INTRODUCTION — The hemoglobinopathies are heterogeneous genetic disorders of hemoglobin (Hb) typically inherited in an autosomal recessive pattern. The clinical presentation ranges from asymptomatic in carriers to mild to severe disease in homozygotes and compound heterozygotes. At the severe end of the spectrum, hemoglobinopathies impact quality of life, require life-long care (typically with regular blood transfusions), and can shorten life expectancy. Significant advances have been made in the understanding of the molecular pathology of these disorders and the ability to predict clinical phenotype from a genotype. Some remaining challenges in implementing these advances include developing optimal screening systems and efficient diagnostic methods. Though the benefit of applying programs for carrier screening (with an option for prenatal diagnosis) is recognized in many countries, the infrastructure to support comprehensive screening and accurate diagnosis are not widely available. In particular, low-income countries where hemoglobinopathies are more prevalent often lack the resources required for screening services and for public education and awareness.
The hemoglobinopathies can be divided into two general types:
●Thalassemias are caused by pathogenic variants primarily in the genes encoding the two alpha or two beta globin chains comprising Hb A, and result in imbalance of the complementary globin chains.
•Beta thalassemia syndromes are generally classified according to the degree of reduction in beta globin production; complete absence of Hb A production (beta zero thalassemia) or partial absence (beta plus thalassemia). Structural variants such as Hb E are also associated with thalassemia phenotypes, and a combination of these two types is possible. In most cases the phenotype can be predicted from the genotype (table 1). However, the clinical phenotype can have marked heterogeneity among patients with similar globin mutations and families need to be made aware of the potential variability.
•Alpha thalassemia syndromes are mostly caused by gene deletions and the clinical severity correlates with the number of deleted genes. The less common nondeletional mutations can result in multiple possible combinations of alpha thalassemia variants with various severities (table 1).
●Sickle cell disorders are caused by the sickle cell variant (mutation) at the beta globin locus of one allele in combination with a second variant affecting the beta globin locus at the other allele. The second variant may be another sickle cell variant, resulting in sickle cell disease (Hb SS) or a different variant, resulting in sickle-beta thalassemia, Hb SC, or others (table 2 and table 3).
The purpose of preconception/prenatal hemoglobinopathy screening is to identify couples whose offspring are at risk of being affected, provide them with information on the expected severity of the hemoglobinopathy if their offspring is affected, and counsel them about their options before/during pregnancy. Screening before pregnancy (ie, preconception) maximizes the couple's future reproductive options as it may be possible to reduce the possibility of conceiving/implanting an affected embryo.
Prenatal (fetal) diagnosis is offered to couples with established pregnancies who have been identified as at risk for having an affected offspring. The information provided to the parents will allow them to make reproductive choices. A definitive diagnosis of fetal hemoglobinopathy can have clinical implications; for example, in cases of alpha thalassemia major, knowing that the fetus is affected would prompt close monitoring of the pregnancy for nonimmune hydrops fetalis, and possibly early initiation of in utero therapy. The clinical sequelae of other hemoglobinopathies manifest later in life and have no adverse effects on the fetus, mother, or neonate. For couples who conceived in part to harvest cord blood hematopoietic stem cells to donate to a previous sibling with a life-limiting hemoglobinopathy, knowledge that the fetus is unaffected or heterozygous confirms the potential for this plan. Some couples may choose to terminate an affected pregnancy.
This topic will review preconception/prenatal screening of couples for hemoglobinopathy and diagnosis of fetal hemoglobinopathy in at risk pregnancies. (Throughout this topic we recognize that sometimes the pregnant person alone rather than a couple is involved in decision-making). Postnatal clinical manifestations, diagnosis, and treatment are discussed separately:
●(See "Diagnosis of thalassemia (adults and children)".)
●(See "Management of thalassemia".)
●(See "Public health issues in the thalassemic syndromes".)
●(See "Hemoglobin variants including Hb C, Hb D, and Hb E".)
●(See "Overview of the clinical manifestations of sickle cell disease".)
●(See "Diagnosis of sickle cell disorders".)
●(See "Overview of the management and prognosis of sickle cell disease".)
●(See "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance".)
