iron deficiency in pregnancy and gynecology: new treatment ... · pdf fileand gynecology: new...

SASOG Congress, Cape Town, South Africa, 18.-21. Mai 2014

Iron Deficiency in Pregnancy

and Gynecology: New Treatment Options

Prof. Dr. Daniel Surbek

Department of Obstetrics and Gynecology University Hospital Bern, Switzerland

Conflict of interest statement

Lecture and consulting fees from Vifor Takeda

WHO: A major public health problem worldwide

2 Billion have iron deficiency!

Dietary Intake

• Negative

– Tea, Coffee, Kakao, red wine

– Fat

– Cereals, Soya products

– Milk, Milk products, calcium

• Positive

– Meat, chicken, fish

– Vegetables (except spinach)

– Fruits

– Sugar

– Aceto

Topics to be Covered

• Pregnancy

• Postpartum period

• Heavy menstrual bleeding

• Perioperative Period in Gynecology

Iron and Pregnancy: What are the issues?

Definition of Anemia What is physiologic in pregnancy?

• Circulating blood volume increases by 50%

• Erythrocyte-cellular mass increases by 20%

-> Difference = Decrease of Hemoglobin and hematocrit = Hydremia of pregnancy

Iron requirements increases in pregnancy (fetus and mother)

Normal Values of Hemoglobin and Ferritin

Hemoglobin-values: Cut-off for definition of anemia

• 1. Trimester: < 110 g/l



Serum-Ferritin-Values:

• <15 mcg/l absolute iron deficiency

• < 30 mcg/l (with normal CRP!): 90% sensitivity for empty iron stores

Iron Deficiency Anemia in Pregnancy: Clinical Significance

• Pregnant women

– Subjective symptoms of pregnancy

– Intrauterine growth restriction

– Preterm birth

– Peripartal blood transfusions

– Postpartalum symptoms (tiredness, breastfeeding problems, postpartum depression)

• Fetus / child – Physiscal and cognitive developmental delay

– Morbidity increased

Anemia in pregnancy: What is behind it?

• Anemia -> Diff. red blood cell count

– normocytic

– makrocytic (MCV > 93 fl)

– mikrocytic (MCV < 80 fl)

– hypochromic (MCH < 27 pg)

• Iron-deficiency -> Ferritin / CRP

• Folic acid deficiency -> Ec-Folsäure

• Vit. B12-deficiency -> Vit. B12

• Genetic: Hemoglobinopathies

– Thalassemie alpha / beta

– Sickle cell anemia

– Weitere Hemoglobinopathies

• Others (anemia of infection etc.)

Iron metabolism

-> RBC count and cellular indices -> Ferritin level, evtl CRP -> consider Transferrin saturation (limit: 20%) In case of anemia, exclude other causes than iron deficiency: - Vit. B12 deficiency - Folate deficiency - Hemoglobinopathies (thalassemia, sickle cell anemia etc.)

Iron Deficiency Anemia in Pregnancy: Diagnostic Aspects

Screening for Iron Deficiency and Anemia in Pregnancy

• Hb, Hk, RBC count 8.-12. week

24.-28. week

36. week

before birth

• Serum-Ferritin 8.-12. week

Folic acid / Vit. B12-Deficiency

• Folic acid deficiency

– Diet

– Alcohol abuse

– Malabsorption

– Drug induced: Antiepileptics, Pyrimethamin

• Vit. B12 deficiency

– Vegetaires

– Pernicious anemia

– Malabsorption

– Gastritis / Hyperemesis

Screening for Hemoglobinopathies

• Ethnicity

• RBC count and morphology

– MCV < 80 fl

– MCH < 27 pg

– Sickle cells

= Primary screening-tool for population at low risk

• Hb-Electrophoresis

• Hb-Chromatography (HPLC, high performance liquid chromatography)

– Fully automated

= Primary screening-tool for population at high prevalence

• Hemoglobinopathy in pregnancy: Check father (RBC count, consider HPLC)

• If positive: offer genetic counseling and prenatal diagnosis

Indications for Iron Therapy in Pregnancy

• Iron deficiency anemia

• Iron deficiency (low ferritin level with normal hemoglobin)

• High hemoglobin levels before delivery desired (Jehova‘s witnesses, high risk for postpartum hemorrhage etc)

Rational for Treatment of Iron Deficiency without Anemia

• Increasing iron requirement in pregnancy

Fetal iron requirements must be covered

• General iron supplementation results in higher birth weigth and less postpartum anemia

• Randomised studies show improvement of fatigue in iron deficiency without anemia

Krayenbühl et al, Blood 2011

Prophylactic Iron for all Pregnant Women?

