The physiological changes during pregnancy can lead to complications in vulnerable patients. Close proximity of fetal and maternal circulations allows nutrient transfer but some substances can harm the mother or baby. Women with pre-existing hematological diseases may be at higher risk during pregnancy. While most pregnancies progress without issues, high-risk cases require coordinated care between obstetrics and hematology specialists.

1. Haematology of pregnancy
Karyn Longmuir
Sue Pavord
PREGNANCY
Abstract
The 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
may result from increased demand. The massive increase in uterine
blood flow and vascular compliance, necessary to maintain the blood
supply 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 progress
without complication, management of high-risk cases should be coordi-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 women’s 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 the
physiological 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-tation
2 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
Screening for haemoglobinopathies must be carried out as early
as possible, to allow genetic counselling and prenatal
diagnosis if the offspring is at risk of major haemoglobinop-athy.
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,
HbSb-thalassaemia, HbSD, HbSE and HbSO-Arab) have a very
high 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
opportunity to discuss the plan for management. General crisis
prevention measures include avoidance of cold, dehydration5,6
and 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.8
Karyn 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.
MEDICINE 41:4 248 2013 Published by Elsevier Ltd.

2. PREGNANCY
Routine 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 decrease
in free protein S concentration and an increased resistance
to activated protein C
increased concentration of inhibitors of fibrinolysis.
Management of acute VTE in pregnancy
Objective diagnosis is crucial but difficult, as there is a progres-sive
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.
Prevention of VTE
All women should be risk assessed at booking and throughout
the 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 for
activated 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 is
a 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
prophylactic LMWH as indicated.
The duration of LMWH depends on the cumulative inherited
and 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 and
venous. Definitions for pregnancy morbidity include:
three or more unexplained consecutive spontaneous
abortions at less than 10 weeks’ gestation
one or more unexplained death of a fetus at 10 weeks’
gestation 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
to switch to therapeutic LMWH,17 either for the duration of
pregnancy or for the period up to 14 weeks and after 36 weeks.
Monitoring 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 Willebrand’s 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 IX
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3. PREGNANCY
level (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 maternal
mortality.19 Haemorrhage is commonly due to uterine atony, but
other 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 if
delivery is imminent when a count of over 50 109/litre is
required.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.20
The differential diagnosis of maternal thrombocytopenia
includes thrombotic thrombocytopenic purpura (TTP), which
does not cause fetal thrombocytopenia but may cause intra-uterine
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 the
transplacental passage of maternal alloantibodies against fetal
paternally-derived red cell antigens, the mother having been
sensitized 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,
quantitative 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
doses.22
NICE recommend that all Rh D negative women be routinely
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.23
Other complications include intracranial haemorrhage, fetal
anaemia and recurrent late miscarriage. Fortunately, the vast
majority 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 is
significant 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 blood
MEDICINE 41:4 250 2013 Published by Elsevier Ltd.

4. sampling with in utero platelet transfusion may be required in
subsequent pregnancies.23 A
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