Antibodies (including use of Anti-D) in pregnancy Flashcards Preview

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Incidence of women with Rh negative blood group



When should women be offered Anti-d? (RANZCOG)

1st Trimester (250IU):
- Miscarriage (but insufficient evidence that THREATENED miscarriage before 12/40 needs Anti-D)
- Abortion (MTOP/STOP)
- Ectopic

2nd and 3rd trimester (starting dose 625IU):
- Obstetric haemorrhage
- Amniocentesis or other invasive procedure
- ECV (regardless of success)
- Abdominal trauma (or any other event that could cause bleeding)
- Abortion
- NHMRC recommends prophylactic dose 625mg at 28 and 34 wks

- within 72 hours if baby Rh +ve on cord blood

Kleihauer should be taken to determine extent of fetomaternal haemorrhage and anti-D dose in 2nd/3rd trimesters and postnatally.


How to administer Anti-D?

- Deep IM injection (can use deltoid if obese)
- Take G+H first to ensure no antibodies present
- Do not give if mother already sensitised, though always check if this is passive acquisition after Anti-D administration (which does NOT preclude giving further anti-D doses)


When should women have their blood group and antibody status checked?

Blood group and antibody status determined at: - booking
- 28/40
- prior to any Anti-D administration
- After potentially sensitising events


What are the implications for the fetus and neonate from red cell antibodies?

Severe fetal anaemia / HDFN
Can result in hydrops and require invasive procedures.
Increased risk of preterm birth, stillbirth. Increased risk for neonate: anaemia, jaundice, kernicterus and increased perinatal morbidity and mortality.


When and how should paternal and fetal genotyping be performed?

Where clinically significant maternal red cell antibodies are detected, the paternal phenotype can be ascertained by serology.

For rhesus D (RhD) antigen: in an antigen-positive father, genotyping is required to determine whether he is homozygous or heterozygous for the RHD gene.

Non-invasive fetal genotyping using maternal blood (NIPT) is now possible for D, C, c, E, e and K antigens.

For other antigens, invasive testing (chorionic villus sampling [CVS] or amniocentesis) may be considered if fetal anaemia is a concern or if invasive testing is performed for another reason (e.g. karyotyping).


Once antibodies identified, when should referral to a fetal medicine specialist take place?

- rising antibody levels/titres,
- a level/titre above a specific threshold
- anti-D >/= 4
- anti-c >/= 7.5
- Anti-K any titre
- All other low risk Abs >/= 32
- ultrasound features suggestive of fetal anaemia.


What thresholds should be used for the various antibodies that could cause fetal anaemia to trigger referral for further investigation or monitoring?

anti-D - >/= 4 IU/ml

anti-c - >/= 7.5 IU/ml

anti-E - potentiates effect of anti-c - so refer even at low levels if detected in presence of another antibody, particularly anti-c.

anti-K (kell) antibodies - once detected. As any level can be associated with severe haemolytic disease of the fetus/newborn.

All lower risk anti-bodies >/= 32 IU/ml.


Once detected how often should antibody levels be monitored during pregnancy?

For high risk antibodies (anti-c, anti-D, anti-K, anti-E) - measure every 4 weeks up to 28 weeks, then every 2 weeks until delivery.

For all other lower risk antibodies just recheck titres at 28 weeks.


How should pregnancies at risk of fetal anaemia be monitored?

The cause of the alloimmunisation, relevant past history and pregnancy outcomes should be
ascertained in order to generate an assessment of risk of HDFN.

Anti- D,c,K should be measured 4 weekly till 28 weeks, then 2 weekly till delivery.
All other lower risk Abs can be retested at 28 weeks.

All women at high risk of HDFN should be referred to MFM.
- anti-D >/= 4 iu/ml
- anti-c >/= 7.5 iu/ml
- anti-E - especially if also anti-c
- anti-K - any titre
- any other Abs with titre >/= 32 iu/ml
- US suggestive of fetal anaemia (raised MCA PSV, hydrops)
- Previous severe HDFN and/or previous fetal intrauterine infusion

If the antibody levels/titres rise to a level that increases risk of anaemia (as above) then weekly MCA-PSV needed

If MCA PSV >1.5MoM (multiples of the median) threshold or if there are other signs of fetal anaemia, consider invasive management (i.e. cord blood sampling and intrauterine transfusion).

(RCOG 2014)


What are the implications for the mother from red cell antibodies?

Delayed blood transfusion if needed


What cord blood investigations should be performed after delivery?

