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  • Nathan Riley, MD

Obgyno Wino Podcast Episode 43 - Prevention and Management of Alloimmunization During Pregnancy

"Wolves and Women have much in common. Both share a wild spirit. Women and Wolves are instinctual creatures, able to sense the unseen. They are loyal, protective of their packs and of their pups. They are wild and beautiful. Both have been hunted and captured. Even in captivity, one can see in the eyes of a Woman, or a Wolf, the longing to run free, and the determination that should the opportunity arise, whoosh, they will be gone..." - Clarissa Pinkola Estes, Women Who Run With the Wolves


2017 Pinot Noir from Longford Estate Wines


PB#192 - Published March 2018, Reaffirmed 2019

PB#181 - Published August 2017, Reaffirmed 2019


Five Pearls

  1. Risk of alloimmunization is around 15% after 2nd delivery of an Rh positive fetus to an Rh negative mother; this risk is decreased dramatically with administration of postpartum RhoGam

  2. RhoGam is never indicated if both mom and dad are Rh negative or in women who are already sensitized (indirect coombs screen)

  3. The KB test can used to determine if excessive feto-maternal hemorrhage has occurred in order to guide RhoGam administration in less obvious cases such as abdominal trauma in pregnancy

  4. Alloimmunization can present as mild to severe anemia; if concerning antibodies are found, serial titers and/or peak systolic velocity of the middle cerebral artery ma be indicated

  5. "Kell kills"

Background

- a woman may carry antibodies against blood cell antigens if they've been exposed in the past, whether from prior pregnancies or blood transfusions

- five major types of Rh antibodies have been identified: Anti-C, Anti-c, Anti-D, Anti-E, and Anti-e (**this is the most common classification system, "Fisher-Race")

- there are also many minor variants

- the antigen complexes are comprised of three proteins, designated as such, in order of decreasing frequency among white people: CDe, cde, cDE, cDe, Cde, cdE, CDE, and CdE (Note: no "d" antigen has been identified, and the use of little "d" presumes the absence of an evident allelic product)

- genotypic combinations of these complexes are expressed in vivo (remember, one complex for each allele)

- the most common combinations are CDe/cde ("CcDe") and CDe/CDe ("CDe")

- most Rh alloimmunization occurs due to the presence of the D antigen

- Rh positive = D antigen present

- Rh negative = D antigen negative (15% of population)





- there is a ton of variants, and Du antigen is relatively common; it's known as "weak D", and alloimmunization is rare

- some other funny antibodies that you may be familiar with are Lewis (Le^a and Le^b) and I antibodies

- these antigens are cold agglutinins ("M" type) and thus are poorly expressed on fetal erythrocytes --> won't cause erythroblastosis fetalis ("Lewis lives")

- Kell antibodies are a different story ("Kell kills")

- usually found in patients w/ history of blood transfusion

- care for patients with sensitization to D or other antibodies is the same

- when mom is Rh negative, there's a risk of Rh alloimmunization if the fetus is Rh positive

- 15% of whites are Rh negative, 5-8% blacks, and 1-2% of Asians and Native Americans





Rh alloimmunization pathogenesis

- occurs if an Rh negative mom's immune system gets a look at the Rh antigen on the blood cells of an Rh positive fetus; if her immune system hasn't been exposed, she probably won't have enough circulating antibodies to mount a significant enough response to cause any issues in the fetus (and the risk is likely low even if she HAS been exposed)

- this means that the first pregnancy is unlikely to be significantly affected (unless in EXTREMELY rare cases like vanishing twin syndrome) if both parents are Rh negative

- if Rh status of father is unknown, it's possible to check for fetal Rh status using cell free DNA testing

- if mom is Rh negative and fetus is Rh positive, mom's immune system will likely be exposed to fetal blood cells during pregnancy or delivery; then in the SUBSEQUENT pregnancies, she may mount an immune system against a future Rh positive fetus' blood cells, which can be catastrophic


What types of events could lead to this exposure?

