2. Anemia in Pregnancy
WHO & CDC recommendation:
Trimester-specific cutoffs for anemia
• 1st trimester <110g/L (8% prevalence)
• 2nd trimester <105g/L (12% prevalence)
• 3rd trimester <110g/L (34% prevalence)
Women at higher risk of IDA due to increased iron
requirements.
WHO recommendations on antenatal care for a positive pregnancy experience, 2016
Postpartum <100g/L
Male Hb13; Non Pregnant Female Hb12
3. Anemia
– a Global Public Health Problem!
IDA – among the most important
contributing factors to the global
burden of diseases
9. This lecture will cover…
• Iron Deficiency Anemia (IDA)
• Anemia of Chronic Disease (ACD) / Anemia of
Inflammation (AI)
• Thalassemia
Main focus – IDA, the most common type of anemia
10. ID / IDA is detrimental for mothers
Camaschella C. Iron Deficiency Anemia. N Engl J Med 2015;372:1832-43.
Breymann 2015 Iron deficiency anaemia in pregnancy; 18. Ponikowski, 2014
JAMA Psychiatry. Dol:10.1001/jamapsychiatry.2019.2309
Published online September 18, 2019
• Inability to tolerate blood loss
• Risk of severe maternal morbidity or mortality after
PPH
• Increased risk in heart failure
• Reduced milk production
• Shorter lactation periods
• Perinatal Mental Health
• Impaired physical function
• Reduced quality of life
11. ID / IDA is detrimental for children
Camaschella C. Iron Deficiency Anemia. N Engl J Med 2015;372:1832-43.
Breymann 2015 Iron deficiency anaemia in pregnancy; 18. Ponikowski, 2014
JAMA Psychiatry. Dol:10.1001/jamapsychiatry.2019.2309
Published online September 18, 2019
• Perinatal mortality, SB
• Premature birth and low birth weight
• IUGR / FGR, SGA
• ID or IDA in newborn
• Long-term adverse effects on brain development
and behavior: ASD, ADHD, ID
Maternal hemoglobin concentrations across pregnancy and
maternal and child health: a systematic review and meta-analysis.
Ann.N.Y.Acad.Sci.1450(2019)47-68
12. ASD: autism spectrum disorder
ADHD: attention-deficit/hyperactivity disorder
ID: intellectual disability
JAMA Psychiatry. Dol:10.1001/jamapsychiatry.2019.2309
Published online September 18, 2019
13. Back to basic – ANEMIA…
• Addressing Maternal Anemia
–to protect Mothers & Newborns
Bread
&
Butter !!
14. Iron Requirement during Pregnancy
Ref: 1. Nils Milman. Prepartum anaemia: prevention and treatment. Ann Hematol (2008) 87:949–959. 2.
Nils Milman. Iron and pregnancy—a delicate balance. Ann Hematol (2006) 85: 559–565
15. Serum Ferritin
• Ferritin – most frequently used test for evaluating
iron stores
• Various cutoffs eg 70ug/L or 100ug/L have been
used
• <30 ug/L : low iron status (92% sen, 98% spec for absolute ID
with or without anemia)
• <15 ug/L : iron depletion
• <12 ug/L : associated with IDA
• Ferritin – acute-phase reactant, levels affected by
inflammation
16. Transferrin Saturation (TSat)
• TSat – iron available for tissue
• Low TSat – insufficient iron supply to support
normal erythropoiesis
• If TSat <20% & Ferritin >100 – Functional ID
(Iron Sequestration) eg anemia of chronic
disease (ACD) / anemia of inflammation (AI)
Current misconceptions in diagnosis & management of iron deficeincy.
Munoz, Blood Transfus 2017
17. Ferritin >100 ng/mL
plus TSAT >20%
Definitions
Ferritin 30-100 ng/mL
plus TSAT >20%
Low Iron Stores
Ferritin <100 ng/mL
plus TSAT <20%
Ferritin <30 ng/mL
Absolute
ID
Ferritin >100 ng/mL
plus TSAT <20%
Iron
Sequestration
(functional ID)
Iron Replete
Munoz et al, Blood Transfus. 2017 Sep;15(5):422-437.
Defining Iron Deficiency
ID accounts for
75% of non-
physiologic anemia
during pregnancy.
