INTRODUCTION — The hemoglobinopathies can be divided into two general types: the thalassemias (which are disorders of decreased globin chain production) and the hemoglobin structural variants (eg, hemoglobin S, hemoglobin C); a combination of the two is also possible.
The purpose of prenatal hemoglobinopathy screening is to identify and counsel asymptomatic individuals whose offspring are at risk of an inherited hemoglobinopathy. Prenatal diagnosis of fetal hemoglobinopathy is offered when the fetus is at risk of being affected. The purpose is to allow parents to make reproductive choices based on this information and, in the case of alpha thalassemia major, to monitor the pregnancy for nonimmune hydrops fetalis and potentially intervene. The clinical sequelae of other hemoglobinopathies manifest later in life and have no adverse effects on the fetus, mother, or neonate.
This topic will review issues related to prenatal screening for and diagnosis of fetal hemoglobinopathy. Postnatal clinical manifestations, diagnosis, and treatment are discussed separately:
●(See "Diagnosis of thalassemia (adults and children)".)
●(See "Hemoglobin variants including Hb C, Hb D, and Hb E".)
●(See "Methods for hemoglobin analysis and hemoglobinopathy testing".)
GENE FREQUENCY — Sickle cell disease and thalassemia are among the most common genetic diseases worldwide. Over 1 percent of couples are at risk for having an affected newborn [1]. (See "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Types of abnormalities'.)
United States — The frequency of carrier conditions for hemoglobinopathies is higher in Black than White individuals, but all racial/ethnic populations in the United States have individuals who carry sickle cell trait [2]. Data from state newborn screening programs showed that 1.5 percent of all infants screened in 2010 had sickle cell trait [2]. The incidence of sickle cell trait was 73.1 per 1000 Black infants, 6.9 per 1000 Hispanic infants, 3 per 1000 White infants, and 2.2 per 1000 Asian, Native Hawaiian, or other Pacific Islander infants screened. Approximately 30 percent of African Americans have alpha thalassemia minor [3].
In the United States, the incidence of sickle cell disease has remained relatively stable (SS disease 1 in 3721 newborns, SC disease 1 in 7386 newborns [4]); however, the prevalence of individuals with hemoglobinopathy, particularly thalassemia, is changing because of the immigration of new ethnic groups, some of whom are carriers of hemoglobinopathies that had been rare in the United States, and the increasing number of pregnancies among couples of discordant ethnicity in the United States [5-7]. This has led to births of infants with hemoglobinopathies that previously had not been seen and births of infants with hemoglobinopathies from multiethnic parents.
These points are illustrated by data from the California newborn universal mandatory screening program for hemoglobinopathies that was initiated in 1990 [6,8]. Each year, approximately 0.05 percent of the 530,000 newborn samples are sent to the Hemoglobin Reference Laboratory for confirmatory testing:
●Between 1998 and 2006, sickle cell disease was the most common hemoglobinopathy (1 in 6600 births) followed by alpha thalassemia (1 in 9000 births) and beta thalassemia disease (1 in 55,000 births) [6]. The confirmatory analysis modified the initial screening in 5 percent of cases and revealed 25 rare or new genotypes. Hemoglobin mutations were noted in infants from diverse ethnicities, including Southeast Asian, Black, Indian/Asian, Middle Eastern, and Hispanic infants.
●A shift of the at-risk groups for beta thalassemias was noted with the majority of cases detected in families of Asian ancestry. In addition, hemoglobin E/beta thalassemia, a "new" hemoglobinopathy condition in California, was found almost exclusively in Southeast Asians with a prevalence of 1 in every 2600 births.
Global data — Globally, an approximate 7 percent of pregnant women are gene carriers of beta or alpha zero thalassemia, or hemoglobin S, C, D Punjab, or E [1]. The incidence of hemoglobinopathy varies worldwide and may be underreported in resource-limited countries where technologically sophisticated diagnostic laboratory tests are not available.
Thalassemia — Thalassemias are the most common inherited single-gene disorder in the world and occur most frequently in malaria-endemic areas including the Mediterranean area, the Middle East, Southeast Asia, Africa, and the Indian subcontinent. Extensive screening programs and prenatal diagnosis have resulted in a consistent decline in the birth of infants with beta thalassemia in Mediterranean at-risk populations [9]. However, thalassemia remains a clinical problem in other parts of the world [10]. (See "Public health issues in the thalassemic syndromes".)
