Iron Deficiency Anemia in PregnancyRole of IV Ferric Carboxymaltose andits Impact on Neonatal Outcomes

1. Iron Deficiency Anemia in Pregnancy
Role of IV Ferric Carboxymaltose and
its Impact on Neonatal Outcomes
PAN DGF CME
1st July 2023

2. Speaker
Dr Anjila Aneja
MD, DNB, MRCOG ,FRCOG (UK), Diploma in Pelvic Endoscopy
Senior Director Obst , Gynae & MAS Gynae at Fortis la Femme

3. • WHO – 32.4 million pregnant women suffer from anemia worldwide
• 0.8 million women are severely anemic
• 50% cases are attributed to Iron deficiency anemia
• 5,91,000 perinatal deaths and 1,15,000 maternal deaths attributed to iron
deficiency anemia directly or indirectly
• Low SES , High parity, endemic malaria, phytate rich Indian diet, nutritional
deficiencies, helminthic infections and inflammatory and infections ds further
increase the IDA in pregnancy

4. • Anemia – qualitative or quantitative reduction in the oxygen carrying capacity
of blood usually resulting from reduced hemoglobin that leads to reduced
oxygen supply to peripheral tissues
WHO defines Anemia in pregnancy as
- Hb < 11gm/dl
- PCV < 33%
- PP patients Hb < 10g/dl

5. Anemia During Pregnancy
Hemoglobin (g/dL)
CDC < 11 ( 1st trimester)
< 10.5 (2nd trimester)
< 11 (3rd trimester)
WHO < 11
WHO classification of severity of anemia in adult females
[ Hemoglobin in g/dL]
Mild Moderate Severe
Non pregnant
women(age >15
years or above)
11–11.9 8–10.9 < 8
Pregnant
women
10–10.9 7–9.9 < 7
Indian J Hematol Blood Transfus. 2018:1-2.
Anemia During Pregnancy: Forming a Consensus
ICMR 10-10.9 7-10 <4

6. Physiologic (dilutional) Anemia
• Physiologic changes during pregnancy result in dilutional anemia despite an overall increase
in red blood cell mass.
• Plasma volume increases by 10 to 15 percent at 6 to 12 weeks of gestation, expands rapidly
until 30 to 34 weeks, and then plateaus or decreases slightly to term.
• The total gain at term averages 1100 to 1600 mL and results in a total plasma volume of
4700 to 5200 mL, which is 40 to 50 percent above that prior to pregnancy
• The RBC mass also increases, but to a lesser extent (approximately 15 to 25 percent).
• Physiological anemia
- >10 to 11 g/dL
- PCV>30
- RBC count > 3.2million
- RBC morphological normal

7. Milman N Ann Hematol 2006; 85(9):559-565 Indian J Hematol Blood Transfus. 2018:1-2.
Total Iron requirement in Pregnancy
Total iron requirement during singleton pregnancy: 1000 to 1200 mg.
• The average daily requirement of
iron
• 0.8 mg/d in the first trimester
• 4mg /Day in 2nd trimester
• 6mg/day in 3rd trimester and
increases to even 7.5 mg/day in late
third trimester.
• The average daily absorption from:
Western diet  1–5 mg/day
Indian diet  0.8 - 2 mg/day

8. Nutritional Deficiencies • Iron, Folic acid, Vitamin B12, Copper, Riboflavin
Hemolysis and abnormal
hemoglobin synthesis
• Thalassemia, Sickle cell anemia
• Malaria
• G6PD deficiency
Blood loss, and defective iron
absorption and metabolism
• Helminthiasis, especially hookworm infestation
• Amoebiasis, Giardiasis, Schistosomiasis
• Bleeding haemorrhoids
• Antepartum haemorrhage
Chronic conditions
• Malignancies, Tuberculosis
• Chronic renal disease including urinary tract infection
• Human Immune deficiency Virus infection
• Chronic rheumatic and rheumatoid disease
Best Practice & Research Clinical Obstetrics and Gynaecology 26 (2012) 3–24
Causes of Anemia in Pregnancy

