Rh isoimmunization

 

 

The process by which fetal Rh+ erythrocytes enter the circulation of an Rh- mother during delivery, causing her to produce IMMUNOGLOBULIN G antibodies, which can cross the placenta and destroy the erythrocytes of Rh- fetuses in subsequent pregnancies

Predisposing factors to FMH

SAB, TAB, Amniocentesis, abdominal trauma, placenta previa, abruptio placenta, IUFD, multiple pregnancy, manual removal of placenta, cesarean section

 

Timeline of Rh Isoimmunization/sensitization

Factors that affect sensitization

amount of FMH

antigen of father

non-responders

concurrent ABO incompatibility

Incidence of sensitization

During pregnancy

Postpartum, with and without AP prophylaxis

 

Management in Pregnancy

Initial OB visit - identify Rh negative woman and determine baseline antibody screen

28 weeks - repeat antibody screen

if +, treat as sensitized, consult and refer

if -, administer full dose RhoGam

 

Management Postpartum

Postpartum - repeat antibody screen and check newborn blood type

if baby Rh+, administer full dose RhoGam within 72 hours

if mother’s antibody screen + and titer >1:4 treat as sensitized

 

Indications for Additional RhoGam

Tests for determination of FMH - if suspect it may be greater than the full dose RhoGam will cover, do Kleihauer-Betke test to determine the extent of bleed.

Amniocentesis

3rd trimester fetal maturity evaluation

SAB/TAB

Abdominal injury

 

 

Frequent Signs and Symptoms

Signs during pregnancy:

    • Decreased fetal growth.
    • Decreased fetal movement.

Signs in a newborn:

    • Paleness.
    • Jaundice (yellow skin and eyes) that begins within 24 hours after delivery.
    • Unexplained bruising or blood spots under the skin.
    • Tissue swelling (edema).
    • Breathing difficulty.
    • Seizures.
    • Lack of normal movement.
    • Poor reflex response.

Causes

The fetus of an Rh-negative (blood type) mother and an Rh-positive father may be Rh-positive. If the father is known to be Rh negative, there is no concern. During delivery, a small amount of the infant's blood is absorbed by the mother through the placenta, stimulating her body to produce antibodies against Rh-positive blood. The antibodies are produced after delivery, so the first infant is not affected. With succeeding pregnancies, the antibodies in the mother's blood can potentially destroy fetal blood cells. With subsequent pregnancy, anti-Ah antibodies cross the placenta and may destroy fetal blood cells. The resulting anemia can be severe enough to cause fetal death. If the fetus survives, antibodies can cross to the baby during birth, causing jaundice and other symptoms shortly after birth.

Risk Increases With

  • Each pregnancy after the first involving different blood types.
  • Previous blood transfusions. These might have contained unidentified, incompatible blood types.

Preventive Measures

  • Obtain prenatal care throughout pregnancy. Medical supervision early in pregnancy is essential to determine the risk of Rh incompatibility.
  • Special anti-Rh gamma globulin (RhoGAM) is given to the mother at 28 weeks' gestation and within 72 hours after delivery, miscarriage, ectopic pregnancy or abortion. This prevents formation of antibodies that might affect future infants. In women who are already producing antibodies, there is no benefit to using RhoGAM.
  • Amniocentesis beginning at 16 to 20 weeks if indicated by elevated antibody titers in the mother. Amniocentesis can be used in specialized laboratories to determine the fetal blood type.
  • Cordocentesis (percutaneous umbilical blood sampling or PUBS) may be recommended, despite some risks, to determine fetal blood type and the degree of anemia.

Expected Outcome

With prompt recognition of the disorder, damage to the infant can be prevented with exchange transfusions. These transfusions are administered directly into fetal circulation by PUBS.

Possible Complications

  • Permanent neurological damage, such as cerebral palsy or hearing loss (rare).
  • Blood-transfusion reaction.

Treatment/Post Procedure Care


General Measures

  • Blood tests to type the mother's, father's and infant's blood, measure the mother's Rh-positive antibodies, and detect hemobytic anemia in the infant's blood
  • Amniocentesis (a small amount of amniotic fluid is withdrawn from the amniotic sac that surrounds the unborn child in the uterus for a diagnostic procedure).
  • Intrauterine blood transfusions (sometimes).
  • Transfusion to completely exchange the infant's blood after birth.
  • Hospitalization. The newborn child will remain in the hospital up to 2 weeks after an exchange transfusion.
  • If you have an Rh-negative blood type, tell any doctor or medical professional who treats you. Make sure this information is in your medical records. Wear a medical alert type bracelet or pendant identifying your medical problem.