- delivery (regardless of mode)

- abdominal trauma in pregnancy

- subchorionic hematoma/hemorrhage

- miscarriage (1-2% risk after SAB, 4-5% risk w/ instrumentation)

- manual removal of the placenta

- external cephalic version (2-6% risk)


How might one determine how much blood has passed into maternal circulation in event of one of these events?

Rosette test

- maternal blood sample collected, anti-D antibodies are added, then an indicator is added

- Ig-Ag complexes will appear as pink "rosettes" on a microscope slide

- qualitative: if positive, must perform quantitative test like KB


Kleihauer-Betke test (KB test)

- fetal RBCs are less sensitive to acidic elution than adult RBCs; with the addition of acid to a maternal blood sample, the maternal RBCs will be lysed and appear as ghostly, empty RBCs; fetal RBCs will retain their pink/red color, then counted microscopically, and the proportion of fetal cells out of 2000 total erythrocytes is used to approximate how much fetal blood was passed to maternal circulation

- a positive test indicates that "excessive fetal hemorrhage" has occurred (i.e. at least 5 mL of fetal blood has entered maternal circulation)

- not a perfect test, but helpful in predicting the degree of mixing that occurred from any of the potential causes above; RhoGam dosing originally dependent on results of the KB test

- expensive and lacks standardization across institutions

- may not be accurate due to conditions in which there is more hemoglobin F, such as sickle-cell disease and the thalassemias


The KB test


How much blood is usually passed from fetus to mom during normal vaginal delivery?

- one clever study that found through fluorescence activated cell sorting that >150 mL of fetal blood was passed to moms circulation during normal vaginal deliveries, which is far more than the lower limits found in other studies


So what's the risk of alloimmunization?

- unfortunately, we don't really know

- our best guess is that the risk without RhoGam, which I'll explain in a minute, is around 15% after delivery of two Rh positive newborns to an Rh negative mom

- in some individuals, very little blood needs to pass from fetus circulation into maternal circulation (<0.1 mL) to cause alloimmunization


Can we prevent alloimmunization?

- it may be possible through the use of RhoGam, an injectable form of anti-D immunoglobulin that prevents the mom's immune system from mounting a response

- in the U.S., it's most often administered within 72 hrs postpartum at 300 mcg (1500 IU) IM for the first pregnancy (if mom Rh negative and newborn Rh positive); this is the dosage that will cover up to 30 mL of feto-maternal hemorrhage

- in subsequent pregnancies, it would administered at 26-28 wga at the same dose then again postpartum

- that 15% risk decreases to 1-2% w/ postpartum administration of a single dose of RhoGam and down to <0.5% with an additional dose given in the 3rd trimester of a subsequent pregnancy

- risk of transmission of blood borne disease is exceedingly low and it has been manufactured without mercury-containing thimerosal since 2001


Unfortunately...the experts aren't as unanimously convinced that it's as helpful prenatally when you consider the rest of the evidence

- according to Cochrane, there's insufficient evidence to support administration of RhoGam during pregnancy, though the evidence looks pretty strong to support administration within 72 hrs postpartum:


"Existing studies do not provide conclusive evidence that the use of anti‐D during pregnancy benefits either mother or baby in terms of incidence of Rhesus D alloimmunisation during the pregnancy or postpartum, or the incidence of neonatal morbidity (jaundice) (low to very low quality evidence). However women receiving anti‐D may be less likely to register a positive Kleihauer test in pregnancy and at the birth of a Rh‐positive infant (low quality evidence). Fewer women who receive anti‐D during pregnancy may have Rhesus D antibodies in a subsequent pregnancy, with benefits for the baby, however this needs to be tested in studies of robust design." - The Cochrane Nerds

- it's important to mention that they only included two studies

- another meta-analysis performed by a cohort of UK researchers included ten studies and concluded that it was effective:


"A bias-adjusted synthesis of all available evidence provides strong evidence for the effectiveness of RAADP in preventing sensitisation, in support of the policy of offering RAADP to all non-sensitised pregnant Rhesus negative women. All three licensed RAADP treatments are expected to be effective in preventing sensitisation. A dose of 1250 IU at 28 and 34 weeks is expected to be most effective and a single dose of 1500 IU at 28–30 weeks is expected to be least effective." - A bunch of UK dweebs

- Cochrane did, however, conclude that postpartum administration was supported by the evidence, but the optimal dose is still debatable, which is why a relatively large dose of 300 mcg (1500 IU) is administered in the U.S.

