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This Clinical Practice Update provides revised guidance on Rh testing and Rh D immune globulin administration for individuals undergoing abortion or experiencing pregnancy loss at less than 12 0/7 weeks of gestation. This document updates Practice Bulletin No. 225, Medication Abortion Up to 70 Days of Gestation (Obstet Gynecol 2020;136:e31-47); Practice Bulletin No. 200, Early Pregnancy Loss (Obstet Gynecol 2018;132:e197-207); and Practice Bulletin No. 181, Prevention of Rh D Alloimmunization (Obstet Gynecol 2017;130:e57-70)., (Copyright © 2024 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Early pregnancy loss, or loss of an intrauterine pregnancy within the first trimester, is encountered commonly in clinical practice. Obstetricians and gynecologists should understand the use of various diagnostic tools to differentiate between viable and nonviable pregnancies and offer the full range of therapeutic options to patients, including expectant, medical, and surgical management. The purpose of this Practice Bulletin is to review diagnostic approaches and describe options for the management of early pregnancy loss.

Early pregnancy loss, or loss of an intrauterine pregnancy within the first trimester, is encountered commonly in clinical practice. Obstetricians and gynecologists should understand the use of various diagnostic tools to differentiate between viable and nonviable pregnancies and offer the full range of therapeutic options to patients, including expectant, medical, and surgical management. The purpose of this Practice Bulletin is to review diagnostic approaches and describe options for the management of early pregnancy loss.

Advances in the prevention and treatment of Rh D alloimmunization have been one of the great success stories of modern obstetrics. There is wide variation in prevalence rates of Rh D-negative individuals between regions, for example from 5% in India to 15% in North America (1). However, high birth rates in low prevalence areas means Rh hemolytic disease of the newborn is still an important cause of morbidity and mortality in countries without prophylaxis programs (1). In such countries, 14% of affected fetuses are stillborn and one half of live born infants suffer neonatal death or brain injury (1). The routine use of Rh D immune globulin is responsible for the reduced rate of red cell alloimmunization in more economically developed countries. First introduced in the 1970s, the postpartum administration of Rh D immune globulin reduced the rate of alloimmunization in at-risk pregnancies from approximately 13-16% to approximately 0.5-1.8% (2, 3). The risk was further reduced to 0.14-0.2% with the addition of routine antepartum administration (2, 3). Despite considerable proof of efficacy, there are still a large number of cases of Rh D alloimmunization because of failure to follow established protocols. In addition, there are new data to help guide management, especially with regard to weak D phenotype women. The purpose of this document is to provide evidence-based guidance for the management of patients at risk of Rh D alloimmunization.

Advances in the prevention and treatment of Rh D alloimmunization have been one of the great success stories of modern obstetrics. There is wide variation in prevalence rates of Rh D-negative individuals between regions, for example from 5% in India to 15% in North America (1). However, high birth rates in low prevalence areas means Rh hemolytic disease of the newborn is still an important cause of morbidity and mortality in countries without prophylaxis programs (1). In such countries, 14% of affected fetuses are stillborn and one half of live born infants suffer neonatal death or brain injury (1). The routine use of Rh D immune globulin is responsible for the reduced rate of red cell alloimmunization in more economically developed countries. First introduced in the 1970s, the postpartum administration of Rh D immune globulin reduced the rate of alloimmunization in at-risk pregnancies from approximately 13-16% to approximately 0.5-1.8% (2, 3). The risk was further reduced to 0.14-0.2% with the addition of routine antepartum administration (2, 3). Despite considerable proof of efficacy, there are still a large number of cases of Rh D alloimmunization because of failure to follow established protocols. In addition, there are new data to help guide management, especially with regard to weak D phenotype women. The purpose of this document is to provide evidence-based guidance for the management of patients at risk of Rh D alloimmunization.

Background: Fetal-maternal hemorrhage is usually spontaneous and goes undetected but can be associated with adverse perinatal outcomes., Case: We describe the detection of a fetal-maternal hemorrhage by abrupt disappearance of prophylactic anti-D on antibody screen in an Rh-negative mother with dichorionic twins admitted for atrial flutter of one twin. Both rosette and Kleihauer-Betke tests were positive. The diagnosis was confirmed by anemia in one twin at birth., Conclusion: Fetal-maternal hemorrhage requires a high index of suspicion for diagnosis. An unexpected sudden decline in Rh immune globulin-related anti-D may be an indication of fetal-maternal hemorrhage.