Medication

If you are pregnant and have Rh-negative blood type, you will be prescribed an anti-Ah gamma globulin injection (RhoGAM) at 28 weeks and again within 72 hours after delivery or termination of a pregnancy for any reason. You may also have antibody titer drawn during pregnancy to see if you are producing anti-Ah antibodies. You do not need RhoGAM if your fetus is Rh negative.

Activity

No restrictions after treatment.

Diet

The infant may be breast-fed or bottle-fed normally.

Notify Your Healthcare Provider If

 

Blood production in the fetus begins at about 3 weeks' and  Rh antigen has been identifed in the red cell membrane bas early as 38 days after conception. [6]

  • The initial  response to D antigen is slow sometimes taking as long as 6 months to develop.
  • Re-exposure to the antigen produces a rapid immunological response usually measured in days.
  • The sensitized mother produces IgG anti-D (antibody) that crosses the placenta and coats D-positive fetal red cells which are then destroyed in the fetal spleen.
  • Mild to moderate hemolysis (red cell destruction) manifests as increased indirect bilirubin (red cell pigment).
  • Severe hemolysis leads to red blood cell production by the spleen and liver.
    • Subsequently, hepatic circulatory obstruction (portal hypertension) with placental edema interferes with placental perfusion and ascites develops.[5]
    • Hepatomegaly, increased placental thickness, and polyhydramnios often precede the development of hydrops (fetal heart failure).[5]
    • As liver damage progresses decreased albumin production results in the development of anasarca, and effusions.
  • Overall, 16% of Rh-negative women will become sensitized after their first pregnancy if not given Rhogam.
    • ABO incompatibility reduces this risk to 4-5%.[5]
      The reduced risk of Rh sensitization with ABO incompatibility may result from the rapid clearance of incompatible red cells thus reducing the overall exposure to D antigen.
  1. Pathophysiology
    1. Maternal antibody Formation to fetal Rh
      1. IgM (Agglutinates in normal saline) forms in 7 days
        1. Does not cross placenta
      2. IgG (Agglutinates in Albumin) forms in 21 days
        1. Crosses placenta easily
    2. Results in Hemolytic Disease of the Newborn
      1. Neonatal Hemolytic Anemia
      2. Fetal Hydrops
  2. Indications for giving RhoGAM (xD) to Rh Negative Mother
    1. Standard Timing
      1. Week 28 gestation
      2. Postpartum (under 3 days postpartum if baby Rh+)
    2. Additional Indications
      1. Placenta Separation
      2. Labor Third Stage
      3. Termination or Spontaneous Abortion after 6 weeks
      4. Antepartum bleed
      5. Abruptio Placenta
      6. Abdominal Trauma
    3. Procedures (Give RhoGAM within 72 hours of procedure)
      1. Amniocentesis or Cordocentesis
      2. Chorionic Villus Sampling
      3. External version
  3. Dosing
    1. Standard RhoGAM Dosing
      1. Before 12 weeks gestation: RhoGAM 50 ug IM
      2. After 12 weeks gestation: RhoGAM 300 ug IM
    2. First Trimester Bleeding or Late Pregnancy Bleeding
      1. RhoGAM dose based on Kleihauer-Betke Test
  4. Labs: Rh Negative mother
    1. Indirect Coombs Test for Rh Antibodies
      1. Identify specific antibodies
      2. Titer may be weakly positive (1:4) from prior RhoGAM
      3. Titer > 1:8 dilution requires evaluation
      4. Follow Antibody titer monthly
    2. Check Rh type of father
  5. Radiology
    1. Fetal Ultrasound: signs of Fetal Hydrops
      1. Fetal Ascites
      2. Scalp edema
    2. Amniocentesis
      1. Obtain every 1-3 weeks when fetus > 26 weeks
      2. Follow Bilirubin level in amniotic fluid
      3. Liley Curve directs management per gestational age
        1. Amniotic Bilirubin level >0.3 at 27 weeks gestation
        2. Amniotic Bilirubin level >0.2 at 31 weeks gestation
        3. Amniotic Bilirubin level >0.1 at 36 weeks gestation
  6. Management (Based on Liley curve - see above)
    1. Ultrasound guided fetal transfusion via Umbilicus
      1. Indicated for Zone 3 on Liley curve beyond 22 weeks
      2. Repeat every 2 weeks as needed
    2. Plasmaphoresis of maternal serum
      1. Lowers Antibody levels

 

 

  • A titer of > 1:4 is considered sensitized.
  • The method used should be stated as the titer will vary according to the method.
  • An albumin titer of 1:16 is equal to an indirect antiglobulin test (IAT) titer of 1:32 to 1:128

Rh-D  Negative  Unsensitized Patients
    For prevention of sensitization:

  • Rh-immune globulin(RhIgG)* 300 mcg (300 mcg covers 15 ml fetal cells) is given at 28 week .
  • Postpartum if the antibody screen is negative a second dose of RhIgG is given if the infant is Rh-positive or Du-positive.
     