Variations in the genotype of the heterozygotes result in differences in thalassemia phenotypes in the affected child [9]:
●African Americans may be heterozygous for both the beta thalassemia gene and sickle cell gene since the two genes are closely linked. Alpha thalassemia minor (also called trait) in Africans most commonly consists of one gene for alpha globin synthesis missing on each chromosome 16 (trans) (loss of two alpha-chain genes: homozygosity for the alpha thalassemia-2 trait [ie, a-/a-]). This deletion does not result in fetal sequelae.
●By contrast, the Southeast Asian pattern of alpha thalassemia minor consists of both genes missing from the same chromosome (cis) (loss of two alpha-chain genes: heterozygosity for the alpha thalassemia-1 trait [ie, aa/--]). If both parents have this pattern, offspring may have all four alpha globin genes absent and will be unable to synthesize any adult hemoglobins or fetal hemoglobin. Tetrameric gamma chains (hemoglobin Bart) in the affected fetus bind oxygen with high affinity, causing severe fetal anemia, which leads to hypoxia, high-output cardiac failure, hydrops fetalis, and death. If one parent has alpha thalassemia minor (cis) and the other is either a silent carrier for alpha thalassemia (one alpha globin gene missing) or has alpha thalassemia minor (trans), this may result in Hemoglobin H disease. (See "Molecular genetics of the thalassemia syndromes", section on 'Molecular lesions causing thalassemia' and "Pathophysiology of thalassemia", section on 'Terminology and disease classification'.)
●Hemoglobin H-constant spring, the co-inheritance of alpha thalassemia minor (cis) and hemoglobin constant spring, a nondeletional mutant alpha globin allele, results in a phenotype that is typically more severe than hemoglobin H disease.
Hemoglobin S, C, E — The structural hemoglobin variants S and C are most common in tropical Africa, and also found in Mediterranean countries, Saudi Arabia, and Caribbean countries [1]. In 2010, more than 300,000 infants were born with homozygous SS disease and over five million infants were born with sickle trait worldwide, with the majority of these infants born in sub-Saharan Africa [11].
Hemoglobin E is found most commonly in Southeast Asia. It is estimated that 30 million Southeast Asians are carriers for hemoglobin E and one million have homozygous EE disease. Hemoglobin EE is relatively benign with minimal anemia and significant microcytosis. However, hemoglobin E co-inherited with beta-thalassemia zero can result in a transfusion-dependent thalassemia.
RATIONALE FOR PRECONCEPTIONAL HEMOGLOBINOPATHY COUNSELING, PRENATAL SCREENING, AND FETAL DIAGNOSIS — The purpose of the prenatal hemoglobinopathy screening is to identify asymptomatic individuals whose offspring are at risk of an inherited hemoglobinopathy. Screening should be offered to all couples. Screen positive couples are offered fetal diagnosis to determine whether the fetus is affected.
Because the thalassemias and hemoglobin structural variants are autosomal recessive genetic disorders, parents who are heterozygote carriers of gene mutations that affect the same globin chain have a 25 percent chance of having an offspring with a hemoglobinopathy. The risk of fetal hemoglobinopathy increases to 50 percent if one of the parents is homozygous for the gene mutation and the other parent is a carrier. The availability of fetal DNA testing provides at-risk couples a definite answer, rather than a statistical estimate, on whether the fetus has a hemoglobinopathy. This information is used by the family to consider their reproductive options. However, fetal diagnosis also raises ethical dilemmas since the clinical phenotype of the affected infant is difficult to predict [12] and parental decisions about pregnancy continuation versus termination strongly depend on the gestational age at diagnosis [13].
In most cases of confirmed fetal hemoglobinopathy, fetal testing does not alter obstetric care, as fetal hemoglobinopathy typically has no adverse effects on the fetus, mother, or course of pregnancy. One exception is homozygous alpha thalassemia with the loss of all four alpha globin chains, which usually results in hydrops fetalis and death during the late second through mid-third trimester of pregnancy in the absence of any intervention. Fetal hydrops can be associated with maternal mirror syndrome, which can be life-threatening for the mother (see "Nonimmune hydrops fetalis", section on 'Mirror syndrome'). The fetal diagnosis of homozygous alpha thalassemia allows the at-risk couple the option of considering intrauterine intervention. One intervention is serial intrauterine transfusions, which has resulted in successful live births, sometimes at full term, but commits the infant to transfusion dependence and its consequences unless postnatal allogeneic hematopoietic cell transplantation is performed [14]. (See "Intrauterine fetal transfusion of red cells" and "Hematopoietic cell transplantation for transfusion-dependent thalassemia".)
