management of rh negative pregnancy
TRANSCRIPT
MANAGEMENT OF RHESUS NEGATIVE PREGNANCY
OBIOKONKWO AC(MBBS, U.PHACOURT)
DEPARTMENT OF OBSTETRICS & GYNAECOLOGY
FEDERAL MEDICAL CENTRE, BIRNIN KEBBI
01/05/23 http://www.facebook.com/imezi 2
Outline Introduction Epidemiology Pathophysiology Management Problems in our setting Recommendations Conclusion References
01/05/23 http://www.facebook.com/imezi 3
Introduction
The Rhesus (Rh) blood group system is one of the 35 current human blood group systems
It's the second most important system after the ABO system
At present, the Rh system consists of 50 defined blood group antigens (Ag), among which the five Ag D, C, c, E, e are the most important
01/05/23 http://www.facebook.com/imezi 4
... Introduction ...
The D Ag, also called the Rh factor is the most immunogenic[1] of them though the others are still clinically relevant
The Rh factor is a red cell surface antigen named after the rhesus monkey in which it was first discovered.[1]
An individual either has or does not have the D antigen on the surface of their red blood cells (RBCs)
01/05/23 http://www.facebook.com/imezi 5
... Introduction ...
The status is usually indicated by the suffices Rh+ for those that have, or Rh- for those who lack the D antigen
These suffices are attached to the ABO blood type An Rh-negative pregnant woman is one who lacks
this antigen on the surface of their red cells.
01/05/23 http://www.facebook.com/imezi 6
... Introduction ...
Historical time line 1937: Rh blood type discovery by Karl Landsteiner &
Alexander Wiener, and noted to be distinct from ABO blood type
1939: The D antigen was incidentally discovered but yet unnamed. This followed a case of haemolytic disease of the newborn observed in a the infant of a 25 year old G2 P1 woman, blood group O who received O type blood
This case was subsequently published[2] by Philip Levine and Rufus Stetson
01/05/23 http://www.facebook.com/imezi 7
... Introduction ... ... Historical time line ...
1940: This unnamed factor was realised to be similar to the earlier discovered blood type and a connection was made to it[3]
1946: Exchange transfusion created by Wiener for treatment of Rh disease
1960: The concept of anti-RhD for the prevention of Rh disease was proposed by Ronald Finn
1963: First successful intrauterine transfusion for treatment of Rh disease was carried out by Sir William Liley
01/05/23 http://www.facebook.com/imezi 8
... Introduction
... Historical time line 1964: First prophylactic injection for Rh disease was given 1968: Immunoglobulin G antibody was first approved for use
in USA (as RhoGAM) and UK @300 mcg within 3 days postpartum
1973: Reports in the USA said 50,000 babies' lives had been saved since approval
1981: Rh IgG approved for routine postpartum and antepartum administration by the US Food and Drug Administration
01/05/23 http://www.facebook.com/imezi 9
Epidemiology
Globally, the Basque population (of Spain) has the highest incidence of Rh negativity (30-35%)[4]
Otherwise, Whites: 15-16% African Americans: 8% Black Africans: 4% Asians and others, 2% or less
01/05/23 http://www.facebook.com/imezi 10
... Epidemiology
Nigerian studies 4.5% prevalence rate at Enugu,[5] Southeast 0.7% incidence rate at Kaduna,[6] North 5.5% prevalence rate at Ogbomosho,[7] Southwest
01/05/23 http://www.facebook.com/imezi 11
Pathophysiology Two commonest systems for blood group classification:[8]
ABO system Rhesus system
ABO system: Groups A, B AB, O antigen (Ag) Rhesus system: C, c, D, E, e and G.[4]
There's no 'd' Ag. The letter represents absence of 'D' Ag The D antigen is considered to be the most immunogenic
(aka Rh factor)
01/05/23 http://www.facebook.com/imezi 12
... Pathophysiology ...
01/05/23 http://www.facebook.com/imezi 13
... Pathophysiology ...