18. Non-Anemic Iron Deficiency (NAID)
• Even in the absence of anemia, ID has negative
impact for both mother & neonate:
Mother: cognitive ability, physical performance, PPH, transfusion,
etc
Neonate: low APGAR, PTB, behavioral problems, etc
• Hb not suitable to assess iron status, esp when
there is various degree of hemodilution (ID on
functional level)
• Ferritin provides info on capacity of body iron
reserves (ID on cellular level)
• Iron deficiency is often seen in first trimester
19. Non-Anemic Iron Deficiency (NAID)
• “Mild anemia” (Hb 11-12 or 13) – a misnomer
• ID already advanced by the time anemia
is detected.
• IV iron replacement for NAID-associated
fatigue (runners - *blood doping)
• How about post-blood donation iron
replacement?
Current misconceptions in diagnosis & management of iron deficeincy.
Munoz, Blood Transfus 2017
Hb concentrations for the diagnosis of Anemia & Assessment of Severity. WHO 2011
20. Non-Anemic Iron Deficiency (NAID)
• Cancer, inflammatory bowel disease – NAID may induce
20 thrombocytosis (>350) independent risk factor for
thromboembolic event.
• ID a preventable cause of thrombosis, especially in the
elderly.
• Obst VTE – adjusted odds ratio (aOR):
o Anemia: 1.6-2.6
o >Parity 1: 1.5-2.4
o >35yr: 1.2-1.4
Current misconceptions in diagnosis & management of iron deficeincy.
Munoz, Blood Transfus 2017
Reducing the Risk of VTE during Pregnancy & the Puerperium, RCOG 2015
21. Iron Homeostasis in Pregnancy
Plasma volume expansion 50%
RBC mass 25%
i.e. Plasma Volume Expansion > RBC mass
Hb
Hematocrit
Nadir at end of T2 till beginning of T3
Normal physiologic anemia of pregnancy
Hemodilution
PVE > RBC
22. Severe antenatal anemia (<60g/L)
Has been associated with:
• Abnormal fetal oxygenation (20 to impaired O2
transport to uterus / placenta / fetus) -FGR
• Non-reassuring fetal heart rate patterns
• Reduced amniotic fluid volume
• Fetal cerebral vasodilatation
• Fetal mortality
Patient Blood Management in Obstetrics: Management of Anemia & Hematinic
Deficiencies in Pregnancy and in the post-partum period: NATA consensus statement
Transfusion Medicine, 2018, 28,22-39
Sifakis & Pharmakides, 2000
Carles et al., 2003
23. High Hb Concentrations
• Failure for plasma volume expansion (PVE)
• Chronic renal impairment (eg lupus nephritis, advanced
diabetes)
Reduced plasma volume expansion
Hemoconcentration
• NOT indicator for good iron status
• Increased blood viscosity
low uterine arterial blood flow, reduced placental
perfusion
Reduced O2 delivery to the fetus
Emerging understanding and measurement of plasma volume expansion in
pregnancy Am J Clin Nutr 2017;106(Suppl):1620S-5S
24. U-shaped relation
U-shaped relation between maternal Hb conc and
adverse pregnancy outcomes.
Hb
Hb*
* Hb >13
Maternal Hemoglobin Levels during Pregnancy and their Associations with Birth Weight of Neonates
Iranian Journal of Pediatric Hematology Oncology Vol5.No4
Hb concentrations & adverse birth outcome in South Asia pregnant women: findings from a
Prospective Maternal & Neonatal Health Registry. Reproductive Health 2020
IUGR, SGA, PTB, LBW, SB,
Preeclampsia*
Hb
Adverse
Pregnancy
outcome
25. How to protect the mother & baby?
Prevent / treat antenatal anemia, to avoid:
• Neonatal outcomes (LBW, SGA, PTB, FGR, etc),
&
• Maternal outcomes (PPH, maternal sepsis,
etc)
...by practicing
Patient Blood Management
26. The Urgent Need to implement Patient Blood Management, WHO Policy Brief, 2021
27. The Urgent Need to implement Patient Blood Management, WHO Policy Brief, 2021
28. 3 Pillars of PBM in Obstetrics
1. Optimise
haemopoiesis
2. Minimise blood loss
and bleeding
3. Harness and
optimise tolerance
of anaemia
•Screen for red cell antibodies
•Screen for & treat anemia
(Hb, Ferritin)
•Iron – oral, parenteral
•?ESA
•Pharmocologic/ haemostatic
agents
•Uterine tamponade
•Cell salvage
•MTP
•Iron – oral, parenteral
29. 1st Pillar of PBM:
optimise haemopoiesis
• Improve diagnosis &
treatment of ID / IDA
• Resort to Parenteral /IV Iron,
if oral hematinics are not
increasing Hb as targeted
• Good response: Hb < 10g/L
in 2w or <20g/L in 4w
Optimise
red cell
mass
30. Anemia during Pregnancy
• Routine
screening for
Iron Deficiency?