9. Indian J Hematol Blood Transfus. 2018:1-2.
Consequences of IDA in Pregnancy
Maternal anemia contributes to 18% of perinatal mortality and 20% of maternal mortality in
South Asian countries including India
Antepartum complications
• Increased risk of
preterm delivery
• Premature rupture of
membranes
• Pre-eclampsia
• Intrauterine Death
• Inter-current infection
• Antepartum
haemorrhage
• Congestive Heart Failure
Fetal outcomes
• Low birth weight
• Prematurity
• Infections
• Congenital
malformation
• Neonatal Anemia
• Abnormal cognitive
development
• Increased risk of
schizophrenia
Intrapartum complications
• Prolonged labour
• Operative delivery
• Fetal distress
• Abruption
Postpartum complication
• PPH
• Puerperal sepsis
• Lactation failure
• Pulmonary thromboembolism
• Subinvolution of uterus
• Post partum depression

10. Approach to Anemia
MCV <80 MCV 80-100 MCV >100
Microcytic anemia
Serum Iron studies
Ferritin <30
Iron
deficiency
Anemia
Low/normal
iron and
Ferritin with
low TIBS
Suggests a
Component of
Anemia of
Chronic ds
With IDA
Normocytic anemia
Reticulocyte count
Reticulocyte
count <2%
Megloblastic Anemia
Reticulocyte
Count>2%
Mentzer Index
(MCV/RBC)<13
Thalassemia
• Leukemia
• Aplastic anemia
• Pure red cell
aplasia
• Other marrow
failure
• Hemorrhage
• Hemolytic
anemia
Megalocytes& segmented
Neutrophils on PBF
Present
megaloblastic
Absent
Non megaloblastic
• Vitamin B12
• Folate
deficiency
• Drug induced
• Alcohol
• Myelodysplastic
Syndrome
• Liver disease
• Congenital
Bone marrow
failure

11. Indian J Hematol Blood Transfus. 2018:1-2.
Diagnosis of IDA in Pregnancy: Importance of Serum Ferritin
• Sr. Ferritin: <30 µg/dl to diagnose and treat ID in pregnancy
• Indications of testing serum ferritin in pregnancy:
• Prior to starting iron therapy in patients with known hemoglobinopathy
• Differential diagnoses of microcytic anemia is under evaluation (chronic inflammation,
lead toxicity, sideroblastic anemia)
• Suboptimal response to oral iron
• In non-anemic women at risk of iron depletion: Previous anemia, multiple pregnancy,
teenage pregnancy, pregnancy with high risk of bleeding, consecutive pregnancies
• Preferably prior to parenteral iron therapy to confirm iron deficiency

12. Normal Carrier
Red Blood cell index Male Female Beta Thal Minor
Mean corpuscular volume
( MCV fl )
89.1+ - 5.01 87.6 +- 5.5 < 80
Mean corpuscular
Haemoglobin
(MCH pg )
30.9+-1.9 30.2+-2.1 <27
Haemoglobin
( Hb g/dl )
12-16gm 11.5-15gm Male – 11.5-15.3 gm
Female 9.1-14gm
Anemia is not a criteria to diagnose Thalassemia

13. Prevention of Iron Deficiency Anemia
• Iron rich food and avoid substances which interfere with iron absorption
• Food fortification with iron ( wheat flour ( salt )
• Screening of adolescent girls and supplementation of Iron wherever is required
• Cooking in Iron utensils
• Hookworm and malaria chemoprophylaxis
• Adequate birth spacing

14. Iron Prophylaxis
During
Pregnancy
Postpartum
Prophylaxis Treatment
WHO Daily 60mg of iron + 400ug
Of folic acid till term
Daily 120mg of iron and
400ug of folic acid till term
Daily 60mg of iron + 400ug
Of folicx 3 months
MoHFW
Daily 100mg of iron +
500ug folic acid for 100
days
Starting after first
trimester at 14-16 weeks
of gestation
• Mild anemia – 2 IFA /day x
100 days
• Moderate anemia –
Parentral iron + oral folic
acid
Daily 100mg of iron + 500ug
folic acidx 6 months

15. Oral Iron Preparation
Preparation Total iron
(mg/tab
Elemental iron
(mg/tab)
% elemental Iron
Ferrous fumarate 200 66 33 High tolerance
bioavaiability
Ferrous sulphate hydrous
Ferrous Sulphate Dessicated
300
200
60
65
20
32
Most common
Least expensive
Ferrous succinate 100 35 35
Ferrous ammonium citrate 160 30 18
Ferrous Ascorbate 730 100 14 Superior
High elemental iron
Sodium Ferederate 231 33 14
Carbonyl Iron 100 98 98

