This chapter should be cited as follows:
Visser GH, Carlo Di Renzo G, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.418863
The Continuous Textbook of Women’s Medicine Series – Obstetrics Module
Volume 16
The prevention and management of Rh disease
Volume Editors:
Professor Gerard HA Visser, Department of Obstetrics and Gynaecology, University Hospital of Utrecht, Heidelberglaan 100, Utrecht 3584EA, The Netherlands
Professor Gian Carlo Di Renzo, University of Perugia, Italy
Chapter
Guidelines for Rhesus Disease Prevention
First published: January 2023
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SUMMARY
Introduction of anti-Rh(D) immunoglobulin more than 50 years ago, has only resulted in a 50% decrease of Rhesus (Rh) Disease globally, due to a low uptake of this prophylaxis. In the recent guidelines from the International Federation of Gynecology and Obstetrics (FIGO), the International Confederation of Midwives (ICM), and the Worldwide Initiative for Rh Disease Eradication (WIRhE), the evidence regarding the usefulness of anti-Rh(D) immunoglobulin is reviewed, taking into account its effectiveness, different doses for different indications and prioritizing its administration by indication. In this chapter these guidelines are presented and compared with some national guidelines.
INTRODUCTION
In 1968, more than 50 years ago, anti-Rh(D) immunoglobulin was approved for use in Rh(D)-negative women to prevent sensitization to the Rh(D) blood group antigen after delivery.1,2 Later this was expanded with anti-Rh(D) prophylaxis during pregnancy to prevent sensitization in the third trimester, as was anti-D prophylaxis in the case of miscarriage, ectopic pregnancy, amniocentesis, bleeding, or abdominal trauma during pregnancy and/or external version in the case of a breech presentation. Recently, fetal Rh determination in maternal blood has been introduced in some countries in early pregnancy, to prevent unnecessary immunoglobulin administration in pregnancies where the fetus appears to be Rh negative.3
This prophylaxis approach is highly effective and in most high-income countries, Rh Disease has almost been eradicated. However, recent data have shown that, in approximately 50% of eligible cases worldwide, on an annual basis, no anti-Rh(D) immunoglobulin is administered.4,5 The reasons vary, but include insufficient supply, cost considerations, ignorance (e.g., simply forgotten to administer anti-Rh(D), lack of access, and use of products that were not tested for therapeutic efficacy.6 It has been estimated that Rh Disease still results in more than 160,000 perinatal deaths and 100,000 cases of disability annually; only a 50% reduction as compared to the era before immunoglobulin administration.4 Such a high burden of a preventable disease should be considered completely unacceptable. Perinatal mortality due to Rh disease still exceeds that of Group B streptococcus infection.
In 2021 the Federation of Gynecology and Obstetrics (FIGO) has published guidelines on the prevention of Rh Disease by immunoprophylaxis, considering the cost effectiveness of the different dose regimens and prioritizing its administration by indication.7 This open access paper has slighted been modified for this chapter, including a brief review of other published guidelines. When quoting these guidelines, please refer to the original publication. The FIGO guidelines and practice recommendations are summarized in Table 1.
1
Practice recommendations: measures to prevent sensitization to Rh(D).
First priority:
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Second priority:
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Low priority:
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BLOOD GROUP AND RH(D) TYPING
A pre-requisite for the prevention of Rh sensitization is the a priori knowledge of the maternal Rh status. Although this is widely agreed upon, it is not the case in many low-resource settings. The Rh(D) factor can be determined using venous or capillary blood samples at local health care facilities, using classical or point-of-care serological methods. The Rh(D) type should preferably be determined in the first trimester, because indications for anti-Rh(D) immunoprophylaxis may arise early in pregnancy; for example, after a miscarriage or an ectopic pregnancy.