    *Rh-immune globulin is an antibody that will help to remove any Rh positive cells in the mother's blood. Rh-immune globulin must be given before the mother begins to produce her own antibody to the Rh factor.

Antibody Sensitized Patient
In general the priniciples used in the management of the Rh-D negative sensitized patient and the management of the patient with atypical blood antibodies do not differ.

·  However, the management of the Kell-sensitized pregnancy may require more intensive surveillance, since maternal titers and amniotic fluid bilirubin levels do not necessarily correlate with disease severity.  May involve marrow suppression.

First Sensitized Pregnancy (no prior severely affected pregnancy).

·  If the father is Rh negative (or negative for the atypical antigen) then no further testing is necessary.

·  IAT titers of < 1:32 or less are managed noninvasively with repeat antibody titers every 2-4 weeks.

·  IAT > 64 amniocentesis q 2 to 3 weeks.

·  IAT titers of  > 1:32 with pregnancies at greater than 27 week are usually monitored with serial amniocentesis

·  If the father is heterozygous (Dd) or his blood is unavailable then PUBS or amniocentesis may be used to determine the fetal Rh (or atypical antigen) status if the IAT titer is > 1:32  or albumin titer  > 1:16.

·  Fetal DNA testing is available for:

·         RhD, RhE, Rhc, RhC, and Kell.
( Send 5.0 ml of fluid in a unbreakable sterile plastic conical -bottom centrifuge tube. DO NOT FREEZE)

·         For RhE, Rhe, RhC, Rhc, Kell ,and Cellano (k) the parents' DNA should be tested concurrently (Send 5.0 ml of blood in a lavender-topped tube on each parent.  DO NOT FREEZE)

·         If the fetus is antigen negative then no further testing is necessary.

·         If the fetus is antigen positive then the pregnancy is followed with serial titers and ultrasound as long as titers remain below the "critical" value.

Previously Affected Pregnancy
For patients with a previously affected pregnancy, the timing of the initial procedure is determined by past clinical history. It is usually performed at least 4-8 weeks earlier than the prior gestational age at which significant morbidity occurred

The risk of RhD alloimmunisation during or immediately after a first pregnancy is about 1.5%. Administration of 100ug (500IU) anti-D at 28 weeks and 34 weeks gestation to women in their first pregnancy can reduce this risk to about 0.2% without, to date, any adverse effects. Although such a policy is unlikely to confer benefit or improve outcome in the present pregnancy, fewer women will have Rhesus D antibodies in their next pregnancy.Adoption of such a policy will need to consider the costs of prophylaxis against the costs of care for women who become sensitised and their affected infants, and local adequacy of supply of anti-D gammaglobulin.

Citation: Crowther CA. Anti-D administration in pregnancy for preventing Rhesus alloimmunisation (Cochrane Review). In: The Cochrane Library, Issue 2, 2004. Chichester, UK: John Wiley & Sons, Ltd.

 

  • here are several classes of antibodies. The two of interest are IgM and IgG. If the antibody can be identifed as an IgM then it does not cross the placenta and there is no risk of hemolysis to the fetus.
    • "Naturally occurring" IgM antibodies may result from antigenic stimulus such as bacteria, which have antigens on their surfaces chemically similar to blood group antigens. Anti-M antibodies are usually IgM , but IgG Anti-M does occur and is capable of causing hemolytic disease.
    • Anti-K, anti-D, anti-E, anti-Fya , anti-Jka, and antibodies directed against Rh antigens comprise the majority of antibodies resposible for hemolytic disease of the newborn .
  • The following antibodies ARE NOT associated with Hemolytic disease of the newborn (HMD):

 

o                                Lewis:Lea, Leb

o                                Lutheran:Lua , Lub

o                               

o                                Duffy: Fy

o                                P

o                                Jk

Vw, Mur, Hil, Hut, Batty, Becker, Berrens, Evans, Gonzales,  Hunt, Jobbins, Rm, Ven, Wrightb ,Ytb, , Ge, Jra, Coa-b,Xga

