What does it mean to be Rh negative in pregnancy?


What does being Rh negative mean?

Rh D is an erythrocyte (red blood cell) surface antigen (protein) found on red blood cells (RBC).

  • Those who carry the Rh D antigen are identified as Rh D positive (+).
  • Those who do not carry the Rh D antigen are identified as Rh D negative (-). 1 in 6 pregnant individuals are Rh negative.

The Rh factor is inherited. 40% of fetuses of Rh D neg pregnant individuals will be Rh D neg. The remained of fetuses are Rh D positive. Rh incompatibility occurs when the fetus is Rh D positive and the pregnant individual is Rh D negative.

What is RhD alloimmunization?

Fetal and maternal circulations are separate, but there can be mixing of fetal and maternal blood during pregnancy. This mixing of blood can occur in various scenarios called "sensitizing events". Scroll down for a list of these events. This mixing of blood is also called a fetal–maternal hemorrhage (FMH). The frequency and volume of FMH increase with advancing gestational age and are highest at delivery. Between 3% and 11% of persons with threatened abortion in the 1st trimester, and approx. 45% giving birth in the 3rd trimester, have a FMH.

Rh D alloimmunization occurs when Rh D neg person is exposed to fetal red blood cells that are Rh D positive when the maternal and fetal circulations mix. The pregnant person then develops anti-D antibodies to Rh D positive red blood cells because they are recognized as being "foreign". The antibodies can then cross the placenta, enter the fetal circulation and destroy fetal Rh D positive red blood cells causing fetal anemia. The volume of fetal blood entering the maternal circulation is 0.1 mL or less in most cases resulting in alloimmunization.

What is done once Rh alloimmunization develops?

Once the titer reaches 1:16 or greater, the fetus will need weekly MCA dopplers studies with an ultrasound to assess for fetal anemia. If this study shows that the MCA dopplers are elevated, a fetal blood transfusion will be recommended. The severity of fetal anemia that develops is primarily influenced by maternal antibody concentration. Hydrops fetalis is a severe form of HDFN where two or more of the following occur in the fetus: skin edema, ascites (fluid in the abdomen), pericardial effusion (fluid around the fetal heart), pleural effusion (fluid around the fetal lungs). This typically occurs when the fetal hemoglobin deficit is at least 7 g/dL below the mean for gestational age (consistent with a hematocrit less than approximately 15% or hemoglobin <5 g/dL).

If the father or sperm contributor is Rh D negative and paternity is certain, additional testing and interventions are not necessary. The fetal Rh D status can be assessed if paternity is not established or the paternal Rh D status is unknown for any reason. An amniocentesis can be used to determine fetal blood type using polymerase chain reaction (PCR) on uncultured amniocytes in 2 mL of amniotic fluid. Chorionic villus biopsy can also be done, but its use should be discouraged because disruption of the villi may result in unnecessary FMH and worsening alloimmunization. Fetal Rh D status can be obtained through cell-free DNA analysis, but this is not widely available.

Screening for anti-D antibodies in pregnancy

We screen every pregnant patient for antibodies to red blood cell antigens (there are many). If the screen comes back showing you have antibodies to the Rh D red blood cell antigen, the blood bank will report a titer of how strong the antibodies are in your blood. There is not concern for Rh D alloimmunization until the titer reaches 1:16. If the antibody titer reaches 1:16 or greater, this means the antibodies can cross the placenta and destroy fetal RBCs causing fetal anemia. The fetal anemia that develops is called Rhesus disease or hemolytic disease of the fetus and newborn (HDFN). Repeated Rh D antibody testing is recommended for all unsensitized Rh D negativie individuals at 24–28 weeks of gestation, unless the sperm contributor is known to be Rh D neg.

Potential sensitizing events that can cause Rh D alloimmunization

These events can allow the maternal and fetal blood to mix, causing the development of anti-D antibodies.

