Anaemia in pregnancy

Dr.L.Krishna1 Dr.N.Shailaja2

Prof & Medical Superintendent Associate ProfessorPES Institute of Medical Sciences & Research , Kuppam, Chittoor Dt, A.P.

Email ID for correspondence: drlkrishnas@gmail.com, drnshailaja@gmail.com

Anaemia is the commonest medical disorder in pregnancy and has a varied prevalence, etiology and degree of severity in different populations. The overall prevalence of anaemia is estimated to be about 40% of world’s population. The prevalence is 35% for non-pregnant women and 51% for pregnant women globally, and tends to be 3-4 times higher in non-industrialized than in industrialized countries (18% vs 56%). The prevalence is very high in South East Asian countries. Nearly half of the global total number of anaemic women live in Indian sub-continent and, in India alone, the prevalence of anaemia during pregnancy may be as high as 88%. The relative prevalence of mild, moderate and severe anaemia are 13%, 57% and 12% respectively.

The word “anaemia” in Greek means “without blood.”In a 2002 report, WHO lists iron deficiency, a major cause of anaemia, as one of the top 10 risk factors in developing countries, for “lost years of healthy life”. Conservative estimates suggest anaemia is the direct cause of 3 to 7 percent of maternal deaths worldwide. Other estimates suggest it is the direct or indirect cause of 20 to 40 percent of maternal deaths. In non-industrialized countries it is responsible for 40-60% of maternal deaths. Reducing the number of women dying in childbirth by 3/4ths by 2015 is one of the key goals of the Millennium Declaration of the World Health Organization. This goal was agreed upon by world leaders from 189 countries at the UN Millennium Summit in September 2000.If we should bring down our maternal mortality and morbidity , we need to tackle anaemia on a war footing.

Definition:Anaemia is the generic name given to a group of disorders characterized by a quantitative

or qualitative deficiency of the circulating erythrocytes.Anemia is a condition of low oxygen carrying capacity of blood in which Hb concentration is two standard deviation below the median for healthy population of same age , sex, and stage of pregnancy.

This, however, is a statistical definition and is not easily understandable and practical.The WHO definition for diagnosis of anaemia in pregnancy is a Hb concentration of less than 11g/dl and a haematocrit of less than 33%, although CDC (Centres for Disease Control, USA) proposes a cut-off of 10.5g/dl during the second trimester.

Physiological anaemia:During pregnancy normal Hb level is 10-12 gm/dl as compared to non pregnant women

of 12-14 gm/dl due to the increase in plasma volume more than RBCs volume.

WHO classification:

Mild anemia 9.1-11g/dl

Moderate anemia 7.1-9g/dl

Severe anemia <7g/dl

ICMR classification:

CDC criteria:

I and III Trimester – 11gm%II Trimester - 10.5gm %

Impact of anaemia on pregnancy:

Tissue enzyme malfunction occurs even in the early stages of iron deficient erythropoiesis and significant effects of iron deficiency anaemia have been described on maternal morbidity and mortality, fetal and infant development and pregnancy outcomes.

Maternal complications:

Iron deficiency may contribute to maternal morbidity through effects on

immune function with increased susceptibility or severity of infections poor work capacity and performance disturbances of postpartum cognition and emotions

During Antenatal period:

Category Anemia Hb level

1 Mild 10-10.9g/dl 2 Moderate 7-10g/dl 3 Severe <7 4 Very severe (decompensated) <4

Poor weight gain, pre term labours, premature rupture of membrane (PROM) , preeclampsia eclampsia, placenta previa, accidental haemorrhage,urinary tract infection etc.

During intranatal period:

Dysfunctional labour, intranatal hemorrhage, shock, anesthesia risk, cardiac failure etc.

During postnatal period:

Postnatal sepsis, sub involution, DVT,embolism,failure of lactation etc.

Fetal and Neonatal complications: The fetus is relatively protected from the effects of iron deficiency by upregulation of placental iron transport proteins (Gambling et al, 2001) but evidence suggests that maternal iron depletion increases perinatal mortality and morbidity rates consequent to preterm deliveries, intra uterine growth restriction, low iron stores, iron deficiency anaemia and cognitive and affective dysfunction in the infant.

Risk factors:

Sociodemographic factors (age, level of formal education, marital status, areas and cities of residence)

Obstetrical factors (multiple pregnancy,parity, history of previous preterm or small-for-gestational-age deliveries)

Behavioral factors (smoking or tobacco usage, alcohol usage, utilization of prenatal care services)

Medical conditions (diabetes, renal or cardio-respiratory diseases, chronic hypertension)

Etiology of Anaemia in Pregnancy:

1) Physiological

Pregnancy causes a state of hydraemic plethora. There is disproportionate increase of plasma volume during pregnancy leading to apparent reduction of RBC, haemoglobin and haematocrit value. Hb is consequently reduced to a varying extent occasionally as low as 80%. The dilution picture is normochromic and normocytic. This is called physiological anaemia.

