Thalassemia Screening in Pregnancy: Nuswil Bernolian

THALASSEMIA SCREENING IN
PREGNANCY
NUSWIL BERNOLIAN
FETOMATERNAL OBGYN CONSULTANT
DEFINITION
▪ Quantitative disorder of globin chain production that either
affect α or β globin chain
Forget BG, Bunn HF. Classification of the Disorders of Hemoglobin. Cold Spring Harbor Perspectives in
Medicine. 2013;3(2):a011684. doi:10.1101/cshperspect.a011684.
QUANTITATIVE DISORDERS OF GLOBIN CHAIN SYNTHESIS/ACCUMULATION (The thalassemia syndromes)
β-Thalassemia
Clinical classification: - β-Thalassemia minor or trait
- β-Thalassemia major
- β-Thalassemia intermedia
Biochemical/genetic classification: Lepore fusion gene
β0-Thalassemia δβ-Thalassemia
β+-Thalassemia εγδβ-Thalassemia
δ-Thalassemia HPFH
γ-Thalassemia “Dominant” β-thalassemia
β-Thalassemia with other variants:
HbS/β-thalassemia
HbE/β-thalassemia
α-Thalassemia
Deletions of α-globin genes: Two genes in trans: homozygous α+-thalassemia (phenotype of α0-thalassemia)
One gene: α+-thalassemia Three genes: HbH disease
Two genes in cis: α0-thalassemia Four genes: Hydrops fetalis with Hb Bart's
Nondeletion mutants:
Hb Constant Spring
De novo and acquired α-thalassemia
α-Thalassemia with mental retardation syndrome (ATR):
Due to large deletions on chromosome 16 involving the α-globin genes
Due to mutations of the ATRX transcription factor gene on chromosome X
α-Thalassemia associated with myelodysplastic syndromes (ATMDS):
Due to mutations of the ATRX gene
Forget BG, Bunn HF. Classification of the Disorders of Hemoglobin. Cold Spring Harbor Perspectives in Medicine. 2013;3(2):a011684.
EPIDEMIOLOGY
Weatherall, DJ. Phenotype-genotype relationships in monogenic disease: Lessons from the thalassaemias. Nature Reviews Genetics 2001;2(4):245-55.
GENETICS
▪ Normal adult hemoglobin (HbA) consists of a tetramer
made up of 2 alpha-globin and 2 beta-globin subunits.
▪ Autosomal recessive pattern of inheritance
▪ α chain
▪ 2 pairs of genes (Total 4; 1 pair from each parent)
▪ Chromosome 16
▪ β chain
▪ 2 genes (1 from each parent)
▪ Chromosome 11
Yasin, Iqra. Thalassemia in pregnancy: RCOG Green-top 2014 guidelines [ppt]
GENETICS
▪ Thalassemia results when mutations affecting the genes
involved in Hb biosynthesis lead to decreased Hb
production.
▪ The clinical phenotype results from both the diminished
amount of the particular globin chain as well as from the
resultant chain imbalance that occurs because of normal
production of the other globin chain.
▪ The clinical phenotype becomes most apparent at 6-9
months of age; due to the HbF to HbA switch that occurs at
that age.
Saxena R, Banerjee T, Aniyery RB. Thalassemia and Its Management during Pregnancy. World J
Anemia 2017;1(1):5-17
Copyright © 2012-2016 McMaster Pathophysiology Review (MPR). Downloaded from http://www.pathophys.org/thalassemia/
THALASSEMIA
THALASSEMIA THALASSEMIA
MAJOR MINOR
HOMOZYGOS HETEROZYGOS
SEVERE FORM MINOR FORM
T.Y. Leung, T.T. Lao. Thalassaemia in pregnancy. Best Practice & Research Clinical Obstetrics and Gynaecology 26 (2012) 37–51
AUTOSOMAL RECESSIVE PATTERN OF INHERITANCE
 THALASSEMIA
Caused by when 1-4 α gene deletion
α thalassemia trait
▪ No/mild anemia in pregnancy
▪ No abnormal Hb found
▪ Not detected by Hb electrophoresis
HbH disease
▪ Chronic hemolytic anemia
▪ Moderate anemia (Hypochromia, marked microcytosis)
▪ 5-30 % HbH Hb in peripheral blood (detected by Hb electrophoresis)
▪ HbH inclusion bodies in red cells (golf ball cells –supravital staining)
▪ Can transmit as α thalassemia trait in children

 THALASSEMIA
α thalassemia major
▪ No α chain
▪ No HbA, HbA2 and HbF
▪ Accumulation of Fetal ϒ4 ( Hb barts*)
▪ *This variant of hemoglobin is so called as it was
discovered at St. Bartholomew's Hospital in London,
also called St. Barts.

