Haematology of pregnancyKaryn Longmuir

Sue Pavord

blood

without complication, management of high-risk cases should be coordi-natal

diagnosis if the offspring is at risk of major haemoglobinop-

HbSb-thalassaemia, HbSD, HbSE and HbSO-Arab) have a very

ion5,6

PREGNANCYKaryn Longmuir MBChB MRCP FRCPath is a Consultant Haematologist at

Kettering General Hospital, UK. Competing interests: none declared.

Sue Pavord MBChB FRCP FRCPath is a Consultant Haematologist and Senior

Lecturer in Medical Education at the University Hospitals of Leicester,

UK. Competing interests: none declared.nated in joint obstetric haematology clinics.

Keywords anaemia; haematology; haemolytic disease; neonatal

alloimmune thrombocytopenia; pregnancy; sickle; thrombocytopenia;

thrombophilia; venous thromboembolic disease

Anaemia

In pregnancy there is an increase in red cell mass of 25% but a fall

in haemoglobin concentration due to a proportionally greater

expansion (50%) of plasma volume. This gives rise to the phys-

iological anaemia of pregnancy, which is maximal at 32 weeks.

Iron deficiency

The total iron requirements of pregnancy exceed 1000 mg;1 this

exhausts most womens iron stores. The consequences of iron

deficiency include fatigue, reduced resistance to infection,

cardiovascular stress, poor tolerance to blood loss at delivery,

and an increased need for transfusion. Iron deficiency may also

increase the risk of intrauterine growth restriction, premature

membrane rupture and early delivery.

Diagnosis is difficult as serum ferritin increases throughout

pregnancy and the usual microcytosis can be masked by thesupply for the developing fetus, can lead to significant haemorrhage at

the time of placental separation. Changes in coagulation factors help to

combat this risk but increase the potential for systemic thromboembolic

events. Women with pre-existing haematological disease may be at

particular risk during pregnancy or the pregnancy may be compromised

by the underlying state. Whilst the majority of pregnancies progressmay result from increased demand. The massive increase in u

blood flow and vascular compliance, necessary to maintain theAbstractThe physiological changes that occur during pregnancy, to meet the needs

of the developing fetus, can lead to complications in vulnerable patients.

Close proximity of fetal and maternal circulations enables effective

transfer of nutrients and oxygen but passage of certain substances can

also have disastrous consequences for mother or baby. For example, tera-

togenicity may arise from maternal drugs, and fetal antigenic material

passing into the maternal circulation may cause maternal alloimmune

sensitization syndromes. Iron deficiency and lack of other haematinics

terineMEDICINE 41:4 248and over-exertion. Compliance with folate supplements (5 mg)

and continuation of prophylactic antibiotics should be empha-

sized along with the need for prompt treatment of infection.

Aspirin is recommended from 12 weeks gestation to reduce the

risk of pre-eclampsia.7 Non-steroidal anti-inflammatory drugs

(NSAIDs) should only be used between 12 and 32 weeks

gestation.8 Hydroxycarbamide, which increases fetal haemoglo-

bin (HbF) and therefore reduces the HbS percentage, is terato-

genic and should be stopped 3 months before conception.8opportunity to discuss the plan for management. General

prevention measures include avoidance of cold, dehydrathigh morbidity risk, with more than half experiencing acute

painful crisis and a quarter requiring peripartum admission to

intensive care.3

In addition to sickle cell crisis and chest syndrome, maternal

complications include severe anaemia, infection e especially

urinary and respiratory4,5 e hypertension and thromboembolic

events. Fetal risks are also higher and include miscarriage,

growth restriction, stillbirth and prematurity.

Women should be counselled preconceptually about potential

problems, screened for end-organ damage and offered an

crisisathy. Screening should be in accordance with the NHS Sickle

Cell and Thalassaemia Screening Programme, using the family

origin questionnaire, routine blood cell indices and tests for

sickle cell and other haemoglobin (Hb) variants, depending on

the risks identified and the prevalence of the local population.

Affected mothers will need close multidisciplinary management

to support their pregnancy.

Sickle cell disease

Women with sickle cell anaemia and other haemoglobin

combinations giving rise to sickle cell disease (such as HbSC,Screening for haemoglobinopathies must be carried out as

as possible, to allow genetic counselling and prephysiological increase in mean cell volume (MCV) of 5e10 fl. A

trial of oral iron supplementation is often helpful. Absorption is

optimized by administration with vitamin C 1 hour before food.

True iron malabsorption is unusual and the most common

indications for parenteral iron are non-compliance and intoler-

ance. Some studies have advocated universal iron supplemen-

tation2 in pregnancy, but others have questioned the value of this

approach.