2) Acquired- Nutritional

The various factors required for erythropoiesis are proteins (erythropoietin), minerals (iron), trace elements (zinc, cobalt and copper), vitamins (folic acid, vitamin B12, vitamin C, pyridoxine, riboflavin and vitamin A), and hormones (androgens and thyroxine).

Folic acid is reduced first to dihydrofolic acid and then to tetrahydrofolic acid (folinic acid) which is required for cell growth and division. Its requirements are increased in pregnancy to meet the needs of the fetus, the placenta, uterine hypertrophy and expanded maternal red cell mass.

Vitamin A is important for cell growth and differenciation, maintainance of epithelial integrity and normal immune function.

Zinc is important in protein synthesis and nucleic acid metabolism.

a) Iron deficiency anaemia (60%),

b) Macrocytic anaemia (10%) due to deficiency of folic acid and/or vitaminB12

c) Dimorphic anaemia (30%) both due to deficiency of iron and folic acid and/or B12

d) Protein deficiency due to protein deficiency in extreme malnutrition

- Haemorrhagic (due to acute blood loss / chronic blood loss -hook worm, bleeding piles)

- Haemolytic anaemia (caused by haemoglobinopathies, drug reaction or infestation with

malaria parasites)

Iron Deficiency AnaemiaIt is the most common type of anaemia (95%)

Normal Negative iron balance

Iron deficient erthropoiesis

Iron deficiency anaemia

Marrow iron stores 1to3+ 0 to1+ 0 0Serum ferritin(µg/L) 50-200 <20 <15 <15TIBC(µg/dL) 300-360 >360 >380 >400S.Iron(µg/dL) 50-150 Normal <50 <30Saturation(%) 30-50 <20 <10Marrow sideroblasts(%)

40-60 <10 <10

RBC protoporphyrin(µg/dL)

>100 >200

RBC morphology Normal Normal Normal Microcytic/hypochromic

Daily Requirements of iron:

Non pregnant state 1 mg/day of absorbed iron

During pregnancy:Iron requirement depends on body weight of the mother and size and maturity of the fetusTotal requirement – Basal iron 280mg Expansion of red cell mass 570 mg Fetus 200-350mg Placenta 50-150mg Blood loss at delivery 100-250mg 1200-1600mg

Iron conserved by amenorrhea 10X (24-48)=240-480mgAdditional iron requirement during pregnancy 500-600mg / 4-6mg/day of absorbed iron <20 weeks 2.5 mg/day 20-32 weeks 5.5mg/day >32 weeks 6-8 mg/day

Iron absorption:Non-pregnant women 10-20%Pregnant women 20-30%Iron deficiency state 30-40% (can go upto 50% with good bioavailable iron)Diet containing non-bioavailable iron 5-8%

Enhancers of absorption Inhibitors of iron absorptionHaem iron PhytatesProteins Calcium and phosphate in milkMeat (Jhatka meat) TanninsAscorbic acid TeaFermentation & Germination CoffeeFerrous iron ChocolateGastric acidity Fortified iron supplementsAlcohol Herbal drinksLow iron stores FibresIncreased erythropoietic activity (high altitude, hemolysis, bleeding)

Iron bio-availability:

Low bio-availability dietCereals, roots and tubers such as maize, rice, beans, whole wheat flour and ragi with negligible amounts of meat, fish and ascorbic acid.

Intermediate bio-availability dietCereals, roots and tubers, but include some animal foods like meat, fish and ascorbic acid.

High bio-availability dietMeat, fish, poultry and foods with generous amount of ascorbic acid.

Iron rich foods:

Non haem iron - Pulses, cereals, jaggery, beet root, green leafy vegetables, legumes, dry beans, iron rich white breads etc.

Haem iron - haemoglobin and myoglobin from red meat, viscera, fish and poultry.Food should be cooked in iron utensils and too much cooking should be avoided.

Note: Dietary advice should be practical. It should be customized to the dietary habits of the region

As absorption is <10%, for a minimum of 4-6mg of absorption, at least 40-60mg of iron should be available in the diet. Diet alone cannot supply such amounts of iron in non-industrialised countries making iron supplementation a necessity in all pregnant women.