EPIDEMIOLOGY OF CARRIER STATE AND DISEASE — The epidemiology of the hemoglobinopathies is a major factor informing decision-making regarding the screening approach. Sickle cell disease and thalassemia are among the most common genetic diseases worldwide. Globally, approximately 7 percent of pregnant individuals are heterozygous carriers of alpha or beta thalassemia trait or hemoglobin (Hb) S, C, D Punjab, or E, and over 1 percent of couples are at risk of having an affected child [1,2]. The incidence varies by country and may be underreported in resource-limited countries where diagnostic testing is not routinely available. The thalassemias are the most common inherited single-gene disorder in the world and occur most frequently in malaria-endemic areas, including the Mediterranean region, the Middle East, Southeast Asia, Africa, and the Indian subcontinent . The structural Hb variants S and C are most common in tropical Africa, and also found in Mediterranean countries, Saudi Arabia, and Caribbean countries. Hb E is most common in Southeast Asia.
●Thalassemias — 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 . However, thalassemia remains a clinical and public health problem in other parts of the world . The incidence may be underreported in resource-limited countries where technologically sophisticated diagnostic laboratory tests are not available. (See "Public health issues in the thalassemic syndromes".)
•More than 300 genetic mutations of clinical significance in the beta globin locus causing beta thalassemia have been described. Co-inheritance of two severe variants (beta zero or compound heterozygous for beta zero and severe beta plus or two severe beta plus mutations) and, less commonly, inheritance of delta/beta thalassemia variants and Hb Lepore, will result in a moderate or severe thalassemia major phenotype. Less severe phenotypes (thalassemia intermedia) will mostly result from compound heterozygous of two milder beta variants or co-inheritance of one severe variant with another structural mutation (such as Hb E) or with alpha gene triplication .
•Africans and, less commonly, other ethnicities, may be compound heterozygous for both a beta thalassemia gene mutation and sickle cell gene resulting in moderate or severe sickle cell disease (S beta plus- or S beta zero thalassemia, respectively). Alpha thalassemia trait (also called alpha thalassemia minor) is common in Africans and most commonly consists of loss of one gene for alpha globin synthesis 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 cause fetal sequelae but generally has a positive effect on the extent of anemia if sickle cell disease also exists.
•Alpha globin gene deletions are more common in carriers than mutations. By contrast to the African type of alpha thalassemia trait, the Southeast Asian pattern of alpha thalassemia trait consists of both genes missing on the same chromosome (cis; alpha thalassemia-1 trait [ie, aa/--]). If both parents have this pattern, the offspring has a 25 percent chance to have all four alpha globin genes absent and will be unable to synthesize any fetal or adult hemoglobin, resulting in severe anemia. Tetrameric gamma chains (Hb Bart's) in the affected fetus bind oxygen with high affinity, which leads to hypoxia, high-output cardiac failure, hydrops fetalis, and death if no intrauterine transfusions are performed to support the fetus. If one parent has alpha thalassemia trait (two alpha genes deleted in cis) and the other parent is either a silent carrier for alpha thalassemia (one alpha globin gene missing) or has alpha thalassemia trait (two alpha genes deleted in trans), this may result in an offspring with three alpha globin genes absent named Hb 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'.)
•Around 200 alpha globin gene mutations have been described (referred to as "nondeletion alpha thalassemia"); most have little or no clinical significance. The co-inheritance of alpha thalassemia trait (cis) and a clinically significant nondeletional mutant alpha globin allele, such as hemoglobin constant spring, results in a phenotype that is typically more severe than Hb H disease. Other less common nondeletional alpha mutations (eg, Hb Quong Sze, Hb Adana, Hb Pakse) will have a similar effect .
•In the United States, in contrast to sickle cell disease, the prevalence of individuals with alpha and beta hemoglobinopathies is more difficult to determine. This is due to changes resulting from shifts in immigration patterns, which include people who are carriers of hemoglobinopathies that had been rare in the United States, and the increasing number of pregnancies among couples of discordant ethnicity leading to births of infants with hemoglobinopathies that previously had not been seen [6-8].
These points are illustrated by data from the California newborn universal mandatory screening program for hemoglobinopathies that was initiated in 1990 [7,9]. 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) . A shift of the at-risk groups for beta thalassemia was noted with the majority of cases detected in families of Asian ancestry. Hemoglobinopathies detected more often include Hb E/beta thalassemia, found almost exclusively in Southeast Asians with a prevalence of 1 in every 2600 births. Population migration and racial intermarriages continue to present new hemoglobinopathies, such as a compound heterozygous Hb SE disease, a moderate form of sickle cell disease diagnosed in the California newborn screening program .