Objective: To examine the cost and clinical outcomes of noninvasive RhD typing with cell-free fetal DNA to selectively deliver antenatal and postnatal prophylaxis with anti-D immune globulin for prevention of alloimmunization in RhD-negative women., Methods: We developed a decision tree to compare the costs and clinical outcomes of three strategies in an RhD-negative nonalloimmunized population as follows: 1) routine antenatal anti-D immune globulin prophylaxis and postpartum prophylaxis guided by cord blood typing (the current approach in most of the United States); 2) noninvasive fetal RhD typing with prophylaxis guided by test results; and 3) no screening or prophylaxis. Costs were estimated for testing and treatment algorithms using hospital billing records and information from the manufacturer of the fetal RhD genotyping test. Probability estimates were derived from published literature. The decision tree and sensitivity analyses were constructed and performed with Microsoft Excel., Results: We estimated the cost of the current approach to prevention of alloimmunization to be $351 per pregnancy, and we estimated the cost of noninvasive determination of fetal RhD status to be $682. Assuming essentially perfect test performance, threshold analysis found the cost must decrease to $119 to break even. The gap widened in favor of routine prophylaxis in most other circumstances (increased false-negative test rate and decreasing prevalence of RhD negativity)., Conclusion: Unless the cost of noninvasive fetal RhD typing is reduced substantially, routine antenatal anti-D immune globulin prophylaxis with postpartum prophylaxis guided by cord blood typing is less costly than noninvasive determination of fetal RhD status.

The postpartum dose of Rh immune globulin varies according to an individual laboratory estimation of fetal red blood cells in each mother's peripheral blood. In the United States, a four-step procedure determines the postpartum dose (number of vials of 300 micrograms; 1,500 international units) of Rh immune globulin (anti-D) for each RhD-negative mother who has delivered an RhD-positive newborn and has not already formed anti-D. The first step is a rosette fetal red blood cell screen to determine whether an excessive (greater than 30 mL fetal whole blood) fetomaternal hemorrhage occurred. If the rosette screen is negative, the mother receives one vial of Rh immune globulin for Rh immunoprophylaxis. If the rosette screen is positive, the blood sample is retested by a quantitative method, typically an acid-elution (Kleihauer-Betke) assay. The result of the acid-elution assay is converted to an estimation of the volume of the fetomaternal hemorrhage, which is the basis for calculating the dose of Rh immune globulin. The acid-elution assay is subjective, imprecise, and poorly reproducible. As a result, the formula for calculating the dose includes a precautionary adjustment, adding an extra vial in borderline situations to prevent underdosing. Flow cytometry is a more precise method for quantifying a fetomaternal hemorrhage. However, few hospitals use flow cytometry, because it is not cost-effective to maintain an expensive, high-technology laboratory service for the relatively few occasions when a precise quantitative determination of fetomaternal hemorrhage is required.

Objective: To evaluate the application of new technologies to the management of the red cell alloimmunized pregnancy., Data Sources: We searched three computerized databases for studies that described treatment or prevention of alloimmunization in pregnancy (MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials [1990 to July 2012]). The text words and MeSH included Rhesus alloimmunization, Rhesus isoimmunization, Rhesus prophylaxis, Rhesus disease, red cell alloimmunization, red cell isoimmunization, and intrauterine transfusion., Methods of Study Selection: Of the 2,264 studies initially identified, 246 were chosen after limiting the review to those articles published in English and crossreferencing to eliminate duplication., Tabulation, Integration, and Results: Both authors independently reviewed the articles to eliminate publications involving less than six patients. Special emphasis was given to publications that have appeared since 2008., Conclusion: Quantitative polymerase chain reaction can be used instead of serology to more accurately determine the paternal RHD zygosity. In the case of unknown or a heterozygous paternal RHD genotype, new DNA techniques now make it possible to diagnose the fetal blood type through cell-free fetal DNA in maternal plasma. Serial Doppler assessment of the peak systolic velocity in the middle cerebral artery is now the standard to detect fetal anemia and determine the need for the first intrauterine transfusion. Assessment of the peak systolic velocity in the middle cerebral artery can be used to time the second transfusion, but its use to decide when to perform subsequent procedures awaits further study. New data suggest normal neurologic outcome in 94% of cases after intrauterine transfusion, although severe hydrops fetalis may be associated with a higher risk of impairment. Recombinant Rh immune globulin is on the horizon. Cell-free fetal DNA for fetal RHD genotyping may be used in the future to decide which patients should receive antenatal Rh immune globulin.