Etiology:1. Inadequate intake of iron (poverty, food faddism, low bio-availability diet, emesis

gravidarum)2. Defective absorption of iron e.g. achlorhydria, drug interaction- calcium, antacids,

vitamins, micro nutrients, phenytoin,phenobarbitone,food- phytates , oxalates and phosphates

3. Increased demand e.g. pregnancy – multiple pregnancy, repeated and closely spaced pregnancies, prolonged periods of lactation, home deliveries with increased incidence of post partum haemorrhage

4. Chronic blood loss e.g. abnormal uterine bleeding and haemorrhoids, esophageal varices, chronic malaria, giardiasis, amoebiasis, schistosomiasis, hook worm infestation (North India – Ankylostoma Duodenale – 0.2ml/worm/day and South India - Necator Americanus – 0.03ml/worm/day)

Clinical presentation:

Storage iron is depleted before a fall in Hb and as iron is an essential element in all cells, symptoms of iron deficiency may occur even without anaemia. These include fatigue, weakness, exhaustion, lassitude, indigestion, loss of appetite, irritability, poor concentration and hair loss.Clinical symptoms and signs of iron deficiency anemia in pregnancy are usually non-specific, unless the anaemia is severe. Fatigue is the most common symptom. Patients may complain of pallor, weakness, headache, giddiness, palpitations, dizziness, dyspnoea and irritability. Rarely pica develops where there is a craving for non-food items such as ice and dirt. Iron deficiency anaemia may also impair temperature regulation and cause pregnant women to feel colder than normal.

Clinical examination :

Pallor,edema, koilonychias (spoon shaped nails),nails become brittle and lose luster, bald and magenta colour tongue, angular stomatitis etc.

Soft systolic murmurcan be heard in the mitral area due to hyperdynamic circulation. There can be fine crepitations at bases of lungs due to congestion.

Investigations: Haemoglobin,RBC,haematocrit (PCV) Blood film: microcytic hypochromic anaemia. Indices MCV( 75-95) fl, MCHC(32-35)g/dl, MCH (27-33)pg are reduced, most sensitive

being MCHC Urine for occult blood, schistosomes and pus cells Stool for ova cyst for 3 consecutive days {Helminthasis }

occult blood { Guaiac test }

avoid turnip ,radish,broccoli ,spinach,meat 3 days prior

In special circumstances Serum iron concentration Serum ferritin Iron binding capacity Transferrin saturation Transferrin receptor – to assess cellular iron status Tfr + ferritin – complete picture of iron status

Bone marrow biopsy – indications a) Refractory anemia (no response to therapy in 6 weeks)b) Kala azar infectionc) Aplastic anemia

Adjunctive Tests: S proteins -- Hypoproteinemia

RFT – Suspected renal disease Fractional Test Meal Analysis (not done now a days as we have better diagnostic

modalities) Osmotic Fragility Test – Hereditary Spherocytosis Sputum & chest xray for pulmonary TB in suspected cases

Propylactic Iron Therapy

National nutritional anemia prophylaxis programme recommends 100 tablets of ferrous sulphate 200mg with 60 mg of elemental iron with folic acid 0.5 mg to all pregnant women in third trimester of pregnancy and lactating women. Also, iron prophylaxis was recommended for family planning acceptor and children of age 1-11 yrs.

WHO recommends universal oral iron supplementation with 60 mg of elemental iron daily for 6 months in pregnancy in areas where the prevalence of iron deficiency is less than 40%.In areas where prevalence is greater than 40%,recommendation is to continue 3 months postpartum

Government of India recommendations– 100 mg elemental iron +500mcg of folic acid in 2nd half of pregnancy for 100 days

Some recent studies have shown that weekly or twice weekly iron supplements also give equally good results. Intramuscular iron dextran 250mg 2-3 doses 4 weeks apart was found to be effective prophylaxis. Iron sucrose also can be used in place of iron dextran.

Suggestions for better prophylaxis

Dietary modifications to add iron rich foods: jaggary ,liver, meat, kidney, eggs,dates and green vegetables are rich in iron

Community based distribution of tablets

Fortification of common food stuffs(eg.wheat and salt)

Educating adolescent girls about diet, personal hygiene – Girls in India are deprived of good diet from their childhood as compared to their brothers and thus enter adulthood with malnutrition, anaemia or low iron stores. So, most women start their pregnancy with anaemia or low iron stores. As a public health approach, prolonged oral supplementation beginning before the women become pregnant may be a better strategy to benefit majority of the population. Hence, women of child bearing age in non-industrialised countries should receive a 2-4 months’ course of 60mg of iron daily.

Hookworm infestation should be treated- Single dose of Albendazole 400 mg or Mebendazole 100mg twice daily for three days should be given to all anaemic patients in 2nd& 3rd trimester. Change in defecation habits & avoid bare foot walking.

Chemoprophylaxis for malaria in endemic and high risk areas

Treatment of Iron deficiency anaemia

Goal of Iron Therapy Is to correct Hb deficit & replenish iron stores in tissues.