16. Response to Oral Iron therapy
5-7 days Reticulocyte count increases ( O.2%/day
2 – 3 weeks Hb increases by 0.8 – 1gm/dl/week
All parameters MCV , MCH , MCHC improve
6-8 weeks Hb – normal range
Serum Ferritin Increases
PBF – normocytic normochromic
Clinical Improvement Optimal response > 2g in 2 weeks

17. Copyrights apply

18. Role of Parenteral Iron Therapy
in IDA

19. Indian J Hematol Blood Transfus. 2018:1-2.
Indicators of Parenteral Iron Therapy
IV iron therapy is superior to oral iron in terms of speed and absolute extent of
rise in hemoglobin and replenishment of iron stores
Indications
• Failure of oral iron therapy
• Non-compliance or intolerance to oral iron
• Late second or third trimester with moderate to
severe IDA
• Rapid rectification of anemia and repletion of iron
stores expected
• Malabsorption (e.g. Bowel-resection/Celiac disease)
• Bleeding diathesis when hemorrhage is likely to
continue
Contraindications
• Gestation period < 12 weeks
• Lack of facilities for resuscitation
• Known history of anaphylaxis or
reactions to parenteral iron
• Known state of iron overload
Arch Gynecol Obstet. 2017 Dec;296(6):1229-1234

20. Iron Oxyhydroxide
core
Carbohydrate
shell – stabilizes the molecule
and
slows release of elemental iron
Parenteral Iron Preparations

21. Iron Dextran
Risk of anaphylaxis
Iron Sucrose
Multiple doses; longer time
of administration
Ferric Carboxymaltose
High amount of iron in single
dose with low risk of
hypersensitivity reactions
Iron Isomaltoside
Contains reduced dextran,
more labile iron v/s FCM,
Low clinical evidence
Parenteral
iron
Selecting Ideal Parenteral Iron

22. Property Ideal Iron dextran Iron sucrose Ferric carboxymaltose
Type I (robust) I (robust) II (semi-robust) I (robust)
Mol wt >100 kD >100 kD 34-60 kD 150 kD
Complex stability High High Moderate High
Half life Long 3-4 days 6 hours 16 hours
pH Neutral Neutral High Near-Neutral
Osmolality Isotonic Isotonic High Isotonic
Antigenicity Low High Low Low
Test dose No Yes No No
Time for injection Short 4 - 6 h for 20mg/kg 3.5 h for 7mg/kg 15 min for 1000mg
Max dose High 20mg/kg 600 mg/week 1000 mg/infusion
Arzneimittelforschung 2010;60(6a):345–353; Arzneimittelforschung 2010;60(6a):399–412
Properties of an Ideal Parenteral Iron

23. Critical Attributes of FCM
Type 1 (robust)
Parenteral iron
Not associated with
dextran-induced
hypersensitivity
Can be administered
in much higher doses
Short infusion time
(minimum 15
minutes)
Iron is released slowly,
avoiding toxicity and
oxidative stress
Structure similar to
ferritin, deposited
easily in RE cells
Test dose is not
required
Low immunogenic
potential
Qualities of FCM are best suited for
real-life clinical usage

24. FCM – Dosage Calculation and Administration
In most of Indian pregnant
women 1000 to 1500 mg is
well suited
Ferric carboxymaltose summary of Product Characteristics. Available from: https://www.medicines.org.uk/emc/product/5910/smpc/print

25. Administration of FCM in Routine Clinical Practice
Dilution Duration
Ferric carboxymaltose summary of Product Characteristics. Available from: https://www.medicines.org.uk/emc/product/5910/smpc/print
• Mix Inj FCM 1000mg in 250 ml of saline and give
over 15 minutes
• Mix inj FCM 500mg in 100ml of saline and give
over 6 minutes
• Monitor Vitals for 45 minutes

