the of fetal The was found to be Rh-positive by This is the only of an early fetus and the of the blood cells may during the of fetal Rh-antigens in a fetus as as after suggests that early abortion could Rh-immunization in the woman. can be used for fetal in of the most used is the or the This method can one fetal red cell in 20 adult red cells it has of and is considered as The method considered most is this analysis the blood is first with anti-D and with cell are found in numbers in blood during early and this method has a for the the method was used for analysis of the have been about as The used it to the of pregnancy. can as early as at weeks weeks This is the when fetal and in the has been and when the of the and the of the fetal heart as low as has been at this of pregnancy the method Hb F cells are found in numbers in of In about of women, the level of Hb F the of at about weeks and may This can be considered as a and the of fetal cells by the In one a majority of women found to have an increase in Hb during the first in the second trimester and at delivery that in of was and that most of the women as a of or was during a pregnancy. In than of the cases more than and in than of the cases more than 20 of could be In to Hb F was the method in women in the second and The from at to at The and of Hb F red cells found to be of and the of the there was a increase in Hb F red cells women with are by Rh-negative women during their first pregnancy. The rate for this is The of Rh-immunization for an Rh-negative women is considered to be during a pregnancy with an Rh-positive in they are The is to be during delivery (3). At delivery after a there is a for than and for more than It is that anti-D IgG against of fetal blood cells or of fetal blood In spontaneous abortion. that spontaneous abortion in the first trimester can cause primary Rh-immunization could not be found in the There is some evidence that only after not after or spontaneous the first to that all women spontaneous or found Hb F red cells in of women with spontaneous abortion in the first and second trimester weeks LMP) of the women a for abortion. to Hb F in women with a pregnancy of the The of Hb F red cells was found to be of the of the pregnancy in which the abortion In all cases the of red cells to a of than It can be that a of than during spontaneous abortion or during the first was the women spontaneous abortion. The suggests that there be no between the of and the for Rh-immunization after abortion. However, the recommendation for anti-D IgG to all Rh-negative women abortion is no Hb F is found or women with spontaneous abortion a of to a control group for women with a of weeks than 20 with abortion as or of the and control used to the pregnancy and the method was used for fetal red cells. The of the not although women with abortion a of In women with a pregnancy a of during the first and early second control was found to have Hb probably to a of Hb F. this not a the for all women with abortion. In the Swedish Board of Health and Welfare a recommendation to anti-D IgG to women after early spontaneous or medical abortion The rate in women with early spontaneous abortion was during the by could no evidence for an increase in Rh-immunization However, there is a that only a year not the The recommendation to was to no the absence of a in in In surgical abortion. The of and fetal during surgical abortion and probably fetal red blood cells the The under may the of fetal red blood cells the to anti-D to all Rh-negative women kind of abortion to a by This is a to or not in women induced abortions than weeks LMP The of the was from LMP and used and used as a before and after the to for fetal cells and with the cells found in two women before the abortion and in after the red blood cells could be found in a number of women with a pregnancy than weeks fetal red blood cells could be found in women at than weeks The that all Rh-negative women at weeks LMP or more be given anti-D IgG induced surgical abortion The with this is the method used to and the of the pregnancy as no was This is a found in blood before and after surgical of pregnancy (and other abortion medical in the first and second increase in the number of Hb F cells was found in of the women after the abortion. In the of the was more than and in of the are given about of pregnancy was the of Rh-immunization to be during the first and at at and The of was to increase with the at abortion. Rh-negative followed during years. antibody in the early phase of their pregnancy. It was that the after abortion at LMP than weeks is and all Rh-negative women have an abortion at or anti-D IgG and The method for as as of abortion not In a Rh-negative women first pregnancy in induced abortion and not given anti-D IgG at the of abortion The was that a never at the of the second pregnancy in In all cases more than between the abortion and the second pregnancy. The rate of to be about It was also that is to Rh-negative women of the Rh group of the However, in a in which the rate of Rh-positive is and with it can be that of the of Rh-negative be Rh-negative because of the of Rh-negative or heterozygous only of the are at of on this the of in Rh-negative women after abortion not to to of first pregnancy and of the pregnancy not in the and the rate of by the end of the first pregnancy was not known. Because of the blood of the fetus during the first trimester it could be that anti-D IgG be during this period anti-D IgG is considered to the women for being Rh-negative women for surgical abortion at weeks LMP The women given of anti-D IgG and for A control group was given anti-D There was no group of of the evidence of The was that Rh-immunization in women to weeks of after surgical abortion. The treatment rate was to be about are only in or in most This it to the recommendation of a in early abortion. In medical abortion In and as by and a in could be between surgical and medical abortion and be to of blood at the of fetal blood the medical abortion and of blood the for fetal cells to the performed a where they in women before a of of was before and at the end of the to a control group with before and after surgical abortion. In the medical abortion group not increase in of the 20 during the between treatment and of in three in the medical abortion to in the control This which was as a is the only that could be found on medical abortion. The of was not The is not for A between and and for Rh-immunization could not be found in the not to medical abortion be of for women abortion in There are abortion providers at in countries and the of of and abortions is to a and women in countries from to medical abortion. a method