Choice of therapy depends on 3 factors

1.Severity of anaemia

2.Gestational age

3.Tolerance of therapy chosen

Mild anemia–treat with oral iron irrespective of gestational age Moderate anemia- <36weeks-oral iron

>36weeks-parenteral iron Severe anemia – Local guidelines for blood transfusion in chronic anemia are broadly

divided into 3 groups-

1.Duration of pregnancy is < 36weeks gestation

Hb ≤ 5g% Hb 5-7g% and in the presence of established or incipient cardiac failure or clinical

evidence of hypoxia, pneumonia or any other serious bacterial infection & malaria

2.Duration of pregnancy ≥ 36 weeks gestation

Hb ≤6g% and >6g% in the presence of established or incipient cardiac failure or clinical evidence of hypoxia, pneumonia or any other serious bacterial infection & malaria

3.When elective caesarean section is planned & there is history of antepartum hemorrhage,post partum hemorrhage,previous caesarean section with Hb 8-10g%,then 1 unit of blood should be cross matched and if Hb is <8g% then 2 units of blood should be cross matched.Severe anaemia with >5g/dl before 36 weeks and >6g/dl after 36 weeks consider parenteral iron therapy in the absence of established or incipient cardiac failure or clinical evidence of hypoxia, pneumonia or any other serious bacterial infection & malaria

The specific indication for blood transfusion in pregnancy should be based on national guidelines & can be modified appropriately to the local situation

Oral iron therapy:Mild & moderate anaemia - ferrous sulphate,ferrous ascorbate , ferrous fumarate,ferrous gluconate

Salt Dose of salt Elemental ironFerrous sulphate 300 60Ferrous gluconate 300 35Ferrous fumarate 200 65Ferrous ascorbate 100

Advise to patient on iron therapy: to take iron half an hour before meals & avoid drugs and food interfering with iron absorption.

Side effects: nausea, vomiting and constipation, abdominal cramping & diarrhea .

Disadvantages of oral therapy Intolerance & unpredictable absorption , non compliance.

Rate of increase of haemoglobin(Both oral and parental iron therapy)Haemoglobin starts raising after 3weeks at the rate of 0.8 – 1gm/wk.After correction of anaemia it takes 3 months for the replenishment of iron stores

Indicators of response to therapy Feeling of well being Improved look Better appetite Reticulocyte count increase in 5-10 days. Increase in Hb and hematocrit in 3 wks.

Reasons of failure to respond to oral therapy: Inaccurate diagnosis (non-iron deficiency microcytic hypochromic anaemia -

thalasemia ,pyridoxine deficiency and lead poisoning) Non-compliance Continuous loss of blood through hook worm infestation or bleeding haemorrhoids Co-existing infections Faulty iron absorption Concomitant folae deficiency

Therapeutic trial with iron and folate supplements Anaemia(Hb <10gm/dl)

Treat with iron and folic acid for 6 weeks Oral tablet 1BD or TDS

Repeat Hb

Response No response( no raise in Hb,RC) Continue treatment

Non compliance poor absorption/ Investigate Ongoing losses for other Give parenteral iron causes

1.Question about intake, MCV, other indices Side effects2.Checking stool low normal/high

Should be black, tarry With reagent strip(Prussian HbA2 megaloblastic blue reaction) blue color is by electrophoresis anemia seen if iron is present raise in HbA2(>5%) thalassemia minor

Stop iron Folic acid supplementation only Blood transfusion SOS Parentral iron therapy:Indications:

a. Intolerance to oral ironb. Poor compliance to oral ironc. Malabsorption syndromed. Rapid blood losse. Inability to maintain iron balance(hemodialysis)

Preparations:Intramuscular

a. Iron-dextran complex(Imferon) b. Iron-sorbitol-citrate complex(Jecofer)

c. Iron sorbital citrate +folic acid+ Vit B12(Jectofer plus)

Usage:100 mg of elemental iron given on alternate days after test dose deep IM by Z technique

Side effects: fever, , myalgia, arthralgia, injection site discolouration and abscess.

IntravenousNewer iron preparations

a. Iron sucrose(Orofer-s)b. Iron carbymaltose (Ferri)

b. Iron gluconate(Globac) c. Fractionated iron dextran

Ganzoni formula: Cumulative iron deficit [mg] = (Normal Hb 12g/dl - pts Hb) × Wt (kg) × 2.4 +500

(Simple method to calculate iron requirement –

250mg of elemental iron for each g of Hb below normal + another 50% should be added for replenishment of iron stores

E.g., For 7g/dl Hb

5 X 250 = 1250 +625 = 1875mg)

Iron Sucrose Each 5ml vial contains 20mg/ml (100mg) of elemental iron . 200mg in 100 ml NS infusion is given in 20 mins on alternate days Excellent tolerance Almost no complications Hb increases within 3 wks

Side effectsSE Iron dextran Iron sucroseSerious life threatening anaphylaxis

0.6-0.7% 0.002%

Hypersensitivity 0.2-3% 0.005%Mild adverse reactions Up to 50% Up to 35%

Ferric carboxymaltose (Ferrinject)

Ferric Carboxymaltose Injection contains iron in a stable ferric state as a complex tightly bound within a carbohydrate polymer. It allows for controlled delivery of iron within the

cells of the reticuloendothelial system (primarily bone marrow) and subsequent delivery to the iron binding proteins ferritin and transferrin.