  • The following antibodies ARE associated with HMD:
     

o                                Rh: D , E , c, C, Cw , e 

o                                Kell: K1 , Kpa, k  , Jsa  ,Jsb 

o                                Duffy: Fya 

o                                MNS: M, S,s, N 

o                                Kidd: Jk

 

Dia, Dib ,PP1Pk, Far, Good, Lan,LW, Mta, U ,Wr a, Zd

 

·  Surveillance

Serial Amniocentesis

Fetuses affected by hemolytic disease secrete abnormally high levels of bilirubin into the amniotic fluid. The amount of bilirubin can be quantitated by spectrophotometrically measuring absorbance at the 450-nm wavelength in a specimen of amniotic fluid that has been shielded from light. Alternatively, percutaneous umbilical blood sampling (PUBS) may be used to determine all blood parameters directly.
If amniocentesis is used to monitor the fetus, the results (delta 450) are plotted on a "Liley" curve.

The Liley Curve [see also below]


The Liley curve is divided into three zones.

·   A result in Zone I indicates mild or no disease. Fetuses in zone I are usually followed with amniocentesis every 3 weeks.

·  A result in zone II indicates intermediate disease. Fetuses in low Zone II are usually followed by amniocentesis every 1-2 weeks.

·  A result above the middle of Zone II may require transfusion or delivery. [11]

Patients with results in zone I or low zone II can be allowed to proceed to term, at which point labor should be induced. In most cases, patients in the middle of zone II can progress to 36-38 weeks of gestation. Depending on gestational age, patients in zone III should either be delivered or should receive intrauterine fetal transfusion.

Although serial determinations of Delta optical density at 450 nm and PUBs are the most common methods for the evaluation of fetal status, Doppler ultrasonography of the middle cerebral artery has also been used to identify fetuses at risk for moderate to severe hemolytic disease.

 

 

Today, the Rh-immunized pregnancy can be evaluated with six complementary modalities:

1. Serial maternal serum antibody titers

2. Middle cerebral artery (MCA) peak systolic velocity

3. AF DNA Rh typing

4. AF OD450 nm

5. Sonographic evaluation

6. Cordocentesis or fetal blood sampling (FBS)

 

In situations where the maternal antibody titer is very low (such as 1:4), fetal disease is usually mild and the outcome is favorable. In such cases, following maternal antibody titers is all that is necessary to evaluate the pregnancy. If the titer is higher, the outcome is not predictable and MCA peak systolic velocity and amniocentesis with AF OD450 and AF DNA Rh typing may be employed.

When severe EBF is suspected, FBS is necessary to determine the fetal hematocrit and perform a fetal transfusion, if indicated.

 

The MCA peak systolic velocity provides a non-invasive modality for determining moderate to severe fetal anemia.4 This technique does not differentiate between mild fetal anemia and no anemia. The sensitivity of an increased peak systolic velocity in the MCA for prediction of moderate to severe fetal anemia is 100 percent either in the presence or the absence of hydrops fetalis and the false positive is 12 percent.4 The major advantage of MCA Doppler studies is that they are a non-invasive means of detecting fetal anemia and indicate when a transfusion is necessary

 

Intravascular Fetal Transfusion
Procedure:
The abdomen is aseptically prepped.
A 22-guage,5-inch spinal needle is then guided into the umbilical vein at the placental insertion under ultrasound guidance.
Fetal blood is aspirated for immediate hematocrit, CBC, blood type and Rh factor.
Prior to transfusion pancuronium bromide is administered as an IV bolus.
Transfusion is performed using type O, Rh-negative,CMV-negative,washed irradiated packed cells, cross-matched against maternal blood.

Donor hematocrit ( 75%) 


Initial fetal hematocrit 
Final fetal hematocrit (~45%) 
EFW (grams) 



Dosage of pancuronium  (mg)

Volume RBCs to transfuse  (mL)



 

 

Neither MCA peak systolic velocity or AF OD450 can differentiate between mild disease and no disease in the fetus. Therefore, at the initial amniocentesis, 5 mL of uncentrifuged AF should be sent for DNA Rh typing. Fetal DNA is isolated from the AF, and specific portions of the fetal D (Rho), C, and E genes are amplified with polymerase chain reaction.5,6 The error rate is 1%. If the fetus tests Rh-negative, no further testing is necessary and the patient can receive routine obstetric care, avoiding unnecessary Doppler studies and invasive procedures.7-9 If the fetus is Rh-positive, further evaluations are required with MCA peak systolic velocity and AF OD450 studies

The AF OD450 value in the Rh-immunized patient is an almost ideal test of fetal condition. If the clinician fully understands the physiologic properties of AF and the pathophysiology of Rh disease, virtually no serious fetal deterioration should go undetected.