Cord samples should be taken for a direct antiglobulin test (DAT), haemoglobin and bilirubin levels.


How should the neonate be managed?

If High risk for fetal anaemia:

- Observe for development of jaundice/anaemia with bili and Hb levels
- assess neurobehavioural state
- Encourage regular feeding as dehydration can worsen jaundice
- Phototherapy or exchange transfusion may be required


Incidence of red cell antibodies

Antibodies in 1.2% pregnancies
Clinically significant- 0.4%


Why are red cell antibodies present?

The mother has mounted an immune response to previous exposure to red cell antigens that are not in her blood group, due to: previous pregnancy, transfusion or transplantation. As part of the adaptive immune response she will have long-term anti-bodies to this antigen, which will rise in response to future exposures/events whereby her blood comes into contact with the antigen again.


Consequence of red cell antibodies

- Transplacental passage of maternal IgG
- results in immune haemolysis of fetal/neonatal red cells
- Development of fetal anaemia or HDFN, increased risk of hydrops, preterm birth, stillbirth, neonatal jaundice, kernicterus and perinatal death.
- May require IUT / early delivery
- Less severe antibodies (including ABO- group) can cause mild neonatal anaemia and hyperbilirubinaemia


Result of severe, untreated fetal anaemia

hydrops, preterm birth or perinatal death


Signs of fetal anaemia on USS (other than MCA-PSV)

polyhydramnios, skin oedema, cardiomegaly


What happens if MCA-PSV suggestive of anaemia?

Sensitivity 100% (prior to 36 weeks)
False positive rate of 12%

Perform fetal blood sampling (carries risk of fetal loss 1-3%, higher if hydropic) and consider Intrauterine transfusion

If close to term may affect timing of delivery.


Until what gestation can MCA-PSV be used reliably?

36/40- after this the sensitivity decreases


If maternal transfusion is required, what type of donor blood or blood components should be used?

Red cell components of the same ABO group and RhD type, and that are K negative and CMV negative.


Timing of delivery if antibodies are present that could cause fetal anaemia?

For red cell antibodies that could cause fetal anaemia but which have been stable throughout pregnancy, delivery should take place at 37-38 weeks.

If an IUT has not been required but antibody levels are rising then consideration for earlier delivery may be necessary.

If an IUT has been required, delivery will need to be timed to ensure that the fetus is not significantly anaemic at birth.

NB. MCA PSV becomes less sensitive after 36 weeks, so a normal USS in the presence of rising titres is not necessarily reassuring and earlier delivery should be considered.

Previous IUT is not an indication for caesarean.

All pregnancies with positive Abs are high risk and need continuous intrapartum CTG monitoring.


Highest risk antibodies?

anti-D, anti-K (-Kell) and anti-c


A woman is referred to you in her 3rd ongoing pregnancy at 20 weeks gestation with anti D antibodies on her recent booking bloods. She has not had any anti-D injections in this pregnancy.

a. Outline the key points in the history you will take. (4 marks)

• Past obstetric history
o Mode of delivery
o Sensitizing events in previous pregnancies e.g. APH, trauma, miscarriage
o Whether anti-D given after event or after deliveries
o Were other pregnancies affected by Rh isoimmunisation, fetal anaemia, hydrops or neonatal jaundice?
• Past gynae history
o TOPs, miscarriages, ectopics
o Whether anti-D given
• This pregnancy
o Antibodies at booking
o Sensitising events – bleeding, falls etc
o General – usual antenatal investigations
• PMHx, meds.
• Previous blood transfusion
• Social history
o JW?
o Paternity of this pregnancies and whether partner’s blood group known
o Previous drug use


RANZCOG Q: (Anti-D present)

List the investigations you will arrange at this visit and discuss the reason for each. (2 marks)

1. Antibody titre
- If this is first affected pregnancy, then critical titre for further investigation is 1:16 – 1:32
- If not first affected pregnancy then pt should be immediately referred for ongoing assessment with MFM team
2. Partner’s blood type and genotype
- If Rh neg, fetus not affected. If Rh pos heterozygote – 50% chance fetus is at risk, and if Rh pos homozygote – 100% chance fetus is at risk

3. Offer fetal genotyping on NIPT
- determines fetal Rh status and if at risk of HDFN
- If unable to get a result discuss/consider possible amniocentesis if deemed high risk for HDFN

4. Routine anatomy USS and request MCA PSV as additional screening for anaemia


Outline the management plan of the pregnancy from now in regards to the rhesus iso- immunisation. (9 marks)