01/05/23 http://www.facebook.com/imezi 14
... Pathophysiology ... There are two possible alleles for each of the c or C, D
and e or E An individual inherits one haplotype from each parent Rh positive: presence of at least one of either C, D or E
antigens regardless of the combination (ie, homozygous or heterozygous)
Rh negative: cde/cde genotype (always homozygous)
01/05/23 http://www.facebook.com/imezi 15
... Pathophysiology ...
01/05/23 http://www.facebook.com/imezi 16
... Pathophysiology ... The D antigen
The Rh-positive father may be homozygous (45%) or heterozygous (55%) for D
If homozygous for D, all children will test positive If heterozygous, his children will have a 50% chance of being
RhD-positive Thus if 'D' antigen is specifically tested, its absence will
give a negative result regardless of the presence of the other antigens (C, E)
01/05/23 http://www.facebook.com/imezi 17
... Pathophysiology ...
01/05/23 http://www.facebook.com/imezi 18
... Pathophysiology ...
The amount of foetal blood necessary to produce Rh incompatibility varies, but as little as 0.1 mL of Rh+ cells have been documented.[4]
Studies have suggested that up to 30% of persons (non-responders) with Rh- blood never develop Rh incompatibility even when challenged with large volumes of Rh+ blood[1]
Rh alloimmunisation occurs by 1 of 2 mechanisms After incompatible blood transfusion
01/05/23 http://www.facebook.com/imezi 19
... Pathophysiology ... After foeto-maternal haemorrhage between mother and an
incompatible foetus Foeto-maternal haemorrhage may occur during pregnancy
(10%) or delivery (90%)[1]
Notwithstanding, foetal RBCs have been detected in the maternal blood in all three (7, 16, 29%) trimesters without an apparent predisposing factor[4]
The initial maternal response to Rh sensitisation is low levels of immunoglobulin (Ig) M antibodies (Ab)
01/05/23 http://www.facebook.com/imezi 20
... Pathophysiology ...
These are confined to maternal circulation being unable to cross the placental barrier
Within 6 weeks to 6 months, IgG Ab are formed These are able to cross the placenta and destroy foetal Rh-
positive cells Therefore, first-born infants with Rh-positive blood type
are not affected The short period of 1st exposure of mother to foetal RBCs is
insufficient for production of significant IgG Ab response
01/05/23 http://www.facebook.com/imezi 21
... Pathophysiology ...
Subsequent pregnancies may trigger a rapid & robust Ab response - Anamnestic response
Anamnestic theories:– Grandmother theory– “Sensibilization” theory
Maternal O blood type appears particularly protective
01/05/23 http://www.facebook.com/imezi 22
... Pathophysiology ... Sequence of inutero events
Maternal IgG enters foetal circulation via placenta Destruction of foetal red cells occur - foetal anaemia [HCT<30%] Haem is formed and converted to bilirubin – foetal
hyperbilirubinaemia Both are neurotoxic, but effectively cleared by placenta and
metabolised by the mother Extramedullary erythropoeisis is stimulated Immature erythroblasts are produced
01/05/23 http://www.facebook.com/imezi 23
... Pathophysiology ... When cell destruction exceeds production
Severe anaemia occurs More demand on extramedullary sites to produce more red cells
– hepatosplenomegaly Heart failure eventually results, with ascites, oedema and
pericardial effusion – erythroblastosis foetalis Hydrops foetalis, occurs when the haematocrit falls below 15%.
Often results in foetal death shortly before or after birth• Male to Female foetus = 13.1 to 1
01/05/23 http://www.facebook.com/imezi 24
01/05/23 http://www.facebook.com/imezi 25
... Pathophysiology ... The risk and severity of sensitisation response increases
with each subsequent pregnancy involving an ABO-compatible foetus with Rh-positive blood
Without prophylaxis, this risk is 16% after two deliveries;– 1.5-2% occur antepartum– 7% within 6 months of delivery– 7% manifest early in 2nd pregnancy
With prophylaxis, the risk drops to 0.1%
01/05/23 http://www.facebook.com/imezi 26
... Pathophysiology The aforementioned risk depends on the 3 main factors
Volume of transplacental haemorrhage Extent of the maternal immune response Concurrent presence of ABO incompatibility (protective –
risk drops to 1.5-2%)[4]
Rh incompatibility is only of medical concern for females who are pregnant, or plan to get pregnant in future
01/05/23 http://www.facebook.com/imezi 27
Management
This includes history taking, clinical examination, appropriate investigations, and treatment
Two groups of women are catered for– Unsensitised Rh-negative women– Sensitised Rh-negative women
There is usually no specific finding on the history and clinical examination for the woman that is not sensitised
01/05/23 http://www.facebook.com/imezi 28
... Management ...