POSTPARTUM ANTI-RH(D) IMMUNOGLOBULIN ADMINISTRATION
Rh(D) sensitization occurs in ~16% of pregnancies of Rh(D)-negative women. Postpartum anti-Rh(D) immunoglobulin administration reduces this risk to ~1.5%,3 and this is the most effective intervention to prevent Rh Disease in subsequent pregnancies. Therefore, this approach should have the highest priority in countries/regions where no, or inadequate, prophylaxis is currently provided. When an Rh(D)-positive child is born to an Rh(D)-negative women, 1,500 IU (or, equivalently, 300 μg) of anti-Rh(D) should be administered intramuscularly within 72 hours after delivery. This is sufficient to neutralize 30 ml of Rh(D)-negative fetal whole blood.8 According to one study, the median fetal–maternal transfusion at birth is ~0.7 mL, with a transfusion exceeding 10 mL in only ~1% of cases.9 Therefore, it has been suggested that an anti-Rh(D) dose of 500 IU (i.e., 100 μg) would be sufficient. Nonetheless, the effectiveness of administering a higher standard dose was never completely established,10,11 although a recent meta-analysis suggests slightly better efficacy of the 1,500 IU regimen.12
In some countries it is the policy to give a double dose of anti-Rh(D) after a cesarean delivery. However, this does not seem to be necessary, because data from a large study from the Czech Republic did not show a greater volume of fetal–maternal transfusion after cesarean delivery.9 The same holds for delivery of a twin pregnancy. In case of uncertainty, a Kleihauer–Betke test may also be performed to estimate the actual volume of the fetal–maternal transfusion. It is calculated that one vial of 1,500 IU will prevent sensitization by 30 mL of fetal whole blood. This test is also reasonable in other settings where there is uncertainty regarding the size of a fetal–maternal hemorrhage (e.g., intrauterine fetal death). With the Kleihauer–Betke test, the percentage of fetal cells in the maternal circulation is calculated by counting the number of fetal red cells in a maternal blood smear (% of fetal red cells as compared to maternal red cells × 50 = amount of fetal whole blood in maternal circulation, in mL) . For a detailed description of the Kleihauer–Betke test and other tests quantifying fetal–maternal transfusion, see Fetomaternal Hemorrhage and Laboratory Methods for its Determination.
ANTI-RH(D) IMMUNOGLOBULIN ADMINISTRATION IN PREGNANCY
Most cases of Rh(D) sensitization occur as a result of labor. Routine antenatal administration of anti-Rh(D) immunoglobulin to prevent sensitization resulting from fetal–maternal hemorrhage during pregnancy, was studied in two randomized controlled trials. These showed a 42% reduction in sensitization, although this reduction was not significant (95% CI: 0.15–1.62).13 However, a ‘’bias-adjusted’’ meta-analysis of data from ten studies estimated the pooled odds ratio for a reduction of sensitization to be 0.31 (95% CI: 0.17–0.56), which was highly significant.3,14 Therefore, this approach appears to reduce sensitization further from ~1.5% (achieved using postpartum anti-Rh(D) immunoglobulin) to ~0.5%.
Antenatal anti-Rh(D) immunoglobulin may be given intramuscularly or intravenously, with no clear differences in effectiveness.15 It may be given once (1,500 IU) at 28–34 weeks of gestation, or twice at 28 and 32–34 weeks of gestation (625 IU or 1,500 IU at both gestational ages). Two recent meta-analyses and an additional randomized controlled trial showed that a single administration, with 1,500 IU, resulted in the lowest proportion of women with detectable circulating anti-Rh(D) at delivery, suggesting that this is the optimal against sensitization during pregnancy.12,16
MISCARRIAGE
The risk for sensitization is most likely extremely low for spontaneous miscarriages before 10 weeks of gestation;17 however, data are scarce. Based on the clinical expertise of a NICE guideline committee, it is suggested to give prophylaxis only to women who are having a spontaneous or medical management of miscarriage after 100/7 weeks of gestation. Moreover, for women having a surgical management, prophylaxis may be considered also before 10 weeks of gestation.17 Given the low fetal blood volume during early gestation, an anti-Rh(D) immunoglobulin dose of 500 IU may be used, although no data supports such a policy.
