Anti-D – Rh(D) Negative Women

https://ranzcog.edu.au/wp-content/uploads/Anti-D-Guidelines.pdf

https://www.health.qld.gov.au/__data/assets/pdf_file/0016/1219003/g-rhd-negative.pdf

🔴 Background & Rationale

• ~1 in 7 women are Rh(D) negative.
• Risk of sensitisation if fetal blood (Rh[D] positive) enters maternal circulation.
• Sensitisation can lead to haemolytic disease of the fetus/newborn in current or future pregnancies.
• Anti-D prevents maternal immune response by neutralising fetal D+ red cells.

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📌 When to Offer Anti-D (Key Indications) – Sensitising events by gestation

Any event where fetal blood may enter maternal circulation → give Anti-D

First Trimester – Up to 12+6 weeks – (250 IU)

• Indicated for:
  • Termination of pregnancy (≥10 weeks; medical/surgical)
  • Miscarriage (Excludes threatened miscarriage)
  • Ectopic pregnancy (any gestation)
  • Molar pregnancy
  • Chorionic villus sampling (CVS)

Second & Third Trimester – From 13+0 weeks onwards (625 IU)

• Procedures / interventions
  • CVS
  • Amniocentesis
  • Cordocentesis
• Clinical events
  • Abdominal trauma
    • Abdominal trauma = trigger (event)
    • Fetomaternal haemorrhage (FMH) = mechanism (fetal blood enters maternal circulation)
    • Antepartum haemorrhage (APH) = clinical presentation (visible bleeding)
• Obstetric interventions
  • External cephalic version (ECV)
    • Even if unsuccessful
• Pregnancy loss
  • Miscarriage
  • Termination
• Delivery
  • Birth of baby (any mode)

Routine Antenatal Prophylaxis (625 IU)

• All Rh(D)-negative women (without preformed antibodies):
  • 28 weeks
  • 34 weeks
• Exception: Not required if fetal RHD genotyping confirms Rh(D)-negative fetus.

Postpartum

• If infant is Rh(D) positive:
  • Quantify feto-maternal haemorrhage
  • Administer appropriate Anti-D dose within 72 hours.
  • Follow Kleihauer test result to determine dose.

Abdominal trauma

• External injury to pregnant abdomen (e.g. fall, MVC, assault)
• May cause placental disruption → FMH ± APH
• Always considered a sensitising event

Fetomaternal haemorrhage (FMH)

• Transfer of fetal RBCs into maternal circulation
• Often occult (no vaginal bleeding)
• Can occur after:
  • Trauma
  • Procedures
  • Antepartum haemorrhage (APH)
  • Also: delivery, ECV, IUFD
• FMH can occur without APH → do not rely on visible bleeding
• Estimate volume of fetomaternal haemorrhage
  • This guides the required dose of anti-D immunoglobulin
  • investigations
    • Initial test: Kleihauer–Betke test (screening) If abnormal / significant bleed suspected → confirm with flow cytometry (gold standard)

Antepartum haemorrhage (APH)

• Vaginal bleeding ≥20 weeks gestation
• Causes:
  • Placenta praevia
  • Placental abruption
  • Trauma
• Can be:
  • Revealed (visible bleeding)
  • Concealed (e.g. abruption, uterine pain ± no bleeding)

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Testing Before Anti-D Administration

Anti-D is PREVENTATIVE, not therapeutic

At first visit (<10 weeks):

• ABO group
• Rh D status
• Antibody screen (anti-D, anti-C, Kell)

Repeat:

• At 28 weeks (Rh-negative women)

Give Anti-D when:

• Mother is Rh D negative
• No pre-existing (immune) anti-D antibodies
• A sensitising event occurs (risk of fetal blood entering maternal circulation)
  • ff already sensitised → Anti-D is not indicated (Anti-D is preventative only, Anti-D is preventative only, If she already has anti-D antibodies (sensitised) → Anti-D will NOT help anymore)
• Routine Prophylaxis
  • 625 IU IM at 28 weeks
  • 625 IU IM at 34 weeks
  • Not required if fetus confirmed Rh negative (NIPT)

At 34 weeks

• Routine antibody titre TESTING may be omitted if:
  • Anti-D prophylaxis was given at 28 weeks
  • After giving Anti-D at 28 weeks:
    • The blood test may show “anti-D present”
    • BUT this is passive (from the injection), not true sensitisation
  • So repeating the test at 34 weeks:
    • Doesn’t change management

When NOT to give Anti-D

• If woman has true (immune) anti-D antibodies → already sensitised
• Exception:
  • If anti-D is passive (from prior Anti-D administration), Anti-D can still be given

If Rh(D) antibody status is unclear

• Check:
  • Medical records
  • Pathology results
  • Treating team

👉 If still uncertain:

• Give Anti-D as a precaution (benefit outweighs risk)

Administration

• Route: Intramuscular (IM)
• Preferred site:
  • Deltoid (especially in high BMI → better absorption)
• Avoid gluteal if possible (variable absorption)

Large doses

• If multiple vials (>4 doses) required:
  • Consider IV Anti-D (e.g. Rhophylac)

Cell-free DNA (NIPT for RhD)

• Can determine fetal Rh(D) status from ~11 weeks
• If fetus is Rh D negative:
  • Anti-D not required

Key clinical pearls

• Always exclude sensitisation first → Anti-D is preventative, not therapeutic
• If unsure → err on side of giving Anti-D
• Passive vs immune anti-D distinction is important
• NIPT may reduce unnecessary Anti-D use (increasingly used in Australia)

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Available Anti-D Products in Australia

Product	Dose	Manufacturer	Route
CSL 250 IU	50 mcg	CSL Behring	IM
CSL 625 IU	125 mcg	CSL Behring	IM
Rhophylac® 1500 IU	300 mcg	CSL Behring	IM or IV (not available in NZ)

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🔍 Evidence Summary

• Cochrane Review (Level I): Antenatal Anti-D reduces alloimmunisation by ~78%.
• NICE Review (Level II/III): Reduction by ~70%.
• Anti-D at 28 & 34 weeks reduces sensitisation from 1% → 0.35%.

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Rh isoimmunisation

is an immune response that occurs when an Rh(D)-negative individual (usually the mother) is exposed to Rh(D)-positive red blood cells (usually from the fetus), leading to the production of anti-D antibodies.

🧪 Mechanism of Isoimmunisation

1. Fetal-maternal haemorrhage (FMH) occurs → fetal Rh(D)+ red blood cells enter maternal circulation.
2. The Rh(D)-negative mother’s immune system recognises Rh(D) as foreign.
3. Mother produces IgG anti-D antibodies.
4. In future pregnancies, if the fetus is Rh(D)+ again, these maternal antibodies cross the placenta, leading to:
   • Haemolysis of fetal red cells
   • Anaemia, jaundice, hydrops fetalis, or stillbirth

📉 Clinical Consequences

• First exposure: usually sensitises mother, fetus often unaffected.
• Subsequent pregnancies: high risk of haemolytic disease of the fetus and newborn (HDFN).

🚨 Haemolytic Disease of the Fetus/Newborn (HDFN)

• Ranges from mild jaundice → severe anaemia → hydrops fetalis → intrauterine death.
• Caused by maternal anti-D IgG antibodies destroying fetal Rh(D)+ RBCs.

📌 Risk Factors for Isoimmunisation

• Delivery of Rh(D)+ infant
• Miscarriage, abortion, ectopic pregnancy
• Invasive procedures (e.g. amniocentesis, CVS)
• Trauma, placental abruption
• External cephalic version
• Unrecognised fetomaternal bleeding