How Common is RhD Isoimmunization?

Patient Presentation
A 1-month-old female came to clinic for her follow-up evaluation.
She was known to have RhD isoimmunization that had required one blood transfusion and phototherapy for 5 days after birth at 38 weeks gestation.
She was seen at 10 days of age, was breastfeeding well, and was past her birth weight.
Her mother reported that she was sleepier than her other two children. The infant cried and easily awoke to feed, fed well for 20-30 minutes and then generally fell back to sleep.
She had no problems sucking, stopping to feed, sweating or color changes during feeding. Her mother also denied any bruising, bleeding or edema.
She also had been urinating and stooling well and her mother reported that the jaundice seems to slowly be fading away.
The family history was positive for the patient’s mother becoming Rh sensitized with her first pregnancy. Her second child did not require intrauterine or post-natal transfusions, but did require prolong phototherapy.
The review of systems was otherwise normal.
The pertinent physical exam showed a sleeping infant who appeared somewhat pale and slightly yellow on her skin and sclera. Her vital signs were normal with a heart rate of 145 beats/minute. Her weight was 3.92 kg (25-50%) and she had been gaining 32 grams/day.
The cardiac examination showed a regular rate and rhythm with no murmur. The abdominal examination showed no hepatomegaly or masses.
The laboratory evaluation showed a total and direct bilirubin of 8.9/0.3 mg/dl. Her complete blood count showed a hemoglobin of 7.4 mg/dl, hematocrit of 23%, platelets of 434 x 1000/mm2 and a reticulocyte count of 28%.
The diagnosis of anemia and jaundice secondary to RhD isoimmunization was made.
The physician contacted the hematologist who had seen the infant just after birth.
The hematologist was comfortable continuing to monitor the patient as an outpatient as the infant did not have any signs or symptoms of end organ failure and had an expected reticulocyte response.
The hematologist did note the sleepiness but felt that this could still be followed as an outpatient.
The infant was to return to the clinic in one week for re-evaluation and sooner if her mother noted any difficulty eating, skin color changes, or any other concerns.

RhD isoimmunization luckily has decreased in incidence since the introduction of RhD immunoglobulin (RhIg) in 1968.
There are 3 major rhesus antigens on red blood cells. The D antigen determines if a person has a positive or negative blood grouping.
An RhD-negative woman is at risk of developing RhD isoimmunization when exposed to RhD-positive antigens from her RhD-positive fetus through fetal-maternal hemorrhage.
Usually her initial antibody response is mainly composed of IgM which is a large molecule and cannot cross the placenta.
But after this IgG is produced which can cross the placenta. A subsequent exposure to RhD-positive blood cells such as with a second pregnancy, produces a rapid and proliferative IgG response.
The infant’s RhD-positive blood cells can then be attacked by the IgG causing fetal anemia, erythroblastosis fetalis and possibly intrauterine fetal death.

Prophylactic RhIg can be given to women which binds to the infant’s red blood cells in the maternal circulation. This blocks the RhD-positive antigen on the infants red blood cells and the mother does not make an antibody reponse to the foreign RhD-positive antigen.
If the mother does become sensitized at some point, she needs to be followed closely during any subsequent pregnancy. The fetus may need intrauterine transfusions.

Neonates affected by RhD isoimmunization may need immediate blood transfusions after birth because of anemia. They are also at risk for severe jaundice.
Both the anemia and jaundice may require exchange transfusion. Some neonates require later blood transfusions in the first few months of life and therefore need to be followed closely.

Learning Point
Without prophylatic RhIg, there is a 16% chance that an RhD-negative woman giving birth to an RhD-postive+ infant will become RhD isoimmunized.

In 1991, the Centers for Disease Control estimated that the incidence of RhD hemolytic disease was 10.6 per 10,000 total births.
This corresponds to ~4000 affected infants. In contrast, in 1970 two years after RhIg was licensed, the incidece was 45.1 per 10,000 total births.

Although there has been a substantial decrease in RhD hemolytic disease over the past 40 years, other red cell antigens continue to cause isoimmunization for some women for which there is no current prophylactic treament available.
For example, frequencies for all women with a positive antibody screen in a New York tertiary care health center were 18.4% for anti-D and 22% for anti-Kell.

Questions for Further Discussion
1. What are the indications for red cell blood transfusions?
2. At what age is the physiological red blood cell nadir? How would this change if the infant was premature, or had intrauterine or neonatal blood transfusions?
3. What are the current guidelines for adminstration with RhIg of a reproductive age female who has experienced a spontaneous abortion, threatened abortion, elective termination, or ectopic pregnancy?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Information prescriptions for patients can be found at MedlinePlus for these topics: High Risk Pregnancy and Blood and Blood Disorders.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

Geifman-Holtzman O, Wojtowycz M, Kosmas E, Artal R. Female alloimmunization with anti-
bodies known to cause hemolytic disease. Obstet Gynecol 1997;89:272-5.

Harkness UF, Spinnato JA.
Prevention and management of RhD isoimmunization.
Clin Perinatol. 2004 Dec;31(4):721-42, vi.

De Boer IP, Zeestraten EC, Lopriore E, van Kamp IL, Kanhai HH, Walther FJ.
Pediatric outcome in Rhesus hemolytic disease treated with and without intrauterine transfusion.
Am J Obstet Gynecol. 2008 Jan;198(1):54.e1-4.

ACGME Competencies Highlighted by Case

  • Patient Care
    1. When interacting with patients and their families, the health care professional communicates effectively and demonstrates caring and respectful behaviors.
    2. Essential and accurate information about the patients’ is gathered.
    3. Informed decisions about diagnostic and therapeutic interventions based on patient information and preferences, up-to-date scientific evidence, and clinical judgment is made.
    4. Patient management plans are developed and carried out.
    5. Patients and their families are counseled and educated.
    8. Health care services aimed at preventing health problems or maintaining health are provided.
    9. Patient-focused care is provided by working with health care professionals, including those from other disciplines.

  • Medical Knowledge
    10. An investigatory and analytic thinking approach to the clinical situation is demonstrated.
    11. Basic and clinically supportive sciences appropriate to their discipline are known and applied.

  • Practice Based Learning and Improvement

    13. Information about other populations of patients, especially the larger population from which this patient is drawn, is obtained and used.

  • Interpersonal and Communication Skills

    19. The health professional works effectively with others as a member or leader of a health care team or other professional group.

  • Systems Based Practice

    24. Cost-effective health care and resource allocation that does not compromise quality of care is practiced.
    25. Quality patient care and assisting patients in dealing with system complexities is advocated.

    Donna M. D’Alessandro, MD
    Professor of Pediatrics, University of Iowa Children’s Hospital

    August 11, 2008