In a complete molar pregnancy organogenesis does not occur, so sensitization to Rh(D) should not occur. However, this differs in a partial molar pregnancy. Since distinction between different forms of molar pregnancy may be difficult, it is generally advised to administer anti-Rh(D) immunoglobulin in this setting.3
ECTOPIC PREGNANCY
A ruptured tubal pregnancy has been associated with a 24% incidence of alloimmunization to Rh(D) in Rh(D)-negative women.18 Therefore, anti-Rh(D) immunoglobulin administration is strictly advised. Fetal blood volume is low at early gestation and the dose of anti-D required may therefore be low.
CHORIONIC VILLUS SAMPLING (CVS) OR AMNIOCENTESIS
Most countries advocate administering anti-Rh(D) immunoglobulin to Rh(D)-negative pregnant women after CVS or amniocentesis, although this recommendation is based on limited scientific evidence.3 In contrast, in Denmark, no immunoprophylaxis is provided in this setting; it was found that there were no differences in alloimmunization at 29 weeks were found between women with invasive testing or otherwise (900 cases needed to prevent one case of immunization).19
LASER TREATMENT OF TTTS
Laser treatment of twin-twin transfusion syndrome (TTTS) results in a positive Kleihauer–Betke test in about 50% of cases and an anti-D immunoglobulin dose of 1,500 IU is advised.20
BLEEDING AND ABDOMINAL TRAUMA IN PREGNANCY
Abdominal trauma may cause fetal–maternal transfusion, which may lead to Rh(D) alloimmunization. Although the exact risks are unknown, it is advised to administer anti-Rh(D) immunoglobulin as prophylaxis. The same holds for second- and third-trimester antenatal hemorrhage.3 The optimal dose of anti-Rh(D) immunoglobulin is not known (1,500 IU is most commonly used).
INTRAUTERINE FETAL DEATH
Fetal death may have been caused by a large fetal–maternal hemorrhage. Therefore, a Kleihauer–Betke test may be useful, both as a part of the workup of the fetal death and – in Rh negative women – to determine the amount of fetal–maternal hemorrhage to calculate the anti-D immunoglobulin dose needed.
EXTERNAL CEPHALIC VERSION IN THE CASE OF BREECH PRESENTATION
The risk of fetal–maternal transfusion during external cephalic version ranges from 2 to 6%.21,22 Therefore, administration of anti-Rh(D) immunoglobulin is advised.3 However, the amount of transfusion is generally low. Based on a large Canadian study, it has been concluded that routine anti-Rh(D) immunoglobulin antenatally at ~32 weeks of gestation, should be enough to prevent sensitization during a subsequent external cephalic version.21
NON-INVASIVE FETAL RH(D) TYPING IN THE FIRST TRIMESTER OF PREGNANCY
Non-invasive first-trimester prenatal testing of cell-free DNA may be used to determine fetal Rh(D) status. Such a policy has recently been introduced into clinical practice in countries such as Denmark, the Netherlands and the United Kingdom. A recent meta-analysis of 60,000 participants showed a very high sensitivity (99.9%; 95% CI: 99.5–100%) and specificity (99.2%; 95% CI: 89.5–99.5%), as compared to testing newborn’s blood.23 First-trimester non-invasive Rh(D) typing may therefore be used to prevent unnecessary anti-Rh(D) immunoglobulin administration in the course of pregnancy (routinely or following amniocentesis etc.). ‘While population-based cfDNA as a method to determine Rh status may not be currently cost-effective in all settings,3 health policymakers should include this non-invasive testing as a future option for combating Rh disease.
AMOUNT ANTI-RH(D) IMMUNOGLOBULIN TO BE GIVEN
Surprisingly little is known about the optimal dose of anti-Rh(D) immunoglobulin. Post-partum a dose of 1,500 IU may be slightly better than 500 IU, but financial restriction may prompt the use of the lower dose. In early pregnancy the amount of fetal–maternal hemorrhage is bound to be low, so a dose of 500 IU should generally be enough. Prophylaxis in the third trimester should optimally consist of a dose of 1,500 IU given once between 28 and 34 weeks. No information is available on the immunoglobulin dose to be given after maternal vaginal bleeding, abdominal trauma, or fetal death. However, the Kleihauer–Betke test is very useful and provides dosing guidance for abdominal trauma or fetal death.