Rhesus immune globulin has decreased the prevalence of rhesus D alloimmunization in pregnancy so that only approximately six cases occur in every 1,000 live births. The rarity of this condition warrants consideration of consultation with or referral to a maternal-fetal medicine specialist with experience in the monitoring and treatment of patients with red cell alloimmunization in pregnancy. Evaluation for the presence of maternal anti-D antibody should be undertaken at the first prenatal visit. First-time sensitized pregnancies are followed with serial maternal titers and, when necessary, serial Doppler assessment of the peak systolic velocity in the middle cerebral artery. In cases of a heterozygous paternal genotype, new DNA techniques now make it possible to diagnose the fetal blood type through free fetal DNA in maternal plasma. When there is a history of an affected fetus or infant, maternal titers are no longer predictive of risk in subsequent pregnancies. Serial peak middle cerebral artery velocities using Doppler ultrasonography can be used in these pregnancies to detect fetal anemia. In some situations, intrauterine transfusion is necessary through ultrasound-directed puncture of the umbilical cord with the direct intravascular injection of red cells. Perinatal survival rates of more than 90% have been reported; hydrops fetalis reduces the chance for a viable outcome by up to 11%. Neonatal and infant outcomes are complicated by the need for repeated transfusions secondary to suppressed erythropoiesis. Long-term studies have revealed normal neurologic outcomes in more than 90% of cases. Future therapy will involve selective modulation of the maternal immune system, making the need for intrauterine transfusions a rarity.

Hemolytic disease of the newborn secondary to rhesus alloimmunization was once a major contributor to perinatal morbidity and mortality. Today, rhesus immune globulin has markedly decreased the prevalence of this disease so that only one to six cases occur in every 1000 live births. The rarity of this condition warrants consideration of consultation or referral to a maternal-fetal medicine specialist. Once sensitization occurs, rhesus immune globulin is no longer effective. Evaluation for the presence of maternal anti-D antibody should be undertaken at the first prenatal visit. First-time sensitized pregnancies are followed with serial maternal titers and, when necessary, serial amniocenteses to detect fetal bilirubin by DeltaOD(450). In cases of a heterozygous paternal genotype, new deoxyribonucleic acid techniques now make it possible to diagnose the fetal blood type through amniocentesis or even from plasma/serum deoxyribonucleic acid analysis. When there is a history of an affected fetus or infant, maternal titers are no longer diagnostic as a screening test. Serial peak middle cerebral artery velocities using Doppler ultrasound can be used in these pregnancies to detect fetal anemia. In some situations, intrauterine transfusion is necessary through ultrasound-directed puncture of the umbilical cord with the direct intravascular injection of red cells. Perinatal survival rates of more than 90% have been reported; hydrops fetalis reduces the chance for a viable outcome by up to 25%. Immediate neonatal outcome is complicated by the need for repeated transfusions secondary to suppressed erythropoiesis. Long-term studies have revealed normal neurologic outcomes in more than 90% of cases. Future therapy will involve selective modulation of the maternal immune system making the need for intrauterine transfusions a rarity.

During dilatation and suction or evacuation abortion operations, the umbilical cord can be delivered and sufficient fetal blood can be sampled to type for the Rho(D) and Du factors in about 30% of cases at 14 menstrual weeks of pregnancy. By 16 weeks, more than 75% can be sampled successfully. When cord blood can be Rh typed, about 40% of the fetuses of Rh negative women were found also to be Rh negative. In these cases, anti-Rho(D) immunoglobulin prophylaxis is unnecessary.