It is administered intravenously, as a single dose of 1000mg over 15 minutes (maximum 15mg/kg by injection or 20 mg/kg by infusion).

Hb(g/dl) Body Wt 35 Kg to<70Kg Body Wt ≥ 70 Kg≥ 10 1000mg 1500mg<10 1500mg 2000mg

Note: A cumulative iron dose of 500 mg should not be exceeded for patients with body weight < 35 kg.

Can be injected undiluted @ 100 mg /minute IV

In case of drip infusion Ferric Carboxymaltose Injection must be diluted only in sterile 0.9% sodium chloride solution as follows:

Iron Maximum volume of normal saline

Maximum time for administration

200 to <500mg 100 ml 6 min500 to 1000 mg 250ml 15 min

An erythropoietic response is seen in a few days, with an increased reticulocyte count. Ferritin levels return to the normal range by 3 weeks as iron is incorporated into new erythrocytes.

Note:

1. All parenteral iron should be given in hospital setting by a doctor. Injection epinephrine, hydrocortisone and oxygen should be available in the event of anaphylactic reaction.

2. Oral iron should be stopped before giving parenteral iron as it is associated with toxic reactions like headache, nausea and vomiting.

Erythropoietin Indications: Anemia of systemic disease Anemia of malignancy Anemia secondary to chemotherapy Anemia of AIDS/HAART Anemia of prematurityRole of erythropoietin in iron deficiency anaemia in pregnancy End stage renal disease Antepartum iron deficiency anaemia

Postpartum anaemia Anemia of pregnant women in chronic hemolytic disorders Emerging use of EPO is treatment of moderate to severe iron deficiency anaemia during pregnancy as an alternative to patients refusing blood transfusion

Recommended dose of EPO:50-150 IU/Kg SC twice or thrice weekly till the course of parenteral iron is over.

Darbepoetin alfa, a molecularly modified EPO with additional carbohydrate, has a half-life in the circulation that is three to four times longer than recombinant human EPO, permitting weekly or every other week dosing.

Side effectsPolycythemiaIncreased viscosity of blood leads to rise in blood pressure and increases the risk of stroke

Blood transfusion Indications :

Haemorrhage Severe anemia >36wks without failure Severe anemia in failure any period of gestation Refractory anemia

Packed Cells -:80-100 ml /day not to be repeated in 24 hrs.Packed cells preferred over whole blood because patient will have less volume overload, less reactions .

One unit will increase hematocrit by 3-4 % & Hb by 1 gm% in 3 days

Complications: Transfusion reaction Precipitated preterm labour Congestive cardiac failure

Exchange Transfusion In severe anemia with CCF

Improvement will be seen in 30 min

Antenatal Care:

More frequent visits Be vigilant to detect and manage the complications of anaemia such as heart failure,

preterm labour,UTI Fetal monitoring for growth and welbeing

Intrapartum Management:

First stage: special precautions that are to be taken during labour The patient should be on bed and should lie in a position comfortable to her. Arrangements for oxygen inhalation is to be kept ready to increase the oxygenation of the

maternal blood and thus diminish the risk of fetal hypoxia Prophylactic antibiotics to be given Avoid ARM unless indicated Strict asepsis is to be maintained to minimize puerperal infection

Second stage: Prophylactic outlet forceps or vacuum delivery may be done to shorten the duration of second stage. Methergin is contraindicated in severe anaemia.

Third stage: Practice active management of third stage of labour.

During puerperium-Continue iron folate therapy for 3 monthsWatch for complicationsTreat infections energeticallySpacing for at least 2 years

Megaloblastic AnaemiaIn megaloblastic anaemia, DNA replication is affected. There is derangement of red cell maturation with production of abnormal precursors known as megaloblasts.It is caused by deficiency of folic acid and / or vitamin B12.Megaloblastic anemia in pregnancy is nearly always secondary to folate deficiency which complicate upto one third of all pregnancies in non-industrialised countries and is more common in multiple pregnancies.

(A) Folic Acid Deficiency Anaemia:

Daily Requirement Non pregnant women-50-100µg/dayPregnant women-800µg/dayLactation-600µg/day Sources: green vegetables, spinach, broccoli, fruits, liver and kidney.Goat’s milk is poor in folic acid.Etiology.