●Hemoglobin S, C, E – 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 [1,11]. With the world population expected to continue to grow, particularly in tropical and subtropical regions, estimations based on demography alone suggest an increase by 33 percent of births affected by sickle cell disease between 2010 and 2050 .
In the United States, data from state newborn screening programs showed that 1.5 percent of all infants screened in 2010 had sickle cell trait . Though the highest frequency is in Black individuals, the sickle cell carrier state is also noted in other racial/ethnic groups: 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 28 percent of African American people have one alpha thalassemia gene deletion, and about 3 percent have alpha thalassemia trait. In the United States, sickle cell disease affects approximately 100,000 Americans. The incidence of sickle cell disease has remained relatively stable (SS disease 1 in 3721 newborns, SC disease 1 in 7386 newborns) . Implications of the various sickle cell genotypes in the newborn are described in the table (table 3). (See "Sickle cell trait", section on 'Genetics and epidemiology'.)
It is estimated that 30 million Southeast Asians are carriers for Hb E and one million have homozygous EE disease. Hb EE has a benign phenotype with minimal anemia and microcytosis. However, Hb E co-inherited with a severe beta-thalassemia mutation, a beta zero mutation causing lack of beta chain synthesis (E-beta zero thalassemia) can result in significant clinical presentation and a transfusion-dependent thalassemia. (See "Hemoglobin variants including Hb C, Hb D, and Hb E", section on 'Hb E'.)
SCREENING GOALS AND POTENTIAL BENEFITS — The goals of preconception hemoglobinopathy screening are to identify couples whose offspring are at risk for having an inherited hemoglobinopathy, provide them with information about the disorder, and discuss their reproductive options. They may choose to proceed with pregnancy with or without prenatal diagnosis for fetal hemoglobinopathy; undergo in vitro fertilization (IVF) and preimplantation genetic testing for monogenic disorders (PGT-M) with implantation of likely unaffected embryos, intrauterine insemination with donor sperm from a noncarrier, or IVF using a donor egg from a noncarrier; adopt; or not become pregnant.
For couples who are already pregnant at the time of screening, early pregnancy identification of those whose offspring is at risk for having an inherited hemoglobinopathy and providing information about the disorder remain important, and prenatal (fetal) diagnosis by chorionic villus sampling (CVS) between 10 and 12 weeks of gestation or amniocentesis after 15 weeks of gestation is an option. Knowledge of an affected offspring allows couples to prepare for the birth of an affected child or consider pregnancy termination; access to pregnancy termination and the upper gestational age allowed for termination vary regionally.
In most cases of confirmed fetal hemoglobinopathy, fetal diagnosis does not alter ongoing obstetric care, as fetal hemoglobinopathy typically has no adverse effects on the fetus, mother, or course of pregnancy. One exception is cases of alpha thalassemia major caused by the loss of all four alpha globin chains, or by other rare combinations of alpha globin mutations and deletions that can also result in alpha thalassemia major [14,15], where early pregnancy diagnosis and the decision to continue the pregnancy would prompt changes in pregnancy management, such as close fetal monitoring for fetal hydrops, possible fetal intervention with serial intrauterine transfusions, and possible participation in a clinical trial of in utero stem cell transplantation, gene therapy, or gene manipulation. Additionally, pregnant individuals with a hydropic fetus are at risk for mirror syndrome (ie, proteinuria, elevated blood pressure, and preeclampsia symptoms), which presents medical risks and may lead to a medically indicated preterm birth. (See 'Postdiagnostic management' below.)
In the case of a parent identified as a sickle cell trait carrier (S trait), in addition to reproductive counseling, the parent should be counseled about the potential clinical implications of S trait in specific circumstances (table 3). Counseling should be provided by an individual with adequate training and understanding of the condition. (See "Sickle cell trait".)
POTENTIAL HARMS OF SCREENING — Screening and diagnosis may increase parental anxiety while waiting for results and when faced with uncertainty if the clinical phenotype of the affected offspring is difficult to predict . If an invasive fetal diagnostic procedure is performed, such procedures carry a small risk of pregnancy loss. (See "Diagnostic amniocentesis" and "Chorionic villus sampling".)