In normal (Rh-negative) pregnancies, the AF OD450 values rise until 24 weeks, then fall until term. In Rh-positive fetuses at risk of dying in utero, the values are higher and the AF OD450 trends rise.

The timing of the initial amniocentesis depends upon the patient's history and antibody titer. If the patient's antibody titer is just at the critical level and the patient has not had a baby with EBF, the initial amniocentesis can be done at 28 to 29 weeks' gestation. If the titer or the history suggests that the EBF may be more severe, then amniocentesis can be performed earlier. In this way, a fetus that needs an intrauterine transfusion can be identified.

 

Rh-negative (unaffected) zone: If the AF OD450 value falls in the Rh-negative zone, DNA Rh typing should be performed on the initial amniocentesis. If the fetus is Rh-negative, no further testing is necessary and the fetus can be delivered at term. If the fetus is Rh-positive, amniocentesis and AF OD450s should be repeated in 3 to 4 weeks. The maternal Rh antibody titer should be monitored to detect any increase in titers.

Indeterminate zone: If the AF OD450 falls in the indeterminate zone, DNA Rh typing should be performed on the initial amniocentesis. If the fetus is Rh-negative, no further testing is necessary and the fetus can be delivered at term. If the fetus is Rh-positive, the AF OD450 should be repeated every 2 to 4 weeks. Decreasing trends generally indicate that the fetus is Rh-negative or has mild or moderate disease. Horizontal or rising trends of AF OD450 values indicate that the fetus has severe disease.

Rh-positive (affected) zone: If the AF OD450 value falls in the Rh-positive zone, amniocentesis should be repeated in 1 to 2 weeks. FBS is indicated if the values remain elevated or the trend rises.

Intrauterine death risk zone: If the AF OD450 value falls in the intrauterine death risk zone, FBS is indicated for fetal evaluation, including hematocrit and possible transfusion or delivery, if the fetus is mature.

This four-zone management scheme exposes the Rh-negative fetus to a minimum of invasive procedures. Fetuses with AF OD450 levels in the Rh-positive or intrauterine death risk zones may require early FBS.

Clinical action for AF OD450 zones

AF OD450 zone

Clinical action

Rh-negative

Get DNA Rh type on initial AF.

 

If Rh-negative, no further testing is necessary.

 

Deliver at term.

1. (unaffected)

If Rh-positive, repeat AF OD450 in 3 to 4 weeks.
Continue maternal antibody titers to detect rise.

Indeterminate

Get DNA Rh type on the initial AF

 

If Rh-negative, no further testing is necessary.
Deliver at term.

 

If Rh-positive, repeat AF OD450 every 2 to 4 weeks.
Decreasing trends generally indicate mild or moderate disease.

 

Horizontal or rising trends indicate the fetus has severe disease.

Rh-positive
(affected)

Repeat AF OD450 every 1 to 2 weeks and do cordocentesis as indicated.

 

Doppler MCA studies are helpful in detecting fetal anemia.

Intrauterine
death risk

Cordocentesis for fetal hematocrit and possible transfusion, or if mature, deliver.

 

 

 

 

Schematic representation of the antigen D on the erythrocyte´s surface. The normal RhD protein is shown (left). Every sphere represents an amino acid. Six extracellular loops of amino acids are shown (light yellow and light grey). Transmembranous protein segments are depicted in reddish. The RhD protein differs from the RhCE protein (not shown) be seven extracellular amino acids only (yellow). All other extracellular amino acids (light yellow and light blue) Schematic representation of the antigen D on the red blood cell´s surface are identical between the RhD- and RhCE-protein. In the DVI-protein (right), two loops carry the RhCE-specific sequence (light blue) rather than the RhD-specific sequence. Thus, the extracellular parts of the DVI-protein differ from the normal RhD-protein by three amino acids only (blue). Other transmembranous and intracellular differences may, however, also effect the protein configuration and are not shown for simplicity. 