In utero hematopoietic cell transplantation is a promising investigational strategy offered at some fetal therapy centers. The introduction of donor cells into a naïve host prior to immune maturation can induce donor-specific tolerance and avoid the potential adverse consequences associated with postnatal hematopoietic stem cell transplantation [15].
IDENTIFYING AT-RISK PARENTS
Candidates for screening — Universal screening will detect more hemoglobinopathy carriers than selective screening based on race and ethnicity, given the increasingly diverse ethnic and geographic distribution of hemoglobinopathy genotypes in the United States and elsewhere [16]. However, the cost-effectiveness of universal screening in pregnant women has not been established. In the United States, the American College of Obstetricians and Gynecologists (ACOG) recommends offering hemoglobinopathy carrier screening with red cell indices to all pregnant women [17]. ACOG recommends a hemoglobin electrophoresis in addition to a complete blood count if there is suspicion of hemoglobinopathy based on ethnicity (African, Mediterranean, Middle Eastern, Southeast Asian, or West Indian descent) or if red cell indices show a low mean corpuscular hemoglobin (MCH) or mean corpuscular volume (MCV).
Characteristics other than ethnicity that are associated with a higher risk that an individual is a hemoglobinopathy carrier include a history of chronic anemia or stillbirth, a relative with a hemoglobin structural variant or thalassemia, and consanguinity [18].
Timing — If not performed before pregnancy, hemoglobinopathy screening is most useful when performed early in pregnancy so that fetal diagnosis, if indicated and desired, can be performed when parents have the option of terminating the pregnancy and are considering termination. In cases of homozygous alpha thalassemia with the loss of all four alpha globin chains, early diagnosis of a continuing pregnancy would prompt changes in pregnancy management (eg, close monitoring for fetal hydrops, serial fetal transfusions, or join a clinical trial of in utero stem cell transplantation).
Laboratory — Laboratory testing is the cornerstone of prenatal screening for hemoglobinopathy (algorithm 1).
●Screening for thalassemia – A complete blood count (CBC) with red blood cell (RBC) indices is a common initial screening test for thalassemia as it is easy to perform, readily available in countries with limited resources, and also provides baseline hemoglobin/hematocrit [19]. An MCV <80 femtoliters (fL) and/or MCH <27 picogram (pg) with elevation in the RBC count in the absence of iron deficiency suggests alpha or beta thalassemia minor and further testing with hemoglobin analysis is indicated to establish a diagnosis [20]. It is important to note that hemoglobin analysis in the setting of combined iron deficiency and beta thalassemia trait can be falsely normal; therefore, iron deficiency should be corrected prior to hemoglobin analysis. (See "Anemia in pregnancy", section on 'Treatment of iron deficiency' and "Diagnostic approach to anemia in adults", section on 'Microcytosis (low MCV)'.)
Maternal hemoglobin analysis can be performed either by high-performance liquid chromatography (HPLC) or isoelectric focusing (IEF) to identify abnormal hemoglobins associated with thalassemia (eg, hemoglobin F, hemoglobin A2, hemoglobin H) (table 1 and table 2). Hemoglobin analysis (either HPLC or IEF) cannot detect alpha thalassemia minor beyond the neonatal period. An MCV <80 fL, normal ferritin, and normal hemoglobin profile, particularly in individuals of Southeast Asian, Mediterranean, or African descent, suggest alpha thalassemia minor. DNA-based testing for alpha globin gene deletions is required to establish a diagnosis. Criteria for diagnosis of the thalassemias and differential diagnosis are reviewed in detail separately.
Silent carriers (ie, alpha thalassemia minima: a-/aa) will not be detected by these tests. This is a benign carrier state; affected individuals are not anemic, their RBCs are not microcytic (although mild hypochromia may be noted on the blood smear), and their hemoglobin analysis is normal. (See "Diagnosis of thalassemia (adults and children)".)