(Hb, Ferritin, KIV TSat)
• Replenish iron
stores before
one progresses
to anemia
31. Oral Iron Therapy (Malaysia)
Iron Product Content per
tablet (mg)
Elemental Iron
per tablet (mg)
Absorbed Iron
per tablet (mg)
Ferrous
Fumarate
200 60 7.5
Zincofer (FF) 350 115 14.4
Iberet Folic (FS) 525 105 13.1
Maltofer + FA
(IPC)
- 100 12.5
Obimin (FF) 90 30 3.8
10-
15%
Daily vs EOD ?
32. Hepcidin in Iron Metabolism
• Major regulator of systemic iron bioavailability
• Produced by liver
• Synthesis of Hepcidin is regulated by 3 signals –
1. Need for increased erythropoiesis: hepcidin
2. Increased plasma iron & iron store: hepcidin
3. Inflammation: hepcidin
• Hepcidin blocks iron absorption & prevent iron
overload iron sequestration
• Hepcidin effect lasts for 48hr (hence EOD dosing)
33. Ferroportin & Hepcidin
• Ferroportin – transmembrane iron transporter
found in duodenal enterocytes and macrophages
• Hepcidin degrades ferroportin preventing
enteral iron absorption and transport of iron from
liver
34.
35. • EOD Iron is associated with increased absorption
• Second trimester – still reasonable to continue oral
iron if Hb is at least 10g/L
• For Hb<10 or in third trimester – IV iron should be
given to ensure adequate iron gets to the fetus.
Michael Auerbach, MD
36. Every Other Day (EOD) Dosing
Alternate days dosing may:
-maximize fractional iron absorption,
-increase dosage efficacy
-reduce GI exposure to unabsorbed iron
-improve tolerance of iron supplements
Blood, 22 October 2015. Volume 126, Number 17
37. Regimes for Oral Hematinics
Iron Deficiency (Prophylaxis)
1/1 EOD
Iron Deficiency Anemia (Treatment)
1/1 Daily
(Maltofer may go as high as 2-3 Tablet OD)
NO Split dosing
NO Double / triple hematinics
NO Weekly intermittent dosing
Prophylaxis 30-60mg Iron / day
Treatment 120-180mg Iron / day
38. Fehr J et al. Praxis 2009;98:1445–1451; Gordeuk VR et al. Am J Clin Nutr 1987;46:1029–1034;
Aapro M et al. Ann Oncol 2012;23:1954–1962
Iron Replacement Therapy
Iron preparations in Malaysia
Oral iron* Intravenous iron
Iron(III) carbohydrate
complexes
• Iron sucrose (Venofer)
• Iron dextran (Cosmofer)
• Iron isomaltoside (Monofer)
Iron(III)
complexes:
• Iron(III)-hydroxide
polymaltose complex
Iron(II)
compounds:
• Ferrous sulfate
• Ferrous fumarate
• Ferrous gluconate
• Others
Do not administer via IM Iron (uncertain absorption, painful, stain)
Parenteral Iron is contraindicated in 1st trimester
39. “The feared anaphylactic reaction is extremely rare and
occurs mainly with the high-molecular-weight ID (iron
dextran)”*
“Thus, it seems that the newer formulations are safer to
administer and no test dose is required”
103 trials included 10,390 patients. IS= Iron sucrose; FCM= Ferric carboxymaltose; FG= Ferric
gluconate
Avni et al. Mayo Clin Proc. 2015 Jan;90(1):12-23.