1. Inadequate intake (insufficient consumption + prolonged cooking)2. Defective absorption (malabsorption syndrome and gastrointestinal diseases)

3. Increased demand e.g. multiple pregnancy, hook worm infestation, bleeding haemorrhoids, hemolytic conditions (chronic malaria) and other infections.

4. Drugs: phenytoin,primidone,barbiturate,sulphasalazine,nitrofurantoin,tetracycline

Pathogenesis: Deficiency of folate and vitamin B12 reduces tetrahydrofolate responsible for thymidylate production. This thymidylate deficiency impairs DNA sunthesis. RNA synthesis proceeds normally leading to to larger proportion of cytoplasm compared to the nucleus resulting inmegaloblasts.

Clinical Picture: Along with other symptoms of anaemia GIT manifestations are present in the form of:

Dyspepsia Anorexia Nausea Vomiting Diarrhoea Beefy (Red, Glassed) Tongue Hepatosplenomegaly Unexplained fever Polyneuropathy Bleeding spots in the skin

Impact on the pregnancy:Diagnosed in third trimester or postpartum period because of the adequate storage of folate upto 20weeks of gestation.

Neural tube defects Increased incidence of spontaneous miscarriage Abruptio placenta Preeclampsia Preterm labour Intrauterine growth restriction Folate deficiency in the newborn

Investigations:1. Blood film:

Oval macrocytes,anisocytosis,poikilocytosis Hypersegmented neutrophils (>5 lobes).

2. Redcell folate level: is low measured by radioimmunoassay (<150ng/ml). In combination with low serum folate level (<3ng/ml) is diagnostic of folic acid deficiency.

3. Bone marrow: abnormal red cell precursors (megaloblasts).For the diagnosis atleast 2 of the following features must be present :

>4 % neutrophilis must have > 5 lobes Presence of orthochromic macrocytes ( diameter >12 mcg ) Nucleated RBC’s are found Howell Jolly bodies Macropolycytes

Folic Acid Prophylaxis: Diet- rich in folic acid like fortified grains,dried beans,green leafy vegetables,liver,egg,

wheat products All women planning for pregnancy are advised to take 500µg /day of folate 3 months

preconceptionally to prevent neural tube defects .Those who have had a previous fetus with neural tube defects, on anticonvulsants or carrying a multiple pregnancy and in malaria endemic areas are advised to take 5mg/day of folic acid.

WHO recommends folic acid intake of 400µg daily for 6 months during pregnancy and continuing for 3 months postpartum in low risk and 5mg/day for high risk

Vitamin C increases folate absorption by converting it into folinic acid.

Treatment:.

If Folic acid deficiency is diagnosed give 5 mg /day orally and continue for 3 months postpartum.

Vit. B12 Deficiency Anaemia (Addisonian Pernicious Anaemia): It is rareDaily Requirement: Non Pregnant – 3 µg/dayPregnancy , Lactation – 4 µg/daySources: Meat, fish, eggs and milk but not in plants, and is not destroyed by cooking.The average daily diet contains 5-30µg of vitamin B12 of which 1-5µg is absorbed.

Aetiology:1. Inadequate intake (rare)2. Deficient intrinsic factor as in atrophic gastritis , gastrectomy, ileal disease and

resection3. Malabsorption syndrome (worm infestation)4. Increased demand e.g. pregnancy

Clinical Features: General symptoms of anaemia GIT manifestations: as folic acid deficiency Neurological manifestations Subacute combined degeneration Peripheral neuritis

Investigations: Decreased serum vit. B12 <90 µg/l

MCV >100fl MCHC 30-36g/dl Peripheral smear –Macrocytosis,anisocytosis,poikilocytosis

Treatment

Oral preparation have unreliable absorption properties & are inadequate for long term preparation

Inj Vit. B12 250µg IM every month Inj Vit. B12 1000µg IM is recommended for once a week for 6-8 wks followed

by 1000µg monthly for maintainance in those who have malabsorption

(When Iron alone is given in Iron deficiency anaemia Folic acid deficiency will get unmaskedWhen Folic acid alone is given in megaloblastic anaemia Vitamin B12 deficiency will become severe and it will increase the neurological manifestations)

Dimorphic anaemiaCombined deficiency of iron, folic acid with findings of both anaemias but dominance of one, commonly seen in tropical countries.Blood film may show macrocytic or normocytic ,normocytic or hypochroic picturesBone marrow shows megaloblastic changesTreatment is correction of all deficiencies

Haemolytic AnaemiasClassification of hemolytic anemias

Intracorpuscular defects Extracorpuscular FactorsHereditary Hemoglobinopathies(Thalassemia,sickle

cell anemia)Enzymopathies(Pyruvate deficiency,G6PD deficiency)Membrane-cytoskeletal defects(Spherocytosis)

Familial (atypical) haemolytic uremic syndrome

Aquired Paroxysmalnocturnal hemoglobinuria (PNH)

Mechanicaldestruction (microangiopathic)Toxic agentsDrugsInfectiousAutoimmune

Thalassaemia An autosomal inherited disorder results from failure of production of either α chain

(α -thalassaemia) or β chain (β -thalassaemia) of the haemoglobin molecule and their replacement with other polypeptide chains.It is estimated that there are 2,00,000 thalassaemics in the world among whom 5,000-8,000 are in India.