3D Model of the Rhesus Antigen on the Red Blood Cell Surface



A transfusion recipient with the DVI phenotype may produce an anti-D-antibody (blue arrow) directed against parts of the normal RhD-protein (yellow) that his or her DVI-protein does not carry, because they are substituted by RhCE-specific parts (light blue and blue). Monoclonal IgM anti-D-antibodies that are used for RhD-typing of patients are directed against these parts fo the RhD-protein. Because the DVI-protein does not carry these protein parts, the monoclonal IgM anti-D cannot bind the DVI-protein and react serologically negative.
 


 

 

 

REFERENCES

1. Queenan JT. Rh and other blood group immunizations. In: Queenan JT, Hobbins JC, eds. Protocols for High-Risk Pregnancies. 3rd ed. Cambridge, Mass: Blackwell Science; 1996:523-534.

2. Allen LH, Diamond LK, Jones AR. Erythroblastosis fetalis: IX. Problems of stillbirth. N Engl J Med. 1954;251:453.

3. Nicolaides KH, Rodeck CH. Maternal serum anti-D antibody concentration and assesssment of rhesus isoimmunization. Br Med J. 1992;304:1155-1156.

4. Mari G, Deter RL, Carpemter RL, et al. Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses. N Engl J Med. 2000;342:9-14.

5. Lightern AD, Overton TG, Sepulveda W, et al. Accuracy of prenatal determination of RhD type status by polymerase chain reaction in amniotic cells. Am J Obstet Gynecol. 1995;173:1182-1185.

6. Van Den Veyver IB, Subramanian SB, Hudson KM, et al. Prenatal diagnosis of the RhD fetal blood type on amniotic fluid by polymerase chain reaction. Obstet Gynecol. 1996;87:419-422.

7. Queenan JT. Practice Strategies: Management of the Rh-immunized patient. Hospital Physician. 1998;Oct:49-56.

8. Queenan JT. Rh and other blood group immunizations. In: Queenan JT, ed. Management of High-Risk Pregnancy. 4th Ed. Cambridge, Mass: Blackwell Science; 1999.

9. Queenan JT. Management of Rh-immunized pregnancies. Prenatal Diagnosis. 1999;19:852-855.

10. Liley AW. Liquor amnii analysis in the management of the pregnancy complicated by rhesus sensitization. Am J Obstet Gynecol. 1961;82:1359.

11. Liley AW. Errors in the assessment of haemolytic disease from amniotic fluid. Am J Obstet Gynecol. 1969;86:485.

12. Queenan JT, Tomai TP, Ural SH, et al. Deviation in amniotic fluid OD450 in Rh-immunized pregnancies from 14 to 40 weeks' gestation: a proposal for clinical management. Am J Obstet Gynecol. 1993;168:1370-1376.

13. Ghidini A, Sepulveda W, Lockwood CJ, et al. Complications of fetal blood sampling. Am J Obstet Gynecol. 1993;168:1339-1344.

14. Forestier F, Daffos F, Galacteros F, et al. Hematological values of 163 normal fetuses between 18 and 30 weeks gestation. Pediatr Res. 1986;20:342-346.

15. Liley AW. Intrauterine transfusion of foetus in haemolytic disease. Br Med J. 1963;2:1107.

16. Watts DH, Luthy DA, Benedetti TJ, et al. Intraperitoneal fetal transfusion under direct ultrasound guidance. Obstet Gynecol. 1988;72:84-88.

17. Pinckert TL, Queenan JT. Intrauterine transfusion. In: Queenan JT, Hobbins JC, eds. Protocols for High-Risk Pregnancies. 3rd ed. Cambridge, Mass: Blackwell Science; 1996:138-145.

18. Schumacher B, Moise KJ Jr. Fetal transfusion for red blood cell alloimmunization in pregnancy. Obstet Gynecol. 1996;88:137-150.

 REFERENCES
1.  Socol ML, MacGregor SN, Pielet BW, Tamura RK, Sabbagha RE. Percutaneous umbilical transfusion in severe rhesus isoimmunization: resolution of fetal hydrops. Am J Obstet Gynecol. 1987 Dec;157(6):1369-75. PMID: 3122574; UI: 88103789

2.Pielet BW, Socol ML, MacGregor SN, Dooley SL, Minogue J. Fetal heart rate changes after fetal intravascular treatment with pancuronium bromide.Am J Obstet Gynecol. 1988 Sep;159(3):640-3.PMID: 3421263; UI: 88338648

3. Rodeck CH, Nicolaides KH, Warsof SL, Fysh WJ, Gamsu HR, Kemp JR. The management of severe rhesus isoimmunization by fetoscopic intravascular transfusions.Am J Obstet Gynecol. 1984 Nov 15;150(6):769-74. PMID: 6437228; UI: 85044018