Folate and vitamin B12 deficiency

Folate requirements increase in pregnancy as nucleic acid

formation escalates. Folic acid supplements (400 mg daily) must

be given in the first trimester to reduce the risk of neural tube

defects in the fetus. A co-existing iron deficiency can mask the

increased MCV of folate deficiency, requiring evaluation of the

blood film to aid diagnosis. Although vitamin B12 concentration

falls in pregnancy, this usually represents a dilutional effect and

an increase in binding globulin, rather than a true tissue defi-

ciency; the concentration returns to normal post-partum without

treatment.

Haemoglobinopathies

early 2013 Published by Elsevier Ltd.

gres-

hout

rited

eous

pregnancy or for the period up to 14 weeks and after 36 weeks.

PREGNANCYthe pregnancy and post partum period. A personal history of

unprovoked or oestrogen-related venous thrombosis is a signifi-

cant risk factor.12 Other risks include a family history of unpro-

voked thrombosis, thrombophilia, age greater than 35 years,

multiparity, obesity and immobilization.11,13

The most common inherited thrombophilias are heterozy-

gosity for either factor V Leiden (FVL) or prothrombin gene

mutation (PTGM), which account for up to 44 and 17% of cases,

respectively. However, the relative risk (RR) of VTE is most

marked with anti-thrombin (AT) deficiency, which has a relative

risk of 119 compared to 6.9 and 9.5 for heterozygosity for FVL

and PTGM, respectively.14

There is no role for routine thrombophilia screening but this

may be indicated if the result would justify a change in manage-

ment (i.e. provision of pharmacological thromboprophylaxis).

If required, testing should include:

antithrombin concentration protein C concentration polymerase chain reaction (PCR) for FVL and PTGM. The

genetic test for FVL is preferable to a phenotypic test forPrevention of VTE

All women should be risk assessed at booking and througsive elevation in D-dimer concentration with pregnancy and

a need to avoid potentially harmful imaging techniques. Once

VTE is suspected, unless there are major contraindications,

treatment should be given until the diagnosis is excluded.10

Meta-analysis has shown low-molecular-weight heparin

(LMWH) to be at least as effective as unfractionated heparin,

with a reduced risk of bleeding.10 The Royal College of Obste-

tricians and Gynaecologists (RCOG) guidelines advise a twice

daily dosing regimen10 to minimize peak and trough concentra-

tions. Anti-Xa activity should be measured if there is renal

impairment or extreme body weight. Treatment should continue

for at least 3 months and until at least 6 weeks post-partum.10

Warfarin should be avoided as it is a teratogen, affecting facial,

skeletal and nervous system development.Management of acute VTE in pregnancy

Objective diagnosis is crucial but difficult, as there is a proRoutine top-up or exchange transfusion may be useful in

reducing painful crises but has not been shown to affect overall

outcome. Transfused blood should be negative for HbS and

cytomegalovirus (CMV) as well as fully Rh phenotyped8,9 to

reduce the development of alloantibodies.

Venous thromboembolic disease

Pregnancy is a prothrombotic state with a 10-fold increased risk

of venous thromboembolic disease (VTE) in the antenatal

period,10,11 increasing to 25-fold in the post-partum period. In

addition to venous stasis due to reduced vascular tone and the

pressure from the gravid uterus, the haemostatic system

undergoes several changes in preparation for delivery:

increased coagulation factors, including VII, VIII, fibrin-ogen and vWF (von Willebrand factor)

reduction in anticoagulation activity, including a decreasein free protein S concentration and an increased resistance

to activated protein C

increased concentration of inhibitors of fibrinolysis.MEDICINE 41:4 249Monitoring with anti-Xa concentration is required. Joint

management between haematology, obstetrics and cardiology, is

essential along with full pre-pregnancy counselling.

Bleeding disorders

Inherited

Pregnant women with von Willebrands disease (vWD) or

carriers of haemophilia have an increased risk of bleeding. Factor

VIII18 and vWF increase from 6 to 8 weeks gestation, reaching

levels of three- to fivefold baseline by term. Whilst this provides

protection for delivery for women with haemophilia A carrier

status and most cases of vWD, they remain vulnerable in early

pregnancy and in the puerperium, when levels may fall abruptly.