Cochrane Review 2012; issue 2

Haider BA et al. BMJ 2013; 346:

Iron Deficiency in Pregnancy: Treatment

• Definition: Hb < 110 g/L or Ferritin low (< 30 mcg/L)

• Initially oral iron treatment (160-200 mg/day)

Principles of Oral Iron Treatment

• Fractionated administration 2 x daily.

• Elementary iron: 160-200mg daily

• Fe3+complexes better tolerated and better absorbed in the GI tract than Fe2+complexes

• 2h before or 4h after antacids

• Consider together with 250mg ascorbinic acid (Vit. C)

• Bad tolerance (gastrointestinal side effects):

– Ingestion together with or directly after food

– Dose reduction

– Liquid iron preparation

–-> iv-iron!

Absorption kinetics of different oral iron

(Fe2+) (Fe3+)

Johnson et al, Exp Hematol 1990; 18: 1064-9

Fe3+: controlled active transport by DMT-1 Fe2+: uncontrolled active and passive transport -> Fe3+ less toxic effects / less adverse events (animal model)

Indications for iv-Iron Treatment

• Lack of response after oral treatment: Hb-increase <10g/L in 2 weeks)

• Hemoglobin < 90 g/L

• Bad tolerance (gastrointestinal side effects)

• Rapid hemoglobin increase desired

• Postpartum hemorrhage expected

• Jehova’s witnesses

Iron Treatment:

oral vs. iv

I.V. iron treatment in general

• I.V. iron is indicated when:

– Oral iron is ineffective or has side effects

– Moderate to large amounts of iron are required

– Need for rapid repletion

• Advantages of i.v. iron over oral iron preparations

– Fast repletion of iron stores even in severe ID

– Effective in patients with inflammatory disease

– Less side effects compared to oral iron preparations (GI side effects!)

• Points to consider

– Risk of hypersensitivity reactions (higher frequency observed with iron

dextrans versus Iron sucrose and ferric carboxymaltose)

– Extravasation needs to be avoided (skin discolouration) Geisser & Burckhardt. Pharmaceutics 2011;3:12–33; Bailie et al. Arzneimittelforschung 2011;61:267–75

Rapid uptake in liver and spleen and iron distribution to the bone marrow

Liver Spleen Transaxial section

Bone marrow

0.5 h 3.5 h Sagittal section

8.0 h

100

75

50

25

0

Radiolabelled iron from FCM is mainly taken up in the bone marrow Uptake in liver or spleen is lower and transient

52Fe/59Fe-labelled Ferric carboxymaltose

Beshara 2003 FCM, ferric carboxymaltose

Al et al, Obstet Gyncol 2005; 106; 1335-40

Hemoglobin Ferritin

CONCLUSION: Intravenous iron treated iron-deficiency anemia of pregnancy and restored iron stores faster and more effectively than oral iron, with no serious adverse reactions.

Al et al, Obstet Gyncol 2005; 106; 1335-40

Intravenous ferric carboxymaltose compared with oral iron in the

treatment of postpartum anemia: a randomized controlled trial.

Van Wyck et al, Obstet Gynecol 2007; 110: 267-78

N= 364


Results for Iron-Carboxymaltose post partum - Well tolerated in high doses - Rapid Hb-increase - Better tolerated than oral iron treatment


Seid et al, Am J Obstet Gynecol 2008; 199: 435 e1-7


N = 291

Correction of anemia


Hemoglobin Increase

Hemoglobin > 120 g/l Hemoglobin increase


Ferritin and Transferrin-Saturation

Ferritin-level Transferrin saturation

Side Effects


Potential Disadvantages of iv Iron Therapy in Pregnancy

• Studies are limited (number small, limited patient number) -> results of large RCT soon available

• Fetal effects and longterm outcome. Longterm outcome not yet studied in detail

• However: Ferric carboxymaltose does not pass the placental barrier (Malek at al.)

Ongoing prospective multicenter RCT: FERASAP-Study

• Pregnant women with iron deficiency anemia

• Ferric carboxymaltose iv vs oral iron

• Results expected for end 2014

Which iv Iron Preparation in Pregnancy?