●Screening for sickle cell trait – Prenatal screening for sickle cell trait is performed with HPLC or IEF; hemoglobin electrophoresis is acceptable if these tests are not available. Sickle cell trait (rather than sickle cell disease) is established by finding both hemoglobin A and hemoglobin S, with the amount of hemoglobin A greater than hemoglobin S. These tests will also detect hemoglobin C or E carriers. Screening and diagnosis of sickle cell disorders are reviewed in detail separately. (See "Sickle cell trait", section on 'Screening' and "Diagnosis of sickle cell disorders", section on 'Laboratory methods'.)
If the results of the maternal hemoglobin analysis demonstrate that the mother is a heterozygote carrier for hemoglobinopathy or homozygous, then paternal evaluation is needed to assess fetal risk. Maternal conditions requiring partner testing include clinically significant maternal hemoglobinopathies (eg, SS, SC, hemoglobin S/beta thalassemia), as well as carrier states (hemoglobin AS, AC, AD-Punjab, AO-Arab, A Lepore, alpha or beta thalassemia minor) [21]. Prior to testing, paternity should be discussed, including the possibility that the putative father may not be the biologic father. The rare possibility of postfertilization mutations, such as uniparental disomy, should also be discussed.
Paternal testing includes CBC and hemoglobin analysis. As indicated above, a MCV <80 fL in the absence of iron deficiency suggests thalassemia minor. If there are time constraints, initiation of the paternal evaluation with a CBC (including a MCV) and hemoglobin analysis can be done simultaneously with the maternal evaluation of hemoglobinopathy.
If the biologic father is unavailable for testing, fetal diagnostic testing can be performed.
PRENATAL (FETAL) DIAGNOSIS
During pregnancy — Fetal diagnostic testing should be offered to pregnant couples at risk of having a fetus with hemoglobinopathy and who understand the risks, limitations, and benefits of testing. After counseling, the at-risk couple should be able to make an informed decision on whether to proceed with genetic testing and should have an understanding of how the results of genetic testing will impact their reproductive choices. The use of fetal diagnosis of hemoglobin structural variants and thalassemia is influenced by the ethical, cultural, and social background of the family. It is estimated that 50 to 70 percent of parents with sickle cell trait or thalassemia minor who have received genetic counseling request fetal testing [22,23]. (See 'Genetic counseling' below.)
●Invasive testing – DNA-based testing for hemoglobins S and C and alpha and beta thalassemia can be performed during the first trimester of pregnancy on villi obtained by chorionic villus sampling (typically performed at 10 to 12 weeks of gestation), or on direct or cultured cells in amniotic fluid cells obtained by amniocentesis (typically performed after 15 weeks of gestation). These procedures are discussed in detail separately. (See "Chorionic villus sampling" and "Diagnostic amniocentesis".)
Celocentesis (ultrasound-guided aspiration of celomic fluid) is another technique for very early prenatal diagnosis of hemoglobinopathy. Recent advances in genomic techniques have enabled reliable results from the small number of fetal cells that are available as early as seven weeks of gestation; however, concerns about possible adverse fetal effects (procedure-related pregnancy loss and transverse limbs defects) need to be addressed by additional large and randomized trials before offering this investigational technique in clinical practice [24]. It is only performed at highly specialized centers and may be most useful for selecting candidates for studies of early fetal intervention (eg, in utero stem cell transplantation) of alpha thalassemia.
●Noninvasive testing – Noninvasive prenatal testing (NIPT) of cell-free DNA in the maternal circulation is routinely used to screen for fetuses at higher risk of certain aneuploidies, such as trisomy 21. Use of NIPT for monogenic autosomal recessive diseases is more challenging. In autosomal recessive conditions like sickle cell disease and thalassemia, 50 percent of the fetal genome is the same as that inherited from the mother. For a fetus to be affected with the hemoglobinopathy, the paternal pathogenic allele would also have to be identified by NIPT and distinguished from the maternally inherited pathogenic allele. This may involve inclusion of other family members for molecular tracking of the pathogenic allele. Although NIPT is available for alpha and beta thalassemia, validation of this testing is ongoing [25,26]. If performed, it should be considered a screening test, with findings confirmed as described above.