For the sensitised woman, her presentation would depend on whether or not she has a previously affected infant. This also guides management.
Some events have been found to increase the chances of formation of anti-D antibodies in Rh-negative women
The goal of the history therefore, is to establish or exclude the occurrence of such events
01/05/23 http://www.facebook.com/imezi 29
... Management ... Potentially sensitising events
Abortion Invasive procedures (amniocentesis, chorionic villus sampling) Abdominal/pelvic trauma Antepartum haemorrhage (placenta praevia, abruptio) Intrauterine foetal demise Multiple gestation Manual removal of the placenta Ectopic pregnancy Caesarean delivery
01/05/23 http://www.facebook.com/imezi 30
... Management ... Other aspects of the history to be explored include
Prior blood transfusion Rh blood type of patient and spouse All previous pregnancies, outcomes, interventions
• History of hydrops = 90% chance recurrence Previous administration of Rh IgG Mechanism of injury in cases of maternal trauma during pregnancy Presence of vagina bleeding Prior invasive procedure
01/05/23 http://www.facebook.com/imezi 31
... Management ...
The objective of antenatal management is– Prevention of Rh alloimmunisation in the Rh-
negative unsensitised woman– Early detection and treatment of foetal anaemia in
the sensitised woman Sensitisation is determined via the indirect
Coombs test, otherwise called antibody screen
01/05/23 http://www.facebook.com/imezi 32
... Management ...
The unsensitised Rh-negative woman History may be uneventful with patient hearing for
the first time of her Rh-negative group First, determine husband's ABO and Rh group. If negative, manage as any other pregnancy. No
further investigation required If positive, screen woman for alloimmunisation at
contact.
01/05/23 http://www.facebook.com/imezi 33
... Management ...
... The unsensitised Rh-negative woman If the antibody screen is negative, repeat at 20, 24 & 28
weeks If still negative by 28 weeks, 300 mcg of Rh IgG is given A repeat dose is given after each invasive procedure, or
after 12 weeks of last dose if pregnancy lasts that long If a positive result is recorded at any time, the patient is
managed as a sensitised Rh-negative woman
01/05/23 http://www.facebook.com/imezi 34
01/05/23 http://www.facebook.com/imezi 35
... Management ... Precautions during delivery
– Ensure consultation with neonatologist– Don't give oxytocics at delivery of anterior shoulder– If manual removal of placenta is required, do so gently– If blood transfusion is indicated, use Rh-negative blood
only– Early clamping of umbilical cord is indicated– Leave a long length of cord, about 15 to 20 cm
01/05/23 http://www.facebook.com/imezi 36
... Management ...
Postpartum management Involve the neonatologist Send cord samples for ABO/Rh typing, DCT, Hb,
bilirubin levels, peripheral smear If foetus is Rh-negative, no further intervention If foetus is Rh-positive, determine the dose of Rh IgG to
be administered by a 4-step laboratory procedure
01/05/23 http://www.facebook.com/imezi 37
... Management ...
The 4-step laboratory procedure– Rosette foetal RBC screen for FMH. If positive,– Acid elution (Kleihauer-Betke) test to quantify the
RBCs in maternal circulation– Estimate the volume of FMH (50 x % foetal RBCs)– Calculate the dose of Rh IgG to be given within 72
hours of delivery
01/05/23 http://www.facebook.com/imezi 38
Rosette Test
Positive rosetteNegative rosette
01/05/23 http://www.facebook.com/imezi 39
Acid Elution Test
01/05/23 http://www.facebook.com/imezi 40
... Management ...