Different i.v. iron formulations

Product SmPC or PI

*Maximum 62.5 mg in some countries; †Maximum 500 mg in some countries; ‡15 mg/kg body weight (bw) for injection; §200 mg for injection

LMW, low molecular weight

Iron

gluconate

Iron

sucrose

Ferumoxytol

Iron

carboxymaltose

LMW iron

dextran

Iron

isomaltoside

Maximum

single iron

dose

125 mg* 200 mg† 510 mg 20 mg/kg bw‡

(1000 mg)

20 mg/kg bw§ 20 mg/kg bw§

Indication IDA ID

(CKD only in US

and AUS)

CKD only ID IDA IDA

Route for

max. dose

Injection or

infusion

Injection or

infusion

Injection Injection or infusion Infusion Infusion

Time for

maximum

dose

Infusion: 1 hour Infusion: 30 min Injection: 17 s Infusion:15 min Infusion: 4–6 h Infusion: 1 hour

Injection: 10 min Injection:10 min Injection:15 min

Dosing

interval

Max 3 times

a week

3–8 days Weekly 2–3 times

a week

Maximum

once a week

Iron Dextran

(High molecular )

Ferric Gluconate

Iron Sucrose

High

Low

Immunogenicity2

Correlates with anaphylaxis risk

High

Toxic effects of labile iron1

Correlates with molecular weight of iron complex

1.Van Wyck DB. J Am Soc Nephrol 2004, 2.Hörl W et al. Nephrol Dial Transplant 2007 22

Ferric Carboxymaltose

47 © Galenica Group 12.06.2014

Stability of iron-carbohydrate complexes

Use of Ferric Carboxymaltose (Ferinject®) in Pregnancy

• In first trimester contraindicated

• In second and third trimester labeled

• Previous standard preparation: Iron Sucrose -> only small dose possible

Clinical Experience in Switzerland

• Ferric carboxymaltose (Ferinject®) is being used routinely in second and third trimester of pregnancy if indicated

• Low rate of side effects

• Retrospective controlled study Bern and Geneva University Hospital

Christoph P et al. J Perinat Med 2012; 40: 469-74

Study of high-dose iv iron therapy in pregnancy

• Pregnant women in 2. and 3. trimester

• Indication for iv iron treatment given

• Group Ferric carboxymaltose (Ferinject®):

– N = 103 Pat.

– iv-administration 15mg/kg BW, max. 1000mg

• Group Iron sucrose:

– N = 103 Pat.

– iv-administration of 2 x 200 mg within 2 days

• Primary Outcome-Parameter: Side effects

Ferric carboxymaltose (n=103) Iron sucrose (n=103)

Mean ± SD Range Mean ± SD Range

Age, years 29 ± 6.1 16-45 30 ± 7.3 15-42

Gestational age, weeks 30.7 ± 6.3 13-40 29.9 ± 6 8-39

Body weight, kg 73.1 ± 13.8 46-119 69.2 ± 12.6 49-119

Haemoglobin (g/l)* 97.4 ± 9.9 77-125 98.6 ± 12.6 82-140

Ferritin (μg/L)* 12.8 ± 29.1 3-256 11.3 ±13.6 3-93

Demographic Data


Rate of Side Effects

2.9

4.9

7.8

2.9

7.8

10.7

0

2

4

6

8

10

12

14

16

18

20

local systemic total

Ferric carboxymaltose Iron sucrose

%

Treatment of Postpartum Anemia

Postpartum Anemia

• Indication for treatment: Hb < 110 g/L (Nadir: 48h pp)

• Ferritin-level not useful because elevated due to postpartum inflammation

• Hb 95 – 110 g/L: orale treatment with 160 – 200 mg iron during 12 weeks

• Hb < 95 g/L: iv-iron treatment

• Hb < 80: evtl. additional administration of EPO (150 E / kgBW 1x daily s.c. over 4 days)

• Transfusion limit: ca. 60 g/L (depending on clinical situation)

Postpartum iv-Iron Treatment

Iron sucrose: max. 200mg short infusion

vs

Iron Carboxymaltose (Ferinject®): max. 1000mg short infusion

J Perinat Med 2012; 40: 397-402

Pfenninger A et al. J Perinat Med 2012; 40: 397-402

Recommendations:

Treatment of iron deficiency in pregnancy

Summary: Iron Treatment in Pregnancy

Indication for oral iron treatment:

• Hemoglobin < 110 g/l (< 105 g/l in 2nd trimester)

• Ferritin < 30 mcg/l

Indication for iv iron treatment:

• Hemoglobin < 90 g/l

• Oral iron badly tolerated (gastrointestinal side effects)