that is to and at low to the health of women anti-D IgG could be from the for Rh-negative women the method probably be even more This could to the method more and probably to a more this an evidence-based recommendation be There are many recommendations for anti-D IgG in early spontaneous and induced medical There are also where no recommendations are and where the anti-D IgG be given is The absence of evidence for of recommendations is not and is in to the of all a treatment that is based on It be as that all recommendations that are and that have the of being are on references that are to or are used as of the for Rh-immunization in Rh-negative women after medical abortion is still The are from on surgical abortion or of induced abortion are in many to the method used for early induced abortion, they are used as references for It is to the number of women at for Rh-immunization from the as the of and the number of women is low in most recommendations are based on in early it be in that is to to the rate of after early abortion. the use of and of of pregnancy it to the of The method may be and is it has to be considered as in the of It is between fetal red cells and adult cells In of or it has been to be and is as of However, of in early pregnancy between and by this method not with some this method to be of no in the of The method for for research is probably the method of has been to be to the other is not The method has a and is more than the A common in is also the method for the of the pregnancy. use and IgG is and against Rh-immunization although the in early spontaneous or induced abortion is not The for anti-D IgG is considered as low and are This leads to the that there is no health associated with the of proteins during However, no or analysis was found anti-D IgG application for Rh-negative women early spontaneous or induced abortion. be a analysis be It is to the of of in of their unit for year of or there are many recommendations based on about the of no a for be based on a between the and of anti-D The of evidence-based on the need for immunoglobulin in early spontaneous and induced medical abortion is a of this of a large number of women are based on a questionable this the of induced abortion. The in to the evidence-based also to women an abortion. The need for to the of is especially when it to medical abortion. number of women in Europe are for this of surgical abortion, a that is to continue in the years. abortion is induced or all Rh-negative women be with D the is to be Rh-negative. Because it is possible to with the D of the all Rh-negative women It is also that be given in where the D type is in the woman is in no be for the use of anti-D immunoglobulin for Rh which anti-D be given to Rh-negative be given to all women having a of by surgical or medical of they are from blood to have and be given to all women have spontaneous or abortion after weeks However, with to abortions in women the are that are It is only after to of not after spontaneous abortion. be given when there has been an intervention to the of before weeks is when there has been no to the of and anti-D is not in pregnancy it is that the is and no of anti-D is on Rh testing and Rh is a health to Rh women recommendation is are to be they be followed in all be and to be to Rh-negative women and references are given Rh-negative women anti-D IgG when the pregnancy is surgical of the is is not the spontaneous abortion is or the pregnancy is by medical and no surgical of the is weeks of of anti-D IgG is the pregnancy is by surgical It was not possible to references for this from the Board of Health and Welfare The recommendations from the have three of and A at one of clinical no clinical and evidence from an for Rh-immunization are on the IgG be given to all RhD women abortion, surgical or medical and of for Rh-immunization and spontaneous abortion are on on which to recommendations in are IgG be given there has been an intervention to the The of by spontaneous before weeks is when there has been no to the of and anti-D IgG is not in IgG be given to all Rh-negative women have a spontaneous or abortion after of anti-D IgG for in the first weeks of pregnancy where the fetus is is not based on and evidence The Rh-negative woman is not Rh anti-D after a pregnancy The use of anti-D is for abortion in the first has not been for abortion in the first trimester as long as the of anti-D IgG is and not to other recommendations it be to anti-D IgG from at of abortions are to for It is to women anti-D is given for or spontaneous abortion anti-D IgG is to red cell IgG is abortions to the by which that all women spontaneous or induced abortion prophylaxis. In Sweden women anti-D IgG with The for Rh-immunization is to about after abortion. are before an anti-D IgG recommendation is as a recommendation for early spontaneous and medical abortions All Rh-negative women type of abortion be with anti-D IgG when the pregnancy is of anti-D IgG is against all during the first trimester All women having induced or spontaneous abortions and probably anti-D IgG is to weeks of gestation. are from research on and spontaneous abortions The Health working group that all Rh-negative women induced abortion at weeks be given anti-D they are and women of where spontaneous abortion is followed by an of the the of a at this This of of fetal cells. In abortion with before weeks and the pregnancy is anti-D IgG be given the woman is most important in Rh D by pregnancy All women be a of anti-D IgG after induced abortion. anti-D IgG after spontaneous abortion in the first trimester is not and The induced abortion in women is to be at abortion is not All Rh-negative women induced abortions at weeks or more anti-D are the woman is or the of the fetus is to be Rh-negative. It is that the for after induced abortion between that for delivery and that of a spontaneous abortion based on surgical and of abortion and on fetomaternal where analysis was The of the fetus that was was not clearly A of anti-D IgG all abortions at weeks or gestation. are women or to be Rh-negative. It is also that the is to all women menstrual although there may not be fetal blood cells to cause at this and there may be in the to by and and references that are from surgical of pregnancy not the number of that pregnancy IgG be given to all women after abortion, where the of the is abortion anti-D IgG is for (3). of anti-D for anti-D all women early pregnancy are of of anti-D for anti-D All women early pregnancy are of of anti-D spontaneous or abortion before weeks and of for In all the use of blood group and rhesus and the of rhesus as as other during pregnancy references are given for this subject