 THALASSEMIA - MANAGEMENT

ΒETA-THALASSEMIA
▪ Caused by defective β gene.
▪ Severity of disease depend upon nature of mutation and
presence of mutation in 1 or both alleles
▪ 2 types of mutation
▪ Β+ reduced function
▪ Βo absent function

ΒETA-THALASSEMIA

ΒETA-THALASSEMIA

ΒETA-THALASSEMIA
(ELECTROPHORESIS)

THALASSEMIA PREGNANCY & FETUS
COMPLICATION
 thalassemia
▪ Severe anemia  failure of O2 delivery to tissue

 Cardiac failure & abnormal organogenesis
 Hydrops fetalis + Polyhydroamnios +
Placentomegaly
▪ Serious Obstetric complications:

▪ Pre-eclampsia,
▪ Difficult delivery due to large fetus and placenta

COMPLICATION
Beta thalassemia (Major)
▪ Maternal Complication
▪ Pre-eclampsia and gestational hypertension (2.5%-20%)
▪ Gestational diabetes (10%-20%)
▪ Placental abruption (3.8–6.7%)
▪ Caesarean delivery (24%-100%)
▪ Cardiac complications (1.1%-15.6%)
▪ Fetus Complication
▪ Miscarriage, abortion, and fetal loss rate as high as 33.3%
▪ Cause of stillbirth = homozygous thalassaemia fetus
▪ IUGR as high as 57.1%
▪ Preterm birth as high as 40%
T.Y. Leung, T.T. Lao. Thalassaemia in pregnancy. Best Practice & Research Clinical Obstetrics and Gynaecology 26 (2012) 37–51
COMPLICATION
Beta thalassemia (Intermedia)
▪ Maternal Complication
▪ Hemolytic anemia, thrombocytopenia, and enlargement of
spleen
▪ Fetus Complication
▪ Abortions (18.3%).
▪ Spontaneous abortions related to high HbF levels.
▪ NICU (38.8%) for 1-3 wk.
Voskaridou E, Balassopoulou A, Boutou E, Komninaka V, Christoulas D, Dimopoulou M, Delaki EE, Loukopoulos D, Terpos E.

Pregnancy in beta-thalassemia intermedia: 20-year experience of a Greek thalassemia center. Eur J Haematol. 2014 Dec;93(6):492-9.
COMPLICATION
Beta thalassemia (Minor)
▪ Higher prevalence of:

▪ Oligohydramnios
▪ Cesarean section delivery
▪ No significant effect on:

▪ Apgar score in 1st and 5thminute
▪ IUGR
▪ Gestational diabetes mellitus
▪ Preeclampsia
Amooee S, Samsami A, Jahanbakhsh J, Karimi M. The pregnancy outcome in patients with minor β-thalassemia. Iranian Journal of
Reproductive Medicine. 2011;9(1):9-14.
COMPLICATION
Thalassemia Trait
▪ The thalassemia trait condition did not affect the risk of

gestational diabetes, postpartum hemorrhage, stillbirth,
preterm birth and puerperal morbidity
Hanprasertpong T, Kor-anantakul O, Leetanaporn R, Suntharasaj T, Suwanrath C, Pruksanusak N. et al.

Pregnancy outcomes amongst thalassemia traits. Arch Gynecol Obstet (2013) 288:1051–1054
Le, Huong. Prenatal diagnostic of complex hemoglobinopathies [ppt].
Royal Prince Alfred Hospital. Sydney, Australia
Copyright © 2012-2016 McMaster Pathophysiology Review (MPR).
Downloaded from http://www.pathophys.org/thalassemia/
Saruvaan, Ibrahim. Health Promotion Presentation [ppt]. Faculty of Health Science, Maldives National University
Saruvaan, Ibrahim. Health Promotion Presentation [ppt]. Faculty of Health Science, Maldives National University
T.Y. Leung, T.T. Lao. Thalassaemia in pregnancy. Best Practice & Research Clinical Obstetrics and Gynaecology 26 (2012)
Le, Huong. Prenatal diagnostic of complex hemoglobinopathies [ppt]. Royal Prince Alfred Hospital. Sydney, Australia
DON’T FORGET TO TEST THE PARTNER
▪ Partner testing is required if a woman has a thalassaemia trait
▪ Because if her partner also has a confirmed carrier trait it will pose risk for the fetus of
major thalassaemia.
▪ The severity of the disorder will depend on the number of abnormal genes present.
Tan Y L & Kidson-Gerber G. Antenatal haemoglobinopathy screening in Australia. MJA, 2016; 204 (6): 226 - 230.
SCREENING AND DIAGNOSIS
▪ Women with thalassemia traits however are often first diagnosed in
pregnancy, unless there is a family history, so that routine antenatal
screening is indicated for the high risk ethnic groups:
▪ Full blood count:
▪ MCV of <80fL
▪ MCH of <27pg can identify most cases of a- and b-thalassemia traits
▪ For b-thalassemia trait, an MCV of <75fL and MCH of <25pg  the