• Oral iron with insufficient Hb-increase

• Rapid Hb-increase needed for clinical reasons (short before term, increased risk for postpartum hemorrhage)

• Jehova’s witnesses

Anaemia treatment recommendations for pregnant women

Additional serum ferritin cut-offs and detailed dosing recommendations in the original publications and the co-positioning slide deck

11 10 9 8

Hb (g/dL)

Asia Pacific3

Switzerland1 Oral iron I.V. iron

Oral iron I.V. iron Germany2

Oral iron I.V. iron

UK4 3rd trimester: I.V. iron

2nd trimester: Oral iron

1. Breymann et al. Arch Gynecol Obstet 2010;282:577–80; 2. Bergmann et al. Geburtsh Frauenhilk 2009;69:682–6; 3. Breymann et al. J Perinat Med 2011;39:113–21; 4. Beris et al. Transfus Altern Transfus Med 2007;9:29–30

Summary: Iron Treatment Postpartum

• Definition: Hb < 100 g/L (<110 g/L)

• Hb 95-110 g/L oral treatment (160-200 mg daily)

• If Hb <95 g/L or bad tolerance of oral iron: iv-iron treatment

• iv-iron treatment: Iron Carboxymaltose (Ferinject®) 20 mg/kg BW, max 1000mg. If Hb < 85 g/L: Repeat after 1 week (same dose)

• If severe anemia < 80 g/L consider additional EPO: rhErythropoietin (z.B. 150 IE/kg BW daily s.c. day 1-4)

Anaemia treatment recommendations for postpartum women

Additional serum ferritin cut-offs and detailed dosing recommendations in the original publications and the co-positioning slide deck

Oral iron I.V. iron

Oral iron I.V. iron

Oral iron I.V. iron

I.V. iron

11 10 9 8

Hb (g/dL)

Asia Pacific3

Switzerland1

Germany2

UK4

1. Breymann et al. Arch Gynecol Obstet 2010;282:577–80; 2. Bergmann et al. Geburtsh Frauenhilk 2009;69:682–6; 3. Breymann et al. J Perinat Med 2011;39:113–21; 4. Beris et al. Transfus Altern Transfus Med 2007;9:29–30

Take home message

• Iron deficiency anemia in pregnancy has consequences for mother anf fetus and should be treated

• Decision if oral or iv iron treatment in pregnancy should depend on clear clinical criteria, according to recommendations

• Iron Carboxymaltose is the drug of choice for iv iron treatment in the second and third trimester of pregnancy and postpartum

Management of Heavy Menstrual Bleeding (HMB)-associated anaemia and

iron deficiency

Intravenous vs. oral iron treatment of HMB-associated anaemia and iron deficiency

• Adult women with HMB:

– Hb <11 g/dL, SF ≤100 ng/mL, transferrin saturation ≤25%

Analysed patients n=453

n=228 Up to 2 weeks

Mean cumulative i.v. dose: 1568 mg iron

I.V. iron (ferric carboxymaltose)*

n=225 6 weeks

Mean cumulative oral dose: 7302 mg iron

Oral iron (ferrous sulfate)**

*Total dose administered in separate injections on Day 0 and, if needed, on Days 7 and 14 **65 mg iron TID

Van Wyck 2009

• Primary efficacy endpoint:

– Hb increase ≥2.0 g/dL within 42 days after baseline (% of patients)

Hb increase with FCM versus oral FS

Van Wyck 2009.

FCM-treated HMB patients achieved more often an Hb increase >2 or >3 g/dL compared to FS-treated patients

Hb increase >2.0 g/dL FCM FS

Hb increase >3.0 g/dL FCM FS

Achieving endpoint (%)

100

75

50

25

0 0 28

Time after initiating treatment (days)

14 42

***

***

***

** **

*

• 477 patients (Hb <11 g/dL, SF ≤100 ng/mL, TSAT ≤25%)

• FCM 1000 mg iron (up to 3-weekly doses), FS 3 x 65 mg iron/day

*P<0.05; **P<0.01; ***P<0.001 (between–group differences) Mean cumulative iron dose FCM 1568 mg, FS 7302 mg

Iron status improvement with FCM versus oral FS

**P<0.01 ***P<0.001

Serum ferritin (ng/mL)

800

600

400

200

0 0 14 28 42

*** ***

Days

*** ***

TSAT (%)

30

20

10

0 0 14 28 42

**

Days

FCM

FS

Rapid and sustained repletion of storage iron in FCM-treated women with HMB-associated anaemia

Van Wyck 2009.