α- Thalassaemia:a) α -Thalassaemia major (homozygotes):The foetus with this disorder is affected in utero showing polyhydramnios, erythroblastosis, anaemia and hydrops resembling Rh-incompatibility. This foetus does not survive due to inability of oxygen transfer as α -chain is responsible for O2 carrying capacity.

b)α -Thalassaemia minor (heterozygotes): Patient develops mild progressive anaemia during

pregnancy.

Effects on pregnancy:1.Silent carrier state – no effect

2.Thalasemia minor Mild microcytic hypochromic anemia Patient tolerates pregnancy Oral iron & folic acid 5mg throughout pregnancy Parentral iron should never be given to prevent iron overload

3.HbH Compatable with extra uterine life Normal life expectancy but chronic hemolytic anemia of moderate to severe degree Anemia worsens during pregnancy & blood transfusion is necessary. Neonate appears well at birth but soon develops hemolytic anemia Severity of hemolytic anemia is similar to thalasemia major.

4.Hb Bart Has increased affinity for oxygen Common cause of still birth in south east asia Non immune hydrops USG at 12 wks is 100% sensitive & specific by measuring cardio thoracic ratio Patient can develop severe preeclampsia if fetus is having hydrops fetalis

1 -α/αα Silent carier 2 --/ αα Thalasemia minor

Mild hemolytic anemia 3 ββ/ββ HbH disease moderate to Severe hemolytic anemia 4 --/-- , γγ / γγ Thalasemia major or Hb Barts

Diagnosis : Low MCV & MCH but normal MCHC

Treatment :1. Transfusion at 20,26 & 32wks ,transfusion dependent infant delivered at 34 wks2. Vitamin C 100-150mg helps in removal of iron.

2 Bone marrow transplantation 3. Stem cell therapy & gene therapy

ß -Thalassaemia:a) ß -thalassaemia major/Cooley’s anemia (homozygotes):The disorder starts in childhood leading to death of the patient mostly in the 2 nd or 3rddecade.

b) ß -thalassaemia minor (heterozygotes):As α thalassaemia minorIncidence 1 in 300- 500

Clinical nomenclatue Genotype DiseaseThalassemia Major Homozygous or compound

heterozygous (β0/β0, β0/β+, or β+/β+)

Severe,requires blood transfusions regularly

β-thalassemia trait β/β+ or β/β◦ Asymptomatic,with mild microcytic anemia,or microcytosis without anemia

βThalassemia Major ( Cooley’s Anemia )A female who thrives to adulthood is usually sterile hence pregnancy is rare due to high

maternal mortality MTP is recommended

Fetal Effects Neonate normal at birth due to HbF but later HbF is replaced HbA2, hence infant is

severely anemic requiring multiple transfusions. Iron overload occurring by end of 1st decade- desferroxamine given. Thalassemia facies – stunted growth with frontal bossing & maxillary prominence Death due to infections Contrceptive advice is of paramount importance.In splenectomised women,oral

contraceptive should be avoided as they have higher risk of thrombosis

β Thalassemia Minor Mild microcytic hypochromic anemia which doesnot respond to iron therapy . Mild splenomegaly is common Folate and oral iron supplements given throughtout pregnancy Parentral iron never to be given Decreased MCV &MCH, normal MCHC HbA2 >3.5% conforming ß thalasemia

Screening For Haemoglobinopathy

Universal screening is not recommended. All pregnant women should be subjected for CBC with RBC indices.Relevant history should be taken. Special attention must be paid to Kutchi Lohanas, Gujaratis, Sindhis, Punjabis, Kojas, Marwaris and patients of South East Asian, Mediterranean or African descent. Those with anaemia, reduced MCV(<80) and normal iron study findings must be screened.

Hb electrophoresis+ full blood count - if normal no further action . If abnormal band or MCH / MCV reduced – examine partners blood Quantitative Hb electrophoresis – normal –probable α thalasemia- Then DNA analysis If raised HbA2(>3.5%) –means ß thalassemia .