DDAVP (desmopressin) can be used to cover first-trimester

procedures and the post-partum period. Oral tranexamic acid is

useful to prevent excessive post partum bleeding. Factor IX level

does not change in pregnancy and women with a low factor IXto switch to therapeutic LMWH,17 either for the duratioabortions at less than 10 weeks gestation

one or more unexplained death of a fetus at 10 weeksgestation or longer.15

Laboratory testing includes detection of anti-cardiolipin anti-

bodies, a lupus anticoagulant or antibodies to b2-glycoprotein, on

two or more occasions distant from the clinical event and more

than 12 weeks apart. The use of aspirin and prophylactic LMWH

in pregnancy has improved the rates of live birth from 10 to

70%.16

Prosthetic heart valves and pregnancy

Anticoagulation for prosthetic heart valves is one indication for

continuing warfarin throughout pregnancy, but the potential for

teratogenic effects, especially with doses greater than 5 mg a day

during weeks 6e9, must be considered. An alternative option is

n ofvenous. Definitions for pregnancy morbidity include:

three or more unexplained consecutive spontanand acquired risk factors. Some women may require treatment

only in the post partum period but if antenatal thromboprophy-

laxis is indicated this should start as soon as the pregnancy is

confirmed as studies have shown that thrombotic risk is elevated

in all trimesters.

Anti-phospholipid syndrome

Anti-phospholipid syndrome (APS) is an autoimmune disorder

and an acquired thrombophilic state. The clinical features vary

significantly but include placental insufficiency, recurrent fetal

loss, thrombocytopenia and thrombotic events, both arterial andprophylactic LMWH as indicated.

The duration of LMWH depends on the cumulative inheactivated protein C resistance as the latter is affected by the

physiological changes to the coagulation system in

pregnancy

anti-phospholipid syndrome (APS) screen (only if there isa personal history of VTE).

Protein S concentration falls in pregnancy and should be tested

after 3 months post-partum.

Management of at-risk pregnancies includes advice on general

deep vein thrombosis (DVT) prevention, including leg care,

compression stockings, mobilization and hydration, along with 2013 Published by Elsevier Ltd.

, but

intra-

fetal

paternally-derived red cell antigens, the mother having been

NICE recommend that all Rh D negative women be routinely

fetal

anaemia and recurrent late miscarriage. Fortunately, the vast

PREGNANCYsensitized by previous transfusion or pregnancy. This can lead to

haemolysis of fetal red cells, causing anaemia and in severe

cases, hydrops and fetal death.

In the UK all pregnant women are tested for alloantibodies at

booking and at 28 weeks.21 If anti-D, c or K is detected,transplacental passage of maternal alloantibodies againstuterine growth restriction and fetal loss. Untreated TTP is asso-

ciated with a 90% maternal mortality. Other causes include

haemolysis, elevated liver enzymes and low platelets (HELLP)

syndrome, pre-eclampsia, haemolytic uraemic syndrome and

conditions resulting in DIC.

Alloimmune disorders

Haemolytic disease of the newborn

Haemolytic disease of the newborn (HDN) is caused by theincludes thrombotic thrombocytopenic purpura (TTP), w

does not cause fetal thrombocytopenia but may causeother causes include placental abruption, placenta praevia or

increta, and uterine rupture, all of which can lead to dilutional

coagulation deficits, disseminated intravascular coagulation

(DIC) and hypovolaemic shock. DIC may also be triggered by

eclampsia, sepsis, retained products or amniotic fluid embolus.

All units should have a transfusion protocol for the management

of massive obstetric haemorrhage.

Thrombocytopenia

The causes of thrombocytopaenia in pregnancy are numerous.

The majority of cases are due to gestational thrombocytopenia,

which affects approximately 6% of pregnancies. The platelet

count tends to fall by about 10%; this is most pronounced in the

third trimester20 and resolves by 6 weeks post-partum.

Immune thrombocytopenia complicates 0.01e0.05% of

pregnancies.20 The maternal autoantibodies may cross the

placenta and cause fetal thrombocytopenia. This is usually mild

with only 10% of babies having a platelet count under 50 109/litre. Treatment for the mother is indicated if there are haemor-

rhagic manifestations, the count is under 20 109/litre or ifdelivery is imminent when a count of over 50 109/litre isrequired.20 First-line therapy is corticosteroids;20 alternatives

include anti-D or intravenous immunoglobin. Azathioprine or

splenectomy in the second trimester can also be considered.

Rituximab has been trialled in severe refractory cases, but

evidence for its use and safety profile in pregnancy is lacking. A

labour plan should be constructed to facilitate safe delivery,

including the avoidance of ventouse, fetal blood sampling,

external cephalic version and rotational forceps. The maternal

platelet count should be over 80 109/litre for an epidural.20The differential diagnosis of maternal thrombocytopenia

hichmortality.19 Haemorrhage is commonly due to uterine atonylevel (carriers of haemophilia B) may require recombinant factor

concentrate for invasive procedures and delivery. Factor levels of

50% are generally considered safe for vaginal delivery and

regional anaesthesia, although levels of 80% are usually required

for caesarean section.