• If father and/or fetus Rh neg on genotyping – normal antenatal care.
• If father pos - counselling – explain problem and potential outcomes

MDT input – MFM, midwife, counselor, family, neonatalogist, blood bank if considering IUT

• Check titre monthly till 28 weeks, then 2 weekly till delivery
• If critical titre – >1:16 or >4IU/ml, or if previously affected pregnancy at any titre – refer to MFM service

• Consider 4 weekly USS for growth, liquor, MCA-PSV, hydrops
• Perform USS for MCA-PSV every 1 weeks if titres above threshold or rising
• If MCA-PSV above 1.5 MOMs – suggests fetal anaemia
• If fetal anaemia – guarded prognosis, although depends on gestation and presence of hydrops– discuss options – TOP, FBS/transfusion/deliver

• If FBS shows Hb >2 SD below mean, discuss benefits and risks of intrauterine transfusion +/- perform IUT

• Timing of pregnancy: 37-38 weeks; earlier if rising titres and/or requiring IUT. Timing to be coordinated with timing of IUT to optimise fetal anaemia prior to delivery.
- No indication for caesarean
- CTG in labour
- ensure maternal valid G&H as approaching expected delivery date when high risk for bleeding (e.g. placenta praevia)

• Neonatal concerns – paeds at delivery. Complex resus if hydrops. Cord blood at delivery – Hb, blood group, direct Coombs, bilirubin level.
• Baby may need – blood transfusion, phototherapy, exchange transfusion, and followup.
• Discuss care for next pregnancy – consider PIGD, sperm donor or surrogate. If same parents – early specialist involvement and frequent MCA Doppler regardless of anti-D titre.


A Rhesus (D) negative woman has a Rhesus (D) positive baby.

a. Describe the immune process, circumstances and requirements that:

i) Lead to Haemolytic Disease of the Newborn (HDN). (3 marks)

• Mother is Rh sensitized – either from incompatible blood transfusion, previous delivery/TOP/miscarriage of Rh positive fetus, or fetomaternal haemorrhage earlier in this pregnancy
• Maternal IgG antibodies to Rhesus D red cell antigen develop and persist in maternal circulation
• These IgG antibodies can cross the placenta and cause autolysis of fetal cells, leading to fetal/neonatal anaemia and neonatal jaundice


ii) Prevent HDN occurring by the use of Rh immunoglobulin (anti D). (3 marks)

• Anti-D attaches to Rh pos antigen on the surface of fetal RBC present in the maternal circulation and destroy the cell before the maternal immune system can recognize it and mount an antibody response.
• If there are no antibodies in the maternal circulation, then there is no autolysis of RBC in fetal circulation
• Requires appropriate dose, with measures of fetal blood in maternal circulation eg by Kleihauer
• Routine administration in the third trimester reduces risk of alloimmunisation from 1% to 0.35% (RANZCOG)


b. List the TWO most important red cell antibodies (in an Australian-New Zealand population), other than anti-D, that may be responsible for a hydropic fetal death. (2 marks)

Anti-Kell and Anti-c


Discuss the implication(s) of each investigation (antibody titre and paternal karyotype) with respect to the risks of this pregnancy being affected by these antibodies. (3 marks)

• Antibody titre or quantification- identifies women with antibodies. The type and titre of antibody determines if there is a low, moderate or high risk of HDFN. Women with positive Abs may need serial abs titres through pregnancy and once over a threshold may require referral to MFM and serial USS MCA PSV measurements. This can also have implications for invasive treatments during the pregnancy, and for timing of delivery. It also determines neonatal monitoring for jaundice and signs of kernicterus. Pre-pregnancy and antenatally it may prompt further counselling and Ix, including paternal or fetal genotyping to check risk of HDFN.
For the mother this also highlights if she is at increased risk of blood transfusion reactions, and there will be delay in receiving cross-matched blood. If high risk needing blood transfusion (e.g. placenta praevia) a regular G&H sample should be obtained as they approach timing of delivery.

• If partner is also Rh pos homozygous, ALL future pregnancies are potentially at risk. If partner is heterozygous 50% of pregnancies, and if Rh negative then no pregnancies will be at risk.

Alternatively, NIPT can be used from maternal serum to do fetal genotyping and detect fetal rhesus status if paternity uncertain. NIPT detects fetal cfDNA. It can be done from 16 weeks, or after 20 weeks for anti-K.