For sensitised women, management is guided by the following
– Presence or absence of history or affected foetus in previous pregnancy (e.g. with severe anaemia or hydrops)
– Maternal antibody titres (where no prior history) Sensitisation may be determined by doing an
antibody screen using indirect Coombs test
01/05/23 http://www.facebook.com/imezi 41
Direct Coombs Test
01/05/23 http://www.facebook.com/imezi 42
Indirect Coombs Test
01/05/23 http://www.facebook.com/imezi 43
... Management ...
The sensitised Rh-negative woman No previous history of affected foetus
– The history might include some of the previously mentioned sensitising events
– Risk of foetal anaemia is proportional to maternal anti-Rh antibody titre
– This relationship is lost in subsequent pregnancies– Obtain the ABO and Rh group of the husband. If
negative, no further testing is needed. If positive,
01/05/23 http://www.facebook.com/imezi 44
... Management ...... The sensitised Rh-negative woman ...
... No previous history of affected foetus...– Screen for alloimunisation. If positive, obtain Ab titres– If below the critical titre, obtain monthly titres– If still below critical level by 36th week, pregnancy
may continue to term, but not allowed to be postdated– If it rises beyond critical value after 34 weeks, deliver
immediately
01/05/23 http://www.facebook.com/imezi 45
... Management ...
... The sensitised Rh-negative woman ... ... No previous history of affected foetus
– If it rises before 34 weeks, further testing includes• Peak systolic velocity of the middle cerebral arteries
using Doppler• Amniocentesis for analysis and spectrophotometry• Ultrasound examination of foetus• Percutaneous umbilical cord blood sampling
(cordocentesis) for HCT, Rh
01/05/23 http://www.facebook.com/imezi 46
... Management ...
... The sensitised Rh-negative woman ... Previously affected foetus
– The history may include, amongst others, that of a stillborn neonate, one admitted for phototherapy or exchange blood transfusion.
– One needs to be proactive to prevent recurrence, and have a high index of suspicion
– Her Rh type should be established as well as sensitisation
01/05/23 http://www.facebook.com/imezi 47
... Management ...
... The sensitised Rh-negative woman ... ... Previously affected foetus
– Evaluation should start early – at least 4 weeks to anniversary of prior affected foetus
– The anti-D titres cannot predict the development of foetal anaemia, thus other tests are indicated
– Cordocentesis may be indicated to determine foetal HCT, and Rh genotype if father is heterozygous for D
– If the foetus is determined to have the D Ag, there is a risk of haemolytic disease and sequelae
01/05/23 http://www.facebook.com/imezi 48
... Management ...
... The sensitised Rh-negative woman ... ... Previously affected foetus
– Amniocentesis may be done for amniotic fluid spectrophotometry and assay
– Initiate middle cerebral artery Doppler (MCAD) surveillance from 18 weeks
01/05/23 http://www.facebook.com/imezi 49
... Management ...
01/05/23 http://www.facebook.com/imezi 50
... Management ...
Middle Cerebral Artery Doppler (MCAD) Velocimetry Accurate & non-invasive screening tool for detecting
moderate to severe foetal anaemia A sensitivity of 100% and a 12% false positive rate for
anaemia Use has resulted in up to 80%[9] reduction in invasive
testing (i.e., amniocentesis, cordocentesis)
01/05/23 http://www.facebook.com/imezi 51
... Management ...
Middle Cerebral Artery Doppler (MCAD) Velocimetry Not useful before 18 weeks of gestation – RES too
immature to haemolyse enough cells to cause significant anaemia[9]
Not a reliable predictor of severe anaemia after 35 weeks GA[10]
Found to be similar[11] or better[12] than amniotic fluid OD450 in prediction of anaemia
01/05/23 http://www.facebook.com/imezi 52
Normal vs abnormal MCA-PSV
Normal MCA Doppler
01/05/23 http://www.facebook.com/imezi 53
... Management ...