best parameter, and microcytosis of >15% can differentiate iron
deficiency anemia and b-thalassemia trait concomitant with iron
deficiency.
▪ Positive screening should be followed by Hb electrophoresis & iron
studies
Lao TT, Obstetric Care for Women with Thalassemia, Best Practice & Research Clinical Obstetrics & Gynaecology (2016),
SCREENING AND DIAGNOSIS
▪ β-thalassemia carriers have increased Hb A2, unless there is
concomitant iron deficiency, and Hb F level may also be elevated.
▪ For α-thalassemia trait, HbH inclusion bodies may be found in the red
cells on a blood film, but in αº-thalassemia, the results may appear
normal and the diagnosis is by exclusion
▪ Routine prenatal screening using MCV alone is cost effective.
▪ In Hong Kong, MCV measurement at the 1st antenatal visit in 25834 women
identified 4.3% with α-thalassemia trait, 2.8% with β-thalassemia trait, 0.1% with
αβ-thalassemia, and 0.2% with other hemoglobin variants, while another 1.1%
had iron deficiency or uncertain causes
Lao TT, Obstetric Care for Women with Thalassemia, Best Practice & Research Clinical Obstetrics & Gynaecology (2016),
College of Obstetricians and Gynecologists. Hemoglobinopathies in pregnancy. ACOG Practice
Bulletin No. 78, January 2007. Obstet Gynecol 2007;109:232.
Saxena R, Banerjee T, Aniyery RB. Thalassemia and Its Management during Pregnancy. World J Anemia 2017;1(1):5-17
PRENATAL DIAGNOSIS ?
RCOG. Management of Beta Thalassaemia in Pregnancy. Green-top Guideline No. 66 March 2014
SCREENING FOR THALASSEMIA - GENETIC
COUNSELING
▪ Hb electrophoresis remains the gold standard for diagnosis & classification of
thalassemia
▪ Where both parents are carriers of the same trait (α–α or β–β couple), genetic
counseling should be performed to achieve prenatal diagnosis.
▪ Informed of the possibility (25%) of a thalassemia major fetus.
▪ Diagnosis is made either by CVS or by amniocentesis.
▪ CVS advantages: can set the diagnosis earlier during the 1st trimester (11th week), more DNA obtained
by placental biopsy, and safer to penetrate the placenta than the amniotic cavity.
▪ Amniocentesis are feasible only after the 16th week.
▪ Risk of miscarriage doesn’t differ between these invasive procedures, estimated to be <1%.
Petrakos G, Andriopoulos P, Tsironi M. Pregnancy in women with thalassemia: challenges and solutions.
International Journal of Women’s Health 2016:8 441–451
SCREENING FOR THALASSEMIAS - GENETIC
COUNSELING
▪ When both parents suffer 
▪ Use of donor gametes screened for hemoglobinopathies – preferably donor sperm, as
sperm can be more easily available from sperm banks
▪ Adoption always remain an alternative.
▪ If the partner of a homozygous parent is heterozygous 
▪ Preimplantation genetic diagnosis should be proposed.
▪ This involves IVF/ICSI, embryo biopsy, and transfer of healthy embryos.
▪ Preimplantation genetic diagnosis can be performed at either cleavage stage or at
blastocyst stage by biopsy of the trophoblast cells.
Petrakos G, Andriopoulos P, Tsironi M. Pregnancy in women with thalassemia: challenges and solutions.
International Journal of Women’s Health 2016:8 441–451
AMNIOCENTESIS
CHORIONIC VILLOUS
SAMPLING
SCREENING FOR THALASSEMIAS - GENETIC
COUNSELING
PREIMPLANTATION GENETIC DIAGNOSIS
▪ The purpose of PGD is to diagnose abnormal embryos to
ensure that they are not transferred back into your uterus
and improve your chances of having a healthy baby.
▪ PGD can only be run if you know that you or your partner
are carriers of a genetic disorder
JOINT SOGC–CCMG CLINICAL PRACTICE
GUIDELINE 2008 RECOMMENDATIONS
▪ Carrier screening for thalassemia and hemoglobinopathies should be
offered to a woman if she and/or her partner are identified as belonging
to an ethnic population whose members are at higher risk of being
carriers. Ideally, this screening should be done pre-conceptionally or as
early as possible in the pregnancy. (II-2A)
JOINT SOGC–CCMG CLINICAL PRACTICE GUIDELINE. Carrier Screening for Thalassemia and Hemoglobinopathies in
Canada. JOGC Octoberr 2008
▪ Screening should consist of a CBC, as well as Hb electrophoresis or Hb
high performance liquid chromatography.
▪ This investigation should include quantitation of HbA2 and HbF.
▪ In addition, if there is microcytosis (MCV <80 fL) and/or hypochromia (MCH < 27
pg) in the presence of a normal Hb electrophoresis or high performance liquid
chromatography  patient should be investigated with a brilliant cresyl blue
stained blood smear to identify H bodies. A serum ferritin (to exclude iron
deficiency anemia) should be performed simultaneously. (III-A)
▪ If a woman’s initial screening is abnormal (e.g., showing microcytosis or
hypochromia with or without an ↑ HbA2, or a variant Hb on
electrophoresis or high performance liquid chromatography)
▪ then screening of the partner should be performed.
▪ This would include a complete blood count as well as hemoglobin
electrophoresis or HPLC, HbA2 and HbF quantitation, and H body staining.
(III-A)
▪ If both partners are found to be carriers of thalassemia or an Hb variant,
or of a combination of thalassemia and a hemoglobin variant, they
should be referred for genetic counselling.
▪ Ideally, this should be prior to conception, or as early as possible in the
pregnancy.
▪ Additional molecular studies may be required to clarify the carrier status
of the parents and thus the risk to the fetus. (II-3A)
▪ Prenatal diagnosis should be offered to the pregnant woman/couple at
risk for having a fetus affected with a clinically significant thalassemia or
hemoglobinopathy.
▪ Prenatal diagnosis should be performed with the patient’s informed
consent.
▪ If prenatal diagnosis is declined, testing of the child should be done to
allow early diagnosis and referral to a pediatric hematology centre, if
indicated. (II-3A)
▪ Prenatal diagnosis by DNA analysis can be performed using cells obtained by
CVS or amniocentesis.
▪ Alternatively for those who decline invasive testing and are at risk of Hb Bart’s
hydrops fetalis (four-gene deletion -thalassemia), serial detailed fetal
ultrasound for assessment of the fetal cardiothoracic ratio (normal < 0.5)
should be done in a centre that has experience conducting these assessments
for early identification of an affected fetus.
▪ If an abnormality is detected, a referral to a tertiary care centre is
recommended for further assessment and counselling.
▪ Confirmatory studies by DNA analysis of amniocytes should be done if a
termination of pregnancy is being considered. (II-3A)
▪ The finding of hydrops fetalis on ultrasound in the 2nd or 3rd trimester in
women with an ethnic background that has an increased risk of -
thalassemia should prompt immediate investigation of the pregnant
patient and her partner to determine their carrier status for 
-thalassemia. (III-A)
JOINT SOGC–CCMG CLINICAL
PRACTICE GUIDELINE. Carrier
Screening for Thalassemia and
Hemoglobinopathies in Canada.
JOGC Octoberr 2008
THANK YOU