Tolerability of FCM versus oral FS

FS (%) FCM (%)

Constipation 14.2 3.0

Nausea 11.9 3.5

Diarrhoea 4.4 1.7

Headache 4.4 6.5

Vomiting 3.1 0.4

Taste distortion 0.9 2.6

Dizziness 0.4 2.2

Transient fatigue 0 2.2

Rash 0 2.2

Van Wyck 2009

Oral FS associated with dose reductions due to adverse drug events (27 oral iron-treated patients versus one FCM-treated patient)

I.V. iron for the treatment of chronic fatigue in iron-deficient women

Fatigue – A common burden and medical need for treatment

• Fatigue is a substantial public health burden1–3

– Fatigue affects 14–32% of patients in primary care

• Growing evidence for association between ID and fatigue4,5

• Prior studies have indicated that iron treatment might reverse ID symptoms in non-anaemic ID patients4–6

1. Bates 1993; 2. Pawlikowska 1994; 3. Cullen 2002; 4. Krayenbühl 2011; 5. Vaucher 2012; Anker 2009.

Blood 2011; 118: 3222-7

800mg iv

N = 90 Ferritin < 50 mcg/l

Favrat et al. PloS ONE 2014; 9: e94217

PREFER trial: Evaluation of FCM for fatigue treatment in women with ID

• Inclusion criteria:

– Menstruating women with Hb ≥11.5 g/dL

– Iron deficiency ([serum ferritin <50 ng/mL and TSAT <20%] or [serum ferritin <15 ng/mL])

– PFS score ≥5 (ie symptomatic fatigue)

• Exclusion criteria:

– Body weight <50 or >90 kg

– Major depression or unstable medical conditions (eg inflammation)

– Use of iron preparations within 4 weeks prior screening

Favrat EHA 2012; Piper 1998

PFS, Piper Fatigue Scale

1:1

1x FCM (1,000 mg iron i.v.), n=145

1x placebo (250 mL NaCl), n=149

N = 294 0 7 28 56 days

Favrat et al. PloS ONE 2014; 9: e94217

Self-rated cognitive function and QoL

• Significantly better improvements of self-rated cognitive function in the FCM versus placebo group

– Alertness, contentment, calmness

• Better improvement in cognitive function tests among FCM-treated patients with serum ferritin <15 ng/mL

– Power of attention, continuity of attention, quality of working memory

• Higher increase in quality of life with FCM versus placebo

– SF-12 mental score

QoL, quality of life

Summary PREFER Study

• Fatigue is a key symptom of ID

• Effective and rapid reduction of fatigue in non-anaemic, ID women with a single Ferric carboxymaltose dose (1,000 mg iron)

• Significant and rapid improvement of cognitive functions and mental quality of life after i.v. treatment

Women with fatigue should be assessed for their iron status

Iron-deficient women with fatigue should be considered for treatment with intravenous iron

Favrat FIGO 2012

Preoperative IV Iron Treatment to Prevent Blood Transfusions

«PATIENT BLOOD MANAGEMENT»

Litton et al, BMJ 2013: 347: f4822

Hemoglobin increase: IV iron vs oral iron


Hemoglobin increase: IV iron vs no iron


Risk of blood transfusion: IV iron vs oral iron


Risk of blood transfusion: IV iron vs no iron


Risk of infection: IV iron vs oral iron


Risk of infection: IV iron vs no iron


Conclusions

• Hb increase 6.5 g/L

• Reduction of RBC transfusion by 24%

• Increase infection risk RR 1.3

Overall conclusions • The decision to choose between oral or i.v. iron treatment during pregnancy

should depend on careful risk–benefit evaluation, clear clinical criteria, and according to recommendations

• I.V. iron is the treatment of choice in women requiring rapid response or being intolerant to oral iron

– More rapid and more frequent Hb normalisation than with oral iron

– In contrast to oral iron, i.v. iron repletes iron stores effectively

– I.V. iron is better tolerated than oral iron!

• FCM is the treatment of choice for iv iron therapy in pregnancy and postpartum

• In women with ID, FCM effectively reduced fatigue and further improved cognitive function and mental QoL

• IV iron can prevent nessicity of RBC transfusion, although with some increased risk of infection

University-Women’s Hospital, Bern, Switzerland

iron deficiency in pregnancy and gynecology: new treatment ... · pdf fileand gynecology: new...

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