26. Clinical Evidence:
FCM in Management of IDA
During Pregnancy

27. Global Evidence of FCM in Pregnancy
Geography
Total no. of
studies
Countries
No. of pregnant
women treated
with FCM
Highest Hb rise
(g/dL)
Highest Ferritin
rise (µg/L)
Global Studies Ten (#10) Switzerland,
United Kingdom,
Australia, Spain,
Korea, Australia,
UAE, Turkey
2495 3.6 188
Indian Studies Seventeen (#17) India 1326 5.5 180
Current evidence highlighted data of FCM usage in 3821 pregnant women with
maximum Hb rise of 5.5 g/dL and ferritin rise of 180 µg/L
Naqash A et al. BMC Womens Health. 2018; 18(1):6 Jose et al. BMC Pregnancy and Childbirth (2019) 19:54

28. Important Clinical Studies of FCM in Pregnancy
Sr.
no.
Study
Patient
population
In FCM
group
Follow Up
(Weeks)
Hb rise (g/dL)
Ferritin rise
(µg/L)
Any Serious
Adverse Event
1 Maheshwari et al 100 4 3.6 47 No
2 Mishra et al 108 3 2.1 168 No
3 Naqash et al 100 4 5.5 31 No
4 Agrawal et al 50 3 3 65 No
5 Gandotra et al 100 2 2.9 65 No
6 Mahaur et al 50 6 2.6 112 No
7 Patel et al 50 3 2.6 101 No
1. Maheshwari et al. Indian J Obstet Gynecol Res. 2017;4(1):96-100.
2. Mishra V et al. Journal of Nepal Health Research Council. 2017 Sep 8;15(2):96-9
3. Naqash A et al. BMC Womens Health. 2018; 18(1):6
4. Agrawal D et al. J Reprod Contracept Obstet Gynecol. 2019 Jun;8(6):2280-2285
5. Gandotra N et al. Int J Res Med Sci. 2020 Oct;8(10):3539-3542
6. Mahaur et al. International Journal of Clinical Obstetrics and Gynaecology 2020; 4(3):
148-152
7. Patel A et al. Int J Reprod Contracept Obstet Gynecol. 2020 Jun;9(6):2437-2441

29. Inclusion Criteria Intervention Parameters
RCT
100 Pregnant women
diagnosed with moderate to
severe IDA
FCM (n=50): Dose as per
calculated iron requirement
Iron Sucrose (ISC) (n=50):
Dose as per calculated iron
requirement
Rise in Hb from baseline after
12 weeks
Jose et al. BMC Pregnancy and Childbirth (2019) 19:54
Indian RCT from AIIMS, New Delhi

30. Rise in hemoglobin at 12 weeks from baseline
Jose et al. BMC Pregnancy and Childbirth (2019) 19:54
• Treatment with FCM resulted in rapid replenishment of iron stores with significantly
higher Hb rise over a 12 week period.
• Convenient dosing with lesser number of total doses to complete the treatment will
lead to better compliance
Indian RCT from AIIMS, New Delhi: Results
The mean rise in Hb at 12 weeks
was significantly higher in FCM
group than Iron Sucrose group
(29 g/L vs 22 g/L; p < 0.001)

31. Insights from Indian Real World Evidence
50 pregnant women in 2nd and 3rd trimester received a single IV infusion of FCM 1000 mg over 15 minutes
Significant increase in Hb of 2.24
g/dl over 4 weeks
Significant improvement in fatigue
score at 4 weeks
International Journal of Reproduction, Contraception, Obstetrics and Gynecology. 2021 Dec 1;10(12):4402-7.

32. Insights from Largest Indian Real World Evidence
Indian real world evidence of 271 pregnant women receiving FCM of ~1000 mg
Gupte et al, J Obstet Gynaecol Res. 2021 Oct;47(10):3464-3470.

33. • 271 pregnant women in 2nd and 3rd trimester
of pregnancy received FCM (Mean dose
∼1000 mg)
• Significant increase in Hb was noted in just
20 days!
• Significant increase in Hb of 4.23 g/dL was
noted in Severe Anemia
Gupte et al, J Obstet Gynaecol Res. 2021 Oct;47(10):3464-3470.
Insights from Largest Indian Real World Evidence: Efficacy
Single large dose administration of FCM led to rapid rise of Hb in moderate-to-severe anemia
during pregnancy in a real-life scenario.