- if RhoGam was administered within 3 weeks of delivery, a postpartum dose is not indicated in the absence of excessive fetal-maternal hemorrhage

- get a KB test if you aren't sure; if it's positive, this would suggest significant hemorrhage and RhoGam should be recommended


When else might RhoGam be indicated?

- risk of alloimmunization before 28 weeks is low, but ACOG additionally recommends RhoGam in the following scenarios:

  • if a mom is Rh negative and hasn't been sensitized, RhoGam 50-120 mcg IM is recommended for miscarriages up to 12 wga and the full 300 mcg for miscarriages after 12 wga (same rules for ruptured ectopics)

  • it's also recommended to give RhoGam 50-200 mcg IM for chorionic villus sampling or amnoicentesis up to 12 wga and 125 mcg or the full 300 mcg if performed after 12 wga

  • ACOG has no official recommendation on RhoGam utility in threatened pregnancy loss at <12 wga (although the D antigen can be found on fetal erythrocytes as early as 38 days from fertilization)

  • in 2nd or 3rd trimester antenatal hemorrhage, the full 300 mcg is also recommended

  • in the event of abdominal trauma, KB test should be performed to determined if excessive feto-maternal hemorrhage has occurred, and RhoGam recommended w/in 72 hrs if so

  • prior to attempt at external cephalic version

- it's NEVER indicated, if a patient is already sensitized or if the father of all of her pregnancies has also been Rh negative


Pearl: get a type/screen anytime you're considering administering RhoGam to ensure that she hasn't already been sensitized


Here's how this might look in most U.S. hospitals...

- in an Rh negative woman's first pregnancy, Rh status of the newborn should be tested

- if Rh positive, RhoGam can be administered to mom within 72 hrs postpartum to prevent alloimmunization

- if Rh negative, no need to adminster RhoGam

- in this woman's next pregnancy, you might recommend that she receives RhoGam





Can we screen for alloimmunization?

- Sure. At every woman's first prenatal visit, it's prudent to perform a "type and screen", which will reveal her blood type as well as the presence of antibodies for erythrocyte antigens

- this "screen" can be repeated in the third trimester or any other time in pregnancy in which there is concern for mixing of maternal and fetal blood

- if screen is positive, the lab will evaluate for the specific type of immunoglobulin and perform "titers"


Tell me more about titers...

- an antibody titer is a dilution process to discover just how much antibody is present in the patient's blood

- a 1:1 titer suggests that after a single dilution, no antibody activity was detected (less of a problem)

- a 1:8 titer suggests that eight dilutions were required to achieve this result (bigger problem)

- if a concerning antibody (see Table 1 from PB below) has a titer that above 1:8, this should warrant further assessment

- if less than 1:8, serial titers should be performed every 4 weeks

- these rules apply for anti-D Ig and other Ig, except Kell ("Kell kills" regardless of titer)


What does "further assessment" entail?

- referral to a high-risk obstetrician who will measure peak systolic velocity of middle cerebral artery

- "moderate or severe anemia was predicted by values of peak systolic velocity in the fetal middle cerebral artery above 1.5 times the median for gestational age with a sensitivity of 100% and a false-positive rate of 12%."


Who cares if the fetus is anemic?

- anemia caused by destruction of fetal blood cells by mom's immune system leads to a condition known as erythroblastosis fetalis

- mild and moderate anemia can present with severe jaundice and hypoxia after birth

- severely anemic fetuses can die in utero from hydrops fetalis (imagine total anasarca on prenatal ultrasound) and thus will benefit from intrauterine erythrocyte transfusion

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