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THALASSEMIA SCREENING IN

Yasin, Iqra. Thalassemia in pregnancy: RCOG Green-top 2014 guidelines [ppt]

Yasin, Iqra. Thalassemia in pregnancy: RCOG Green-top 2014 guidelines [ppt]

Yasin, Iqra. Thalassemia in pregnancy: RCOG Green-top 2014 guidelines [ppt]

Yasin, Iqra. Thalassemia in pregnancy: RCOG Green-top 2014 guidelines [ppt]

Yasin, Iqra. Thalassemia in pregnancy: RCOG Green-top 2014 guidelines [ppt]

Yasin, Iqra. Thalassemia in pregnancy: RCOG Green-top 2014 guidelines [ppt]

Yasin, Iqra. Thalassemia in pregnancy: RCOG Green-top 2014 guidelines [ppt]

▪ Severe anemia  failure of O2 delivery to tissue

▪ Serious Obstetric complications:

Yasin, Iqra. Thalassemia in pregnancy: RCOG Green-top 2014 guidelines [ppt]

Voskaridou E, Balassopoulou A, Boutou E, Komninaka V, Christoulas D, Dimopoulou M, Delaki EE, Loukopoulos D, Terpos E.

▪ Higher prevalence of:

▪ No significant effect on:

▪ The thalassemia trait condition did not affect the risk of

Hanprasertpong T, Kor-anantakul O, Leetanaporn R, Suntharasaj T, Suwanrath C, Pruksanusak N. et al.

▪ For b-thalassemia trait, an MCV of <75fL and MCH of <25pg  the

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