Risks of reactions with IV Iron
*IMFERON (high
molecular weight Iron
Dextran) is not
available in Msian
market since ?2005
40. Reactions
(1) Infusion Reaction / Fishbane Reactions
• Self-limited; 1:100-250 administrations
• Due to labile free iron
• Acute chest / back tightness, myalgia, flushing, diarrhea,
swelling of hand / feet
• No BP, wheezing or stridor
• Minor reactions;
• hypersensitivity
• Re-challenge with lower infusion rate or switch to other IV
iron formulation
• If urticaria - Antihistamine &/or Corticosteroid
41. Reactions
(2) Hypotension
• Hypersensitivity, or vascular reaction
• Self-limited
• Related to:
Rapidity of administration
Labile iron content
• If hypotension - lie horizontally with leg elevation,
IV fluid load (500ml), antihistamine, corticosteroid
42. Reactions
(3) Anaphylaxis
• IgE mediated
• CARPA (complement activation related pseudoallergy)
• Related to rapidity of administration
• Exceedingly rare (<1:250,000 administrations)
• With CVS & RS manifestations
• Rx: epinephrine, fluid, corticosteroid
• Antihistamine may delay efficacy of epinephrine
*Delayed reaction – can’t be predicted by test dose
Gomez-Ramirez et al. Prevention & Management of Acute Reactions to IV Iron in Surgical Patients.
Blood Transfus 2019
43. Various IV Iron Preparations
LMWID IS FDI/IIM FCM
Molecular wt
(Daltons)
103000 43300 1000 150000
Structure Iron core, CHO shell Iron core, CHO shell Linear, non-
branched CHO
Iron core, CHO shell
Labile iron(%) 2% 3.5% 1% 0.5%
Stability High Medium High High
Maximum single
dose
20mg/kg 7mg/kg
(200mg boluses or
500mg TDI)
20mg/kg
(1000-2000mg)
15mg/kg
(1000mg)
Max admin time 4-6hr 10-30min (bolus) 15-30min 15min
Issues Longer time Lower dose Higher dose,
Faster Hb
Faster Hb
Name of Iron
Product
Cosmofer Venofer Monofer Ferinject
LMWID: Low Molecular Weight Iron Dextran (Cosmofer®); IS: Iron Sucrose (Venofer®)
FDI/IIM: Ferric Derisomaltose / Iron Isomaltoside (Monofer®) FCM: Ferric Carboxymaltose (Ferinject®)
44. IV iron is indicated with or without trial
of oral iron
IV iron may be
indicated when
rapid increase of
Hb and iron stores
are required
Camaschella C. Iron-Deficiency Anemia.
N Engl J Med. 2015 Jul 30;373(5):485-6.
45. …early IV Iron therapy is
recommended in postoperative
period if iron is necessary. Where
possible, it should be
administered using a single high-
dose preparation for the
repletion of iron stores
46.
47. When should we consider IV Iron?
• When not responding to oral hematinics
• When there is an urgency to top up Hb (before
surgery / delivery)
• When massive bleeding is anticipated.
• Surgery / O&G:
Pre-operatively / Antenatally
Post-operatively / Postnatally – after PPH has
been controlled & patient stabilized
Intraoperatively
48. Iron Requirement Calculation
• Oxygen Delivery (Iron for Hb)
~200-250gm Iron per g/dL Hb
Target Hb >13g/dL
• Oxygen Utilization (Iron for store & other non-haem
functions)
1g/L Ferritin = ~8mg stored iron
Target serum Ferritin >100g/L
Munoz etal. Blood Transfus 2017; 15:422-37
Ganzoni formula
Total iron dose = BW in kg x
Hb deficit x 2.4 + Iron stores
in mg
*IV Iron is CONTRAINDICATED in 1st Trimester
49. How about ESA?
Anemia of Chronic Disease (ACD) / Anemia of
Inflammation (AI) – 2nd most common (after IDA)
Typically: NcNc (may progress to Mc); Serum iron; TSat;
reticulocytes; Ferritin may be (acute phase protein);
Hepcidin
• Impaired EPO production
• Blunted marrow erythroid response to EPO
• Iron-restricted erythropoiesis
• Pool of EPO-responsive cells
Hypoproliferative anemia / functional ID
50. IDA vs ACD
Iron Deficiency
Anemia
Anemia of Chronic
Disease
Hb Low Low
MCV Low Normal (low in 30% pts)
Ferritin Low High
Serum Iron Low Low
TIBC High / Normal Normal / Low
TSat Low Low
Erythropoietin level High Inappropriate low for
degree of anemia
Inflammatory markers Negative Raised
Hepcidin Low Raised
54. Iron Therapy – Intravenous (IV)
• Uncertain absorption
• Painful injection
• Staining of injection site
55.
56.