APPROACH TO SCREENING
Sequential partner screening — Our approach to sequential partner screening is shown in the algorithm (algorithm 1). Prior to testing a partner, paternity should be discussed, including the possibility that the putative father may not be the biologic father.
Universal (nonselective) hemoglobinopathy screening is ideal when possible because it can detect more hemoglobinopathy carriers than selective screening based on race and ethnicity, especially given the increasingly diverse ethnic and geographic distribution of hemoglobinopathy genotypes in the United States and elsewhere. Challenges to this approach include cost-effectiveness, optimal timing (adolescent, premarital, preconception, early pregnancy) to maximize reproductive options, and need for appropriate public awareness and education and access to screening services. Due to these limitations, selective screening of at-risk individuals is a common accepted strategy whereby care providers adjust their hemoglobinopathy carrier screening strategy to the population served, taking into consideration its diversity, individual family histories, and the masking effect of iron deficiency anemia on hemoglobin and mean corpuscular value (MCV) and mean corpuscular hemoglobin (MCH).
●Because individuals may not be fully aware of their race/ethnicity background and family history of a hemoglobinopathy, at a minimum, all pregnant patients should have a complete blood count (CBC), which is easy to perform, readily available in countries with limited resources, and also provides baseline hemoglobin/hematocrit.
●If the MCV and/or MCH is low (ie, MCV <80 femtoliters [fL], MCH <27 picogram [pg]) in the absence of iron deficiency, maternal hemoglobin analysis can be performed by protein chemistry methods, typically by either capillary electrophoresis or by high-performance liquid chromatography (HPLC), or less commonly by isoelectric focusing or hemoglobin electrophoresis. Overall, these "first-line" hematological and protein chemistry tests will detect most common hemoglobinopathies (table 2 and table 1); however, the diagnosis of both alpha and beta variants is still considered presumptive without a DNA-based analysis because this conventional first-line screening approach has some deficiencies:
•In some rare, atypical beta thalassemia trait cases the percentage of Hb A2 and Hb F are not elevated so these carriers will be missed.
•Two alpha gene deletions (alpha thalassemia trait) will not be detected directly, although exclusion of a beta thalassemia carrier in cases of microcytosis and normal protein chemistry testing will indicate alpha thalassemia trait. Subsequent DNA testing will be required for confirmation.
•A one alpha gene deletion (alpha thalassemia minima or silent carrier: a-/aa) will not be detected by a CBC as affected individuals are not anemic, their red blood cells (RBCs) are not microcytic (although mild hypochromia may be noted on the blood smear), and their protein chemistry analysis is normal. Case reports have described females with a normal CBC who were silent carriers and gave birth to a child with Hb H disease when the partner was a carrier of an alpha 0-thalassemia trait (two alpha genes in cis).
•Similarly, some cases of nondeletional alpha gene variants such as a constant spring carrier state often display normal MCV and MCH. Though these minor variants mostly do not have a role in the prevention of Hb Bart's hydrops fetalis, they do contribute to the risk for an offspring with three alpha genes affected (Hb H disease) if the partner of the carrier is an alpha 0-thalassemia trait carrier (two alpha genes in cis).
It is important to note that hemoglobin analysis by protein chemistry methods in the setting of combined iron deficiency and beta thalassemia trait can miss typical changes characteristic of thalassemia trait (primarily increase in Hb A2); therefore, iron deficiency, particularly when severe (estimated at ferritin level less than 15 ng/mL), should be corrected prior to making a definitive diagnosis by these methods. If timely correction is not possible, DNA-based testing can be performed since results are independent of iron status. (See "Anemia in pregnancy", section on 'Treatment of iron deficiency' and "Diagnostic approach to anemia in adults", section on 'Microcytosis (low MCV)'.)
●DNA-based confirmatory tests are typically performed when:
•First-line screening test results are abnormal or ambiguous (eg, microcytosis with normal protein chemistry tests) OR
•The patient has normal first-line screening test results but epidemiologic or familial risk factors for alpha thalassemia (see "Diagnosis of thalassemia (adults and children)", section on 'Epidemiology') OR
•The pregnancy is at an advanced gestational age where definitive diagnosis needs to be achieved rapidly for pregnancy management.