Ultrasound markers can also be used to screen fetuses of couples at risk [27]. The cardiothoracic ratio, placental thickness, and middle cerebral artery peak systolic velocity (MCA-PSV) are most commonly used. The cardiothoracic ratio appears to be the most effective for detecting fetal alpha thalassemia major during early gestational weeks. A cardiothoracic ratio >0.5 before 17 weeks; a placental thickness >18 mm before 15 weeks or >30 mm at ≥18 weeks or greater than the mean plus 2 standard deviations for gestational age; or MCA-PSV >1.5 multiples of the median (MoM) for the gestational age after 15 weeks is suggestive of an affected fetus [28]. Other ultrasound markers can be used but require highly trained staff [29].
Prior to implantation — Preimplantation genetic testing to identify affected and unaffected embryos in vitro has been performed successfully in couples who are thalassemia heterozygotes [30,31]. However, this procedure can only be performed in conjunction with in vitro fertilization (IVF), which is a major disadvantage in couples who do not require IVF for treatment of subfertility. Nevertheless, some couples choose to undergo preimplantation genetic testing provided molecular diagnostics are possible because at-risk embryos can be identified before embryo transfer to the uterus, thereby avoiding the need to consider termination or potentially morbid in utero and postnatal therapy of an affected pregnancy. (See "Preimplantation genetic testing".)
GENETIC COUNSELING — If prenatal diagnosis results in diagnosis of fetal hemoglobinopathy, parents should be thoroughly counseled about the natural history of the specific disorder, how it may affect their child, and treatment approaches, as well as their reproductive options.
●(See "Overview of the clinical manifestations of sickle cell disease".)
●(See "Overview of the management and prognosis of sickle cell disease".)
●(See "Sickle cell trait".)
●(See "Diagnosis of thalassemia (adults and children)".)
●(See "Management of thalassemia".)
●(See "Public health issues in the thalassemic syndromes".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Prenatal screening and diagnosis" and "Society guideline links: Sickle cell disease and thalassemias".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Beta thalassemia (The Basics)" and "Patient education: Sickle cell trait (The Basics)" and "Patient education: Sickle cell disease (The Basics)" and "Patient education: When your child has sickle cell disease (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Hemoglobinopathies are divided into disorders of decreased globin chain production (thalassemia) and hemoglobin structural variants (S, C, and E are most common). (See 'Gene frequency' above.)
●The purpose of preconceptional counseling and prenatal hemoglobinopathy screening is to identify couples whose future offspring or current pregnancy is at high risk of an inherited hemoglobinopathy. All pregnant women should be screened. After identification of couples at risk for having an offspring with an inherited hemoglobinopathy, prenatal diagnosis is offered to determine whether the fetus is affected. (See 'Rationale for preconceptional hemoglobinopathy counseling, prenatal screening, and fetal diagnosis' above.)
●The purpose of prenatal diagnosis is to allow parents to make reproductive choices based on this information and, in the case of alpha thalassemia major, to monitor the pregnancy for nonimmune hydrops fetalis and potentially intervene. The clinical sequelae of other hemoglobinopathies manifest later in life and have no adverse effects on the fetus, mother, or neonate. (See 'Rationale for preconceptional hemoglobinopathy counseling, prenatal screening, and fetal diagnosis' above.)
●If prenatal screening by history or laboratory findings suggests an increased risk of hemoglobinopathy, hemoglobin analysis is indicated to establish a diagnosis (algorithm 1). (See 'Identifying at-risk parents' above.)
●DNA-based testing for fetal hemoglobinopathies can be performed during the first trimester of pregnancy on cells obtained by chorionic villus sampling (typically performed at 10 to 12 weeks of gestation) or on direct or cultured amniotic fluid cells obtained by amniocentesis (typically performed after 15 weeks of gestation), if the couple desires. Noninvasive prenatal testing of cell-free DNA in the maternal circulation is being developed for hemoglobinopathies. (See 'Prenatal (fetal) diagnosis' above.)
●If prenatal diagnosis results in diagnosis of fetal hemoglobinopathy, parents should be thoroughly counseled by a hematologist or expert in the management of hemoglobinopathies about the natural history of the specific disorder, how it may affect their child, and treatment approaches, as well as their reproductive options. (See 'Genetic counseling' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Dr. Brigitta U Mueller, who contributed to earlier versions of this topic review.