Chorionic villus sampling, amniocentesis, cordocentesis

  • CVS: 14% risk of FMH of 0.6 mL or more
  • amniocentesis: 2–6% rate of FMH

Ectopic pregnancy

Evacuation of molar pregnancy


Antepartum hemorrhage

Abdominal trauma

Intrauterine fetal death

External cephalic version

  • 2–6% rate of FMH


  • 45% of patients giving birth in the 3rd trimester have a FMH

1st and 2nd trimester spontaneous pregnancy loss

  • 1.5–2% risk of FMH

1st trimester threatened miscarriage/abortion

  • Between 3% and 11% have a fmh

Uterine instrumentation (eg, dilation and curettage or evacuation)

  • 4–5% risk of FMH

What is Rhogam?

Rhogam is NOT a vaccine. It is an immune globulin (Ig) used to bind the Rh D antigen present on fetal red blood cells in the maternal circulation; aka Rh D immune globulin (Rh Ig) or anti-D immune globulin (anti-D Ig). It is given as an injection. This prevents the maternal antibodies from attacking the fetal red blood cells causing fetal anemia. Rhogam is extracted by cold alcohol fractionation from plasma donated by individuals with high-titer anti-D immune globulin G antibodies. The risk of viral infection from receiving anti-D immune globulin is exceedingly low. Since 1985, all plasma used for the production of anti-D immune globulin has been tested for viral infections, and several fractionation and purification steps are used to remove and inactivate viruses. Anti-D immune globulin has been manufactured without mercury-containing thimerosal since 2001. Risks include an allergic reaction. However, the risk of becoming allommunization is greater than having an allergic reaction.

Rhogam is given in every pregnancy if your are Rh D negative to prevent alloimmunization from occurring. Although, the pregnancy in which alloimmunization occurs is not affected. It is the subsequent pregnancies that are at risk. A prophylactic dose of 300 micrograms of anti-D immune globulin can prevent maternal Rh D alloimmunization after exposure to up to 30 mL of Rh D positive fetal whole blood or 15 mL of fetal red blood cells. Rhogam cannot be given once there are anti-D antibodies present in your blood.

There are four licensed sources of Rh IG in the US:

  • HyperRHO—(intramuscular injection) manufactured by Grifols Therapeutics LLC
  • RhoGAM—by Kedrion Biopharma Inc.
  • Rhophylac (intravenous)—manufactured by CSL Behring AG
  • WinRho (intravenous)—manufactured by Kamada Ltd.

When is Rhogam given in pregnancy?

28 weeks:

  • Asymptomatic FMH during the 3rd trimester triggers alloimmunization in 2% of at-risk persons before delivery.
  • This rate is reduced to < 0.2% with Rhogam.

Within 72 hours of birth:

  • If the infant is Rh D positive and the patient is not sensitized, a single dose reduces the rate of Rh D alloimmunization by 80–90%.
  • In 2–3 per 1,000 deliveries, a FMH may be > 30 mL.
    • Rh D negative persons who give birth to Rh D positive infants should have additional testing to determine the amount of Rh D immune globulin needed after birth. Additional Rhogam may be needed if there was a larger exchange of fetal and maternal blood.

1st trimester miscarriage:

  • Spontaneous (1.5-2% risk)
  • Instrumentation (4-5% risk)

Termination of pregnancy, either medical or surgical

Ectopic pregnancy

Antenatal hemorrhage >20 weeks

Abdominal trauma

Fetal death in the 2nd or 3rd  trimester

All invasive diagnostic procedures, ie CVS and amniocentesis, if fetus may be Rh D pos

External cephalic version, regardless of success

Evacuation of suspected molar pregnancy

When is Rhogam not necessary?

If paternity is certain and the sperm contributor is known to be Rh D neg, antenatal Rhogam is unnecessary.

The fetal Rh status can be obtained with the cell-free DNA testing done for the risk of fetal chromosomal abnormalities.differences. If cell-free DNA testing shows the fetus is Rh D negative, Rhogam is not necessary. Before offering this test, the patient should be counseled that there is a chance of an inconclusive result, in which case Rhogam will be recommended. Due to the current costs, noninvasive assessment of fetal Rh D status is not recommended for routine use at present.

Additional resources

ACOG: The Rh Factor: How It Can Affect Your Pregnancy

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