Results MCAD Velocimetry[4]
Unaffected/mildly affected foetus– Normal MCAD. Doppler is repeated monthly. Deliver at or near term after
lung maturity. Low risk of IUFD
Moderately affected– MCAD about 1.5 multiples of median (MoM). Repeat 1-2 weekly. Deliver
after lung maturity. Enhancement of lung maturity may be necessary
Severely affected– MCAD >1.55 MoM or has frank evidence of foetal hydrops. Foetus needs
help to attain lung maturity before delivery. High risk of IUFD
01/05/23 http://www.facebook.com/imezi 54
Spectrophotometry charts
QueenanLiley
Not accurate before 26 weeks GA Can be used from 14th to 40th week GASensitivity 10% superior to Liley curve
01/05/23 http://www.facebook.com/imezi 55
... Management ...
01/05/23 http://www.facebook.com/imezi 56
... Management ...
Intrauterine Blood Transfusion[8]
Recommended treatment for severe (haemolytic) anaemia inutero
Typically carried out between 18 and 35 weeks GA May be given intraperitoneal or intravascular O RhD negative packed cells with HCT of 80% is used Amount to be transfused in mL is (GA-20) x 10 where GA>
20 weeks
01/05/23 http://www.facebook.com/imezi 57
Intravascular IUBT
01/05/23 http://www.facebook.com/imezi 58
... Management ...
... The sensitised Rh-negative woman Postpartum management of the neonate
– Baby, if alive should be admitted into the neonatal intensive care unit
– An urgent exchange blood transfusion is indicated in moderate to severely affected neonates
– Phototherapy for mild affectation.
01/05/23 http://www.facebook.com/imezi 59
... Management ... Special foeto-maternal risk states[4]
Abortion: Up to 5% chance of sensitisation. Fifty microgram is recommended
Invasive foetal procedure: Up to 11% of sensitisation. A dose of 300 mcg is recommended
Antepartum haemorrhage: 300 mcg stat, to be repeated 12 weeks later if pregnancy lasts that long
External cephalic version: Up to 6% chance of sensitisation. Dose is 300 mcg
01/05/23 http://www.facebook.com/imezi 60
... Management
– Delivery with foeto-maternal haemorrhage• The normal amount of foetal blood that enters the
maternal circulation is <0.5 mL.[13]
• Dose of Rh IgG given @ 300 mcg will neutralize nearly 30 mL whole foetal blood (or 15 mL Rh+ foetal RBCs)
• Management is guided by the estimated volume of FMH determined by the 4-step lab tests
• Dose of Rh IgG given after sensitisation is at least 20 mcg/mL of foetal RBCs[1]
01/05/23 http://www.facebook.com/imezi 61
Recent Advances
Non-invasive foetal RhD genotyping (from foetal cell-free DNA in maternal circulation)[14]
Point-of-care-tests (POCT), i.e., rapid tests for determining Rh status[15]
A lower 50 mcg dose preparation of Rh IgG for use following first trimester abortions[1]
Concept of partial D and weak D antigens (usually test positive, but can also form anti-Rh antibodies)[16]
01/05/23 http://www.facebook.com/imezi 62
Take home points
1. Every woman of childbearing age should have her ABO and Rh types done at first contact
2. Obtain the ABO/Rh types for husbands of women found to be Rh-negative
3. Ensure ICT is done at 20, 24 and 28 weeks of pregnancy with appropriate prophylaxis
4. A single postpartum dose may be inadequate in cases of severe foeto-maternal haemorrhage
01/05/23 http://www.facebook.com/imezi 63
Problems in our setting
High cost of the immunoglobulin Lack of resources to adequately investigate and
monitor foetus inutero Low turnout for antenatal clinics – missed cases Poor documentation of prior sensitising events –
some are yet to fully grasp the import Loss of case notes
01/05/23 http://www.facebook.com/imezi 64
Recommendations
Advocacy for partnership by Government and NGOs to help subsidize the cost of the immunoglobulin
Special insurance cover for Rh-negative women to ensure ease of procurement when needed
Involvement of clergy as part of premarital counsellors Creation of special fora/groups for Rh-negative people
where potential Rh-negative spouses can be met
01/05/23 http://www.facebook.com/imezi 65
Conclusion
Rhesus alloimmunisation is a real problem and real efforts need to be made to mitigate its impact
Although its incidence has decreased dramatically, yet the consequences of haemolytic disease of the newborn remain
Great advancements have been made in the detection and management of this condition, and many of our Rh-negative women can now have a happy obstetric career.