Acquired

Maternal haemorrhage remains a significant cause of maternalMEDICINE 41:4 250majority of cases are uneventful but in 20%, long-term neuro-

logical sequelae are seen and 10% of cases are fatal.24 If the

neonatal platelet count is under 30 109/litre or there issignificant neonatal bleeding, platelet transfusion is required.

Ideally these should be HPA compatible, but if this is not

possible, random platelets can be used, although these have

lower efficacy and survival.

The diagnosis is confirmed by laboratory testing of both

parents and has implications for future pregnancies, requiring

careful counselling. Maternal treatment with intravenous

immunoglobulin with or without corticosteroids and fetal bloodOther complications include intracranial haemorrhage,offered 500 IU of anti-D at 28 and 34 weeks of pregnancy.22 Some

units give 1500 IU at 28 weeks, which is effective, more conve-

nient and improves compliance.22

Whilst routine antenatal anti-D prophylaxis has substantially

reduced the number of cases of HDN,22 there are still new cases

of sensitization to Rh D each year, mostly due to non-compliance

with the national guidelines or occult feto-maternal haemorrhage

occurring before 28 weeks. In addition, anti-D prophylaxis has no

effect on the development of other alloantibodies, for example

anti-c, anti-A or -B, or anti-K, which together account for 5% of

cases of clinically significant HDN.

Neonatal alloimmune thrombocytopenia

In neonatal alloimmune thrombocytopenia (NAIT) the mother

produces antibodies against paternally derived antigens, which

are expressed on fetal platelets, usually HPA-1a or 5b23 It is one

of the most common causes of severe thrombocytopenia in the

neonate, affecting 1/2000 births.23 Around 50% of cases occur in

the first pregnancy as opposed to HDN, where the first baby is

usually unaffected.23

The diagnosis is suspected if the neonate has bruising,

purpura or an unexpectedly low platelet count post-delivery.23doses.22quantitative monitoring is required on a monthly and then fort-

nightly basis.21 If antibodies are detected, the father can be tested

for the corresponding antigen to determine the risk to the baby.21 If

the father is heterozygous, fetal DNA can be extracted from

maternal blood samples from 12 weeks to determine the status of

the fetus; red cell antigens that can be detected include D, c and K.

Fetal ultrasonography, incorporating middle cerebral artery

Doppler to screen for fetal anaemia, has replaced invasive tech-

niques such as amniocentesis and has revolutionized the

management of affected pregnancies, guiding the need to

undertake intrauterine transfusion.

Prevention of sensitization

In the 15% of women who are Rh D negative, sensitization can

be prevented by giving intramuscular anti-D within 72 hours22

following events such as termination of pregnancy, threatened

abortion, abdominal trauma, chorionic villus sampling, amnio-

centesis and delivery. A dose of 250 IU is sufficient for gestations

up to 20 weeks, but at least 500 IU are required in later preg-

nancy. This dose covers 4 ml of feto-maternal haemorrhage, so

a Kleihauer test or flow cytometry should routinely be requested

after 20 weeks to exclude larger haemorrhages requiring bigger 2013 Published by Elsevier Ltd.

sampling with in utero platelet transfusion may be required in

subsequent pregnancies.23 A

REFERENCES

1 Woodward M, Hoffbrand AV. Iron metabolism, iron deficiency and

disorders of haem synthesis. Postgraduate Haematology. 5th edn.

Oxford: Blackwell Publishing, 2005.

2 Milman N, Bergholt T, Eriksen L, et al. Iron prophylaxis during preg-

nancy e how much iron is needed? A randomized dose-response

study of 20e80 mg ferrous iron daily in pregnant women. Acta

Obstet Gynecol Scand 2005; 84: 238e47.

3 Knight M, McClymont C, Fitzpatrick K, et al on behalf of UKOSS.

United Kingdom oObstetric Surveillance sSystem (UKOSS) Annual

Report 2012. National Perinatal Epidemiology Unit. Oxford, 2012.

4 Pastore LM, Savitz DA, Thorp JM Jr, Koch GG, Hertz-Picciotto I, Irwin DE.

Predictors of symptomatic urinary tract infection after 20 weeks gesta-

tion. J Perinatol 1999; 19: 488e93.

5 Ladwig P, Murray H. Sickle cell disease in pregnancy. Aust NZ J Obstet

13 Walker ID, Greaves M, Preston FE. Investigation and management of

heritable thrombophilia. Br J Haematol 2001; 114: 512e28.