34. Insights from Largest Indian Real World Evidence: Safety
• Adverse events reported in just 4% of pregnant women! (Most common – rash
and itching)
• No hypersensitivity reactions observed in any pregnant women
• Continuous monitoring of vitals and oxygen saturation up to 45 min did not
report any negative safety signals
Absence of any hypersensitivity reactions and no negative safety signal in vital
parameters observed during continuous monitoring supports excellent safety
of FCM in moderate-to-severe anemia during pregnancy in a real-life scenario
Gupte et al, J Obstet Gynaecol Res. 2021 Oct;47(10):3464-3470.

35. • Data of 162 newborns born to mothers who had received FCM in
pregnancy was analyzed in terms of:
• Mean gestational age at delivery
• Mean birth weight
• Apgar score
• Stillbirth, perinatal, and early neonatal mortality rates
• Requirement of hospitalization
No adverse effects in terms of perinatal and neonatal outcomes were observed
in newborns of women who received FCM during pregnancy
Insights from Largest Indian Real World Evidence: Neonatal Outcomes
Gupte et al, J Obstet Gynaecol Res. 2021 Oct;47(10):3464-3470.

36. Global Clinical Studies: FCM and Neonatal Outcomes
Christoph et al. Journal of perinatal medicine. 2012 Sep 1;40(5):469-74
• 206 pregnant women: Treated either with
FCM or iron sucrose
• Among women treated with FCM, no signs of
negative effects of the FCM treatment were
detected on the fetus or newborn babies.
• 95 pregnant women: Treated with FCM; 83
women among them received single dose of
FCM 1000mg
• Neonatal outcomes (week of pregnancy at
delivery, Apgar scores, and birth weight) were
NOT adversely affected due to FCM
Aporta Rodriguez et al. Obstetrics and gynecology international. 2016 Jan 1;2016

37. Global Clinical Studies: Neonatal Outcomes
Breymann et al. Journal of perinatal medicine. 2017;45(4):443-53
• 126 pregnant women: Treated with FCM
(1000 – 1500 mg)
• No complications associated with FCM
treatment of the mothers were evident in the
newborns
• 83 pregnant women: Treated with FCM (1000
mg single dose)
• FCM administered to pregnant women did
not affect fetal outcomes (Apgar scores,
weight, length or head circumference of the
baby, neonatal resuscitation or
complications)
Khalafallah A et al. InSeminars in hematology. 2018; 55(4):223-234

38. Mild anemia (Hb 10-10.9g/dL) & Moderate anemia ( 7-9.9 g/dL)
First level of treatment
Two tablets of iron and folic acid tablet (100 mg elemental
iron and 500 mcg folic acid) daily for 6 months
Parental iron (IV Iron Sucrose or FCM) may be considered as
the first line of management in pregnant women who are
detected to be anemic late in pregnancy or in whom
compliance is likely to be low (high chance of lost to follow-
up).
If no improvement,
after first level of
treatment
• Referral to higher health facility
• The case may be managed with IV Iron Sucrose/Ferric
Carboxymaltose
Anemia Mukt Bharat Guidelines 2018
Anemia management protocol for Pregnant women

39. Severe anemia (Hb 5-6.9 g/dL)
First level of
treatment
Immediate hospitalization if it is the third
trimester of pregnancy where round-the-clock
specialist care is available
The treatment will be done using IV Iron
Sucrose/Ferric Carboxymaltose by the medical
officer.
Anemia Mukt Bharat Guidelines 2018
Anemia management protocol for Pregnant women

40. FCM in Management of IDA in Pregnancy: Conclusion
• FCM is superior to oral iron and other IV irons in terms of speed and absolute extent of rise
in hemoglobin and replenishment of iron stores
• FCM administration does not require test dose; not associated with dextran-induced
hypersensitivity; can be administered safely in a higher dose in short duration
• FCM infusion during pregnancy is not associated with severe hypersensitivity reactions and
negative safety signals in vital parameters
• Substantial Global and Indian evidence encompassing 3821 pregnant women with maximum
Hb rise of 5.5 g/dL and ferritin rise of 180 µg/L
• FCM administered to pregnant women for treatment of IDA did not adversely affect
neonatal outcomes (Apgar score, birth weight, mortality rates, hospitalization rates, etc.)