Prenatal DiagnosisBy fetal DNA analysis from trophoblast by

1. CVS at 9-10 wks2. Amniocentesis >16 wks3. DNA analysis by PCR or oligonucleotide hybridization assay method.

Fetal blood sampling done by fetoscope or USG guided cordocentesis at 18 -20 wks but this carries increased risk of fetal loss so not done now a day.

Rationale for screening Thalassemia major management is extremely expensive so screening allows MTP at early gestation. Sickle Cell Anaemia

An autosomal recessive inherited disorder in which glutamic acid in position 6 of the β -chain of the haemoglobin molecule is replaced by valine. This leads to production of HbS. Hb S on exposure to hypoxia forms insoluble aggregations and RBCs become sickle-shaped and are subsequently fragmented

Sickle-shaped cells increase the blood viscosity and occlude blood vessels of various organs

The manifestations appear usually in homozygous not in heterozygous state

Sickle cell syndrome Sickle cell trait ( Hb AS ) Sickle cell disease (HbSS) Compound heterozygotes like sickle cell Hb C disease ( Sc ), sickle cell ß thalassemia

Effects of pregnancy on disease Increased crisis during late pregnancy , labour, puerperium

Effects on pregnancy

Maternal effects : Less common in pregnancy due to earlier mortality Increases ischaemic necrosis of multiple organs Increases frequency of osteonecrosis of femoral neck & femoral head causing severe pain Preeclampsia Pulmonary complications –pneumonia Risk of puerperal sepsis Overt bacteriruria & acute pyelonephritis Increase cardiac dysfunction from ventricular hypertrophy Ventricular failure due to severe preeclampsia & serious infections. Preterm labour Serious sickling in twin pregnancies Maternal mortality 25%

Fetal effects Spontaneous abortion IUGR Prematurity IUD

Clinical Features:1. Features of anaemia and haemolytic jaundice.2. Multiple infarcts due to obstruction of microcirculation in the spleen, kidney, CNS,

retina, bone, lungs and heart.3. Increased susceptibility to infections especially urinary attacks of severe abdominal pain

and fever are common due to ischaemia and infarctions.4. Pre-eclampsia like- syndrome with hypertension, oedema and proteinuria may develop.5. Increased foetal wastage from abortion, preterm labour and growth retardation associated

with placental insufficiency due to maternal placental bed thrombosis.

Lab Diagnosis1. Hb electrophoresis , persistent reticulocytosis ( 10-20 %)2. Sickling test –In emergency cases it is a rapid test.

Management of Sickle Cell Disease during Labour Prepregnancy –counselling

I Trimester :

Terminate if fetus homozygous SCD Early,frequent checkups ,fetal survillance .antibiotics,blood transfusion Comprehensive assessment & adequate hydration . 5mg folic acid OD

II ,III TRIMESTER

Genetic testing/ maternal serum markers

Screen –UTI,HTN,Multiorgan failure

Fundal Ht , serial scans after 20 wks

Growth scan from 24 – 28 wks

Antenatal fetal surveillance from 32 wks

Fundoscopy in 3 rd trimester for retinopathy

Prophylactic antibiotics – Oral Pencillin 250 mg BD

Multiorgan Failure exchange transfusion 2 U removed for every 3- 4U lower HbS < 30 % ,PCV 30 %

Maintain Hb A 60 % & Hematocrit 30 %

3 – 4 Units @ 6wks intervals

Sickle crisis – IV hydration Opioids

O2 inhalation Packed cell transfusion Antibiotics Exchange transfusion

Prenatal Diagnosis CVS Amniocentesis

Drugs Hydroxyurea Recombinant erythropoietin Decitabine Nitric oxide Poloxamer 18 Fructose 1-6 diphosphate

Screen for asymptomatic bacteruria in all pts & treat appropriately Air travel in unpressurized aircraft is avoided .Polyvalent pneumococcal vaccine & H.influenza vaccine.

Intrapartum : Avoid hypoxiemia hypovolemia hyperviscosity acidosis & hypotension to prevent sickling .

Newborn :Monthly Prophylactic injection of pencillin G if baby is homozygous .

Other Therapies Bone marrow transplantation In utero stem cell therapy with HbA cells Gene therapy

Contraception Ocp’s not recommended Progesterone –prevent painful sickle crisis IUCD contraindicated as it increases risk of infections Condoms + foams & diaphragms – safest but high failure rates Sterilization with one child due to short life span of mother

References :

1) Williams obstetrics 23rd edition, pg:1079-1090 2) D.K.James - High risk pregnancy management options 4rd edition,Pg:683-7033) Steven G Gabbe -Obstetrics 5th edition ,Pg:1050-10604) John Studd - Progress in obstetrics & gynaecology volume 15(Pg:103-121)5) Sheila Balskrishna -Text Book of Obstetrics,Pg:335-346