OTHER RH PREVENTION GUIDELINES
Guidelines on anti-Rh(D) immunoglobulin administration are generally similar. They only vary with regards to the level of detailed information given on the various indications and on the dose of anti-D indicated for the different indications. The latter holds especially for the dose given for potential sensitizing effects during pregnancy and for a single prophylaxis at 28 weeks versus a repeated administration at 28 and 34 weeks (see comparison four national guidelines).24 This is not surprising, given the limited knowledge about optimal dose for these indications.
MEASURES TO PREVENT ANTI-RH(D) SENSITIZATION
These measures are summarized in Table 1 and prioritized considering the cost effectiveness of the different dose regimens and prioritizing its administration by indication. When studying the gap between the annual doses of anti-Rh(D) given and the annual doses required, it can be concluded that the first priority is only met in high-income countries and in Brazil, Czech Republic, Croatia, Greece, Hungary, Iran, Lithuania, Malaysia, Saudi Arabia, Sri Lanka, South Korea, Thailand, Turkey, and Uruguay.5 There is still a long way to go.
CONFLICTS OF INTEREST
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REFERENCES
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Practice Bulletin No. 181: Prevention of Rh D Alloimmunization. Obstet Gynecol 2017;130(2):e57–70. | |
Bhutani VK, Zipursky A, Blencowe H, et al. Neonatal hyperbilirubinemia and Rhesus disease of the newborn: incidence and impairment estimates for 2010 at regional and global levels. Pediatr Res 2013;74(Suppl 1):86–100. | |
Pegoraro V, Urbinati D, Visser GHA, et al. Hemolytic disease of the fetus due to Rh(D) incompability: a preventive disease that still produces significant morbidity and mortality in children. Plos One 2020;15(7):e0235807. | |
Visser GHA, Di Renzo GC, Spitalnik SL. The continuing burden of Rh disease 50 years after the introduction of anti-Rh(D) immunoglobin prophylaxis: call to action. Am J Obstet Gynecol 2019;221(3):227.e1–4. | |
Visser GHA, Thommeson T, Di Renzo GC, et al. FIGO/ICM guidelines for preventing Rh disease; a call to action. Int J Gynecol Obstet 2021;152:144–7 | |
Crowther C. Anti‐D administration in pregnancy for preventing Rhesus alloimmunisation. Cochrane Database Syst Rev 1999;(2):CD000020. (updated January 2009). | |
Lubusky M, Simetka O, Studnickova M, et al. Fetomaternal hemorrhage in normal vaginal delivery and in delivery by cesarean section. Transfusion 2012;52(9):1977–82. | |
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Turner RM, Lloyd-Jones M, Anumba DO, et al. Routine antenatal anti-D prophylaxis in women who are Rh(D) negative: meta-analyses adjusted for differences in study design and quality. PLoS One 2012;7(2):e30711. | |
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White SW, Cheng JC, Penova-Veselinovic B, et al. Single dose v two-dose antenatal anti-D prophylaxis: a randomised controlled trial. Med J Aust 2019;211(6):261–5. | |
Schmidt-Hansen M, Lord J, Hawkins J, et al. Anti-D prophylaxis for rhesus D (RhD)-negative women having an abortion of a pregnancy up to 13(+6) weeks' gestation: a systematic review and new NICE consensus guidelines. BMJ Sex Reprod Health 2020:bmjsrh-2019-200536. doi: 10.1136/bmjsrh-2019-200536. | |
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Kristensen SS, Nørgaard LN, Tabor A, et al. Do chorionic villus samplings (CVS) or amniocenteses (AC) induce RhD immunisation? An evaluation of a large Danish cohort with no routine administration of anti-D after invasive prenatal testing. BJOG 2019;126(12):1476–80. | |
Chon AH, Korst LM, Grubbs BH, et al. Risk factors for fetomaternal bleeding after laser therapy for twin-twin transfusion syndreom. Pren diagn 2017;37:1232–7 | |
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