14 Clinical updates in womens healthcare: thrombosis, thrombophilia

and thromboembolism, vol. VI. No. 4. American College of Obstetri-

cians and Gynaecologists, 2005.

15 Hunt B, Greaves M. Acquired venous thrombosis. In: Hoffbrand V,

Tuddenham E, Catovsky D, eds. Postgraduate haematology. 5th edn.

Oxford: Blackwell Publishing, 2005.

16 Rai R, Regan L. Antiphospholipid antibodies, infertility and recurrent

miscarriage. Curr Opin Obstet Gynecol 1997; 9: 279e82.

17 Chan WS, Anand S, Ginsberg JS. Anti-coagulation of pregnant women

with mechanical heart valves: systematic review of the literature.

Arch Intern Med 2000; 160: 191e6.

18 Chi C, Lee CA, Shiltagh N, Khan A, Pollard D, Kadir RA. Pregnancy in

carriers of haemophilia. Haemophilia 2008; 14: 56e64.

19 Centre for Maternal and Child Enquiries (CMACE). Saving mothers

lives: reviewing maternal deaths to make motherhood safer:

2006e08. The Eighth Report on Confidential Enquiries into

PREGNANCYGynaecol 2000; 40: 97e100.

6 Embury SH. Sickle cell disease. In: Hoffman R, Benz Jr EJ, Shattil SJ,

Furie B, Cohen HJ, eds. Haematology: basic principles and practice.

2nd edn. New York: Churchill Livingstone, 1995.

7 RCOG Green-top Guideline No. 61 Management of sickle cell disease

in pregnancy. London: Royal college of Obstetricians and Gynaecol-

ogists, 2011.

8 Standards for the clinical care of adults with sickle cell disease in the

UK. Sickle Cell Society. Available at: http://www. sicklecellsociety.org/

Carebook.pdf; 2008 (accessed 24th December 2008).

9 BCSH. Guidelines for the management of the acute painful crisis in

sickle cell disease. Br J Haematol 2003; 120: 744e52.

10 RC OG green-top guideline No. 28 Thromboembolic disease in

pregnancy and the puerperium: acute management. London: Royal

College of Obstetricians and Gynaecologists, 2007.

11 RCOG Green-top Guideline No. 37 Thromboprophylaxis during preg-

nancy, labour and after vaginal delivery. London: Royal College of

Obstetricians and Gynaecologists, 2004.

12 Zotz RB, Gerhardt A, Scharf RE. Inherited thrombophilia and gesta-

tional venous thromboembolism. Best Pract Res Clin Haematol 2003;

16: 243e59.MEDICINE 41:4 251maternal deaths in the United Kingdom. Br J Obstet Gynaecol

2011;118(suppl 1):1e203.

20 Guidelines for the investigation and management of idiopathic

thrombocytopenic purpura in adults, children and pregnancy. Br J

Haematol 2003; 120: 574e96.

21 Gooch A, Parker J, Wray J, Qureshi H. BCSH guidelines for blood

grouping and antibody testing in pregnancy. London: BCSH, 2006.

Available at: http://www.bcshguidelines.com/pdf/pregnancy_

070606. pdf.

22 Parker J, Wray J, Gooch A, Robson S, Qureshi H. Guidelines for

the use of prophylactic anti-D immunoglobulin. London: BCSH,

2006. Available at: http://www.bcshguidelines.com/pdf/Anti-D_

070606. pdf.

23 Letsky EA, Greaves M. Guidelines on the investigation and manage-

ment of thrombocytopenia in pregnancy and neonatal alloimmune

thrombocytopenia. Maternal and Neonatal Haemostasis Working

Party of the Haemostasis and Thrombosis Task Force of the British

Society for Haematology. Br J Haematol 1996; 95: 21e6.

24 Kaplan C, Morel-Kopp M-C, Clemenceau S, Daffos F, Forestier F,

Tchernia G. Fetal and neonatal alloimmune thrombocytopenia:

current trends in diagnosis and therapy. Transfus Med 1992; 2:

265e71. 2013 Published by Elsevier Ltd.

Haematology of pregnancyAnaemiaIron deficiencyFolate and vitamin B12 deficiency

HaemoglobinopathiesSickle cell disease

Venous thromboembolic diseaseManagement of acute VTE in pregnancyPrevention of VTEAnti-phospholipid syndromeProsthetic heart valves and pregnancy

Bleeding disordersInheritedAcquiredThrombocytopenia

Alloimmune disordersHaemolytic disease of the newbornPrevention of sensitizationNeonatal alloimmune thrombocytopenia

References