57. Thalassemia
• Most common genetic disorder, 4.5% of world
population
• 4-6% of Malaysians are carriers
• Sabah has the highest carrier rate of Beta
Thalassemia (more than national rate)
58. Beta Thalassemia
Impaired production of beta globin chains
1.Beta thalassemia minor/trait/silent carrier
2.Beta thalassemia intermedia
3.Beta thalassemia major
59. Beta Thalassemia Minor / Trait
• During pregnancy, women with beta thalassemia trait
sometimes exhibit a tendency to develop a more
profound "physiologic" anemia of pregnancy than normal
mothers, and may require transfusion
• However, pregnancy outcomes are generally favorable
60. Beta Thal Minor vs IDA
Beta Thal Minor Iron deficiency
anemia
PBF
•Microcytosis
•Hypochromia
•Target /tear drop cells
+++
+
+++
+
+++
+
RBC count +++ +
Hematocrit >30%
MCV <75 fL >80 fL
RDW Normal Increased
61. Beta Thalassemia Intermedia
• Usually do not require transfusion during at least the
first few years of life, and are able to survive into the
second decade of life without chronic hypertransfusion
therapy
• While they may not require transfusion therapy at all, or
as often as those with thalassemia major, have increased
absorption of dietary iron, and may ultimately develop
signs and symptoms of iron overload
• They may also suffer from the complications of chronic
hypoxia, such as high cardiac output, increased
pulmonary vascular resistance, pulmonary hypertension
and heart failure
62. Beta Thalassemia Major
• Characteristic clinical features
• Transfusion dependant
• Iron overload
63. Alpha Thalassemia
Impaired production of alpha globin chains
1. Alpha thalassemia minima: loss of one of the four alpha globin genes
2. Alpha thalassemia minor: loss of two of the four alpha globin genes
3. Hemoglobin H disease: loss of three of the four alpha globin loci
4. Hydrops fetalis with Hb Barts:loss of all four alpha globin loci
64. Alpha Thalassemia Minima
• essentially asymptomatic
• Adult patients are not anemic, their red cells are not microcytic,
and their hemoglobin electrophoresis pattern is normal. The
complete blood count and peripheral smear are usually normal,
although very slight hypochromia and microcytosis might be
evident by microscopic examination
• The diagnosis of alpha thalassemia minima can be reliably made
only via DNA analysis
65. Alpha Thalassemia Minor
• Resembles mild beta thalassemia trait
• Adult patients may have mild anemia, their red cells are
hypochromic and microcytic and target cells are present
• Hemoglobin electrophoresis pattern is normal
• The diagnosis can be reliably made only via DNA analysis
66. Alpha Thalassemia: HbH Disease
• HbH disease exhibit all of the stigmata of chronic
hemolytic anemia, including hepatosplenomegaly,
indirect hyperbilirubinemia, elevated LDH, reduced
haptoglobin, leg ulcers, and premature biliary tract
disease
• Resembles patients with beta thalassemia intermedia.
Even though transfusion support is not necessary early
in life, splenectomy or institution of transfusion support
during the second or third decade of life is often
necessary
• Iron overload due to increased iron absorption is also a
significant issue
67.
68.
69. Thalassemia: Prenatal screening/diagnosis
PCR of fetal DNA extracted from:
1. Amniotic cells via amniocentesis
2. Trophoblast via chorionic villi sampling (CVS)
3. Erythroblast from cordocentesis
71. General Mx Outline
• If pt is a carrier, screen partner
• If both are carrier – counsel & offer prenatal diagnosis
• Cascade screening if not done yet (including other
children yet to be screened)
• Thal carrier pt – can be under KK / O&G follow up
(monitor Hb)
• Thal major pt – under MFM / O&G combined follow up
with Hematologist (iron overload complications)
• Iron therapy only for Thal carrier with concurrent IDA
• Keep Hb >7
72. Bring-to-Work Message
• ID / IDA is important modifiable factor– early
investigation, Rx of ID before progressing to IDA
• Consider screening ferritin / TSat beside Hb –
diagnose ID / IDA
• EOD Oral Iron for prophylaxis, daily oral iron for
Rx.
• Resort to IV Iron if patient does not respond to oral
hematinics (Treat mother & prevent anemia in fetus / newborn)
• Postpartum anemia – use IV Iron for faster
response
• Consider ESA for ACD / AI (consultation with Hematologist)
73. Bring-to-Work Message
• Anemia is a risk factor for PPH
• Addressing Maternal Anemia
–to Protect Mothers & Newborns
• PBM prevents / reduces / manages PPH
• Start providing IV Iron in KK setting
• Thal Carrier couple – screen partner,
prenatal diagnosis if indicated