01/05/23 http://www.facebook.com/imezi 66
THANK YOU FOR LISTENING
01/05/23 http://www.facebook.com/imezi 67
References
1. Salem L, Singer KR. Rh Incompatibility. [Updated: Feb 06, 2014]. Available from http://emedicine.medscape.com/article/797150
2. Levine P, Stetson RE. An unusual case of intragroup agglutination. JAMA. 1939. 113:126-7.
3. Landsteiner K, Wiener AS. An agglutinable factor in human blood recognised by immune sera for rhesus blood. Proc Soc Exp Biol Med. 43: 223-4.
4. Roman AS. Late pregnancy complications. In: Decherney AH, Nathan L, Laufer N, Roman AS, editors. Current Diagnosis & Treatment: Obstetrics & Gynaecology. 11th ed. United States: McGraw-Hill Companies Inc; 2013: 250-266.
5. Okeke TC, Ocheni S, Nwagha UI, Ibeghulam OG. The prevalence of Rhesus negativity among pregnant women in Enugu, Southeast Nigeria. Niger J Clin Pract. 2012 Oct-Dec; 15(4): 400-2
01/05/23 http://www.facebook.com/imezi 68
... References ...
6. Onwuhafua JA. Pregnancy in Rhesus Negative Women in Kaduna, Northern Nigeria. Trop J Obstet Gynaecol. 2004; 21(1): 21-23
7. Adeyemi AS, Bello-Ajao HT. Prevalence of Rhesus D-negative blood type and the challenges of Rhesus D immunoprophylaxis among obstetric population in Ogbomosho, Suthwestern Nigeria. Ann Trop Med Public Health. 2016; 9(1):12-15.
8. Saxena R, editor. Bedside Obstetrics and Gynaecology. 1st ed. New Delhi: Jaypee Brother Medical Publishers (P) Ltd; 2010: 105-120.
9. Scheier M, Hernandez-Andrede E, Carmo A, Dezerenyz V, Nicholaides KH. Prediction of fetal anemia in rhesus disease by measurement of fetal middle cerebral artery peak systolic velocity. Ultrasound Obstet Gynecol. 2004; 23: 432-436.
01/05/23 http://www.facebook.com/imezi 69
... References ...
10. Zimmermann R, Durig P, Carpenter RJ, Jr, Mari G. Logitudinal measurement of peak systolic velocity in the fetal middle cerebral artery for monitoring pregnancies complicated by red cell alloimmunization: A prospective multicentre trial with intention to treat. Br J Obstet Gynaecol. 2002; 109: 746-752
11. Bullock R, Martin WL, Coomarasamy A, Kilby MD. Prediction of fetal anemia in pregnancies with red-cell alloimmunization: comparism of middle cerebral artery peak systolic velocity and amniotic fluid OD450. Ultrasound Obstet Gynecol. 2005;25:331-334
12. Pereira L, Jenkins TM, Berghalla V. Conventional management of maternal red cell alloimmunization compared with management by Doppler assessment of middle cerebral artery peak systolic velocity. Am J Ostet Gynecol. 2003;189:1002-1006
01/05/23 http://www.facebook.com/imezi 70
... References
13. Pessel C, Tsai MC. The Normal Pueperium. In: Decherney AH, Nathan L, Laufer N, Roman AS, editors. Current Diagnosis & Treatment: Obstetrics & Gynaecology. 11th ed. United States: McGraw-Hill Companies Inc; 2013: 190-213
14. Kolialexi A, Tounta G, Mavrou A. Noninvasive fetal RhD genotyping from maternal blood. Expert Rev Mol Diagn. 2010 Apr; 10(3): 285-96
15. Rapidtest® Rh Test kit. Available from http://nbi-sa.co.za/index.php/products/30-products/71-diagnostics
16. Gonsorcik VK, Zhou L. Rh Typing. [Updated: Nov 06 2013]. available from http://emedicine.medscape.com/article/1731224