Knowledge of the exact variants(s) can assist in predicting the clinical phenotype and discussing it with the prospect parent(s).
For suspected beta-thalassemia carriers, if beta sequencing is not diagnostic, then further testing is available, such as beta multiplex ligation dependent probe amplification (MLPA) for rare beta globin deletions as well as testing for hereditary persistent fetal hemoglobin. Alpha multiplex gap polymerase chain reaction (PCR) and alpha MLPA are specific methods for detection of alpha globin deletions (as well as alpha globin duplications). Various DNA-based diagnostic strategies have been developed; some use targeted mutation-specific methods to detect either point mutations or gene deletions, while others use more generic DNA methods (such as automated Sanger sequencing for detecting point variants) that better address multiethnic populations . Some specialized laboratories for hemoglobinopathy testing located in the United States are listed in the table (table 4). (See "Diagnosis of thalassemia (adults and children)" and "Sickle cell trait", section on 'Screening' and "Diagnosis of sickle cell disorders", section on 'Laboratory methods'.)
Role of simultaneous partner screening — If the time to obtain test results is important for maximizing reproductive options, then both members of the couple are screened simultaneously. This might require DNA-based testing early on to obtain a definite diagnosis quickly and efficiently, particularly if there is parallel iron deficiency that has not yet been corrected.
Male partner unavailable for screening — If the male partner is unavailable for or declines screening, fetal diagnostic testing should be discussed and offered, especially in high-risk ethnicities.
Recommendations of select organizations
●American College of Obstetricians and Gynecologists – In the United States, the American College of Obstetricians and Gynecologists (ACOG) recommends carrier screening and counseling for genetic conditions, ideally before pregnancy. Firstline for hemoglobinopathy carrier screening, includes a CBC evaluating red cell indices in all pregnant individuals . A hemoglobin electrophoresis (or other protein chemistry method) is performed in addition to a CBC 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 MCV or MCH. Characteristics other than ethnicity that are associated with a higher risk for an individual to be a hemoglobinopathy carrier include a history of chronic anemia or stillbirth, a relative with a hemoglobin structural variant or thalassemia, and consanguinity .
A study assessing the outcomes of these ACOG recommendations showed 5 percent positivity rate among 42,166 patients analyzed by RBC indices and HPLC; a third of the positive cases were 'possible alpha thalassemia trait,' which was confirmed as alpha thalassemia trait by DNA testing in 41 percent . These findings suggest that an initial analysis that evaluates RBC indices and HPLC will have some nonspecific results that require molecular diagnosis; thus, concurrent DNA testing would be faster, more informative, and a better method for identifying alpha thalassemia carriers but may be inaccessible due to cost. In 2022 ACOG updated its recommendations to offer universal hemoglobinopathy testing to people planning pregnancy or at the initial prenatal visit if no prior testing results are available for interpretation . This is based on a high frequency of a hemoglobinopathy trait, in particular S trait, in the United States and noting that race and self-identified ethnicity are poor alternatives for genetics.
●Canadian College of Medical Geneticists – The Canadian College of Medical Geneticists (CCMG) has similar recommendations to those of ACOG, suggesting that screening should be done in the preconception period or as early as possible in pregnancy . They also point out that the use of ethnicity alone in carrier risk identification may create screening inconsistency and missed opportunity for carrier identification and therefore advise adding a "high clinical suspicion" for screening decisions.
●European Network for Rare and Congenital Anaemias – The European Network for Rare and Congenital Anaemias (ENERCA) recommends that carrier detection should be mandatory with current hematological and protein chemistry tests. However, DNA analysis should be applied in complex cases or when results to these initial tests are unclear .
Investigational approaches — Next generation sequencing (NGS) methodology is a promising investigational approach for universal screening because of high sensitivity for carrier detection and ability to detect new variants . In a Chinese population that was not ethnically diverse, a large-scale premarital carrier screening program for alpha and beta thalassemia reported a higher thalassemia carrier rate using NGS screening compared with the traditional approach (ie, RBC indices combined with hemoglobin electrophoresis and subsequent genotyping of screen positives by gap-PCR and reverse dot blot hybridization or sequencing; 49.5 versus 22 percent) . Another study of the traditional prepregnancy approach among 944 couples in China reported that it had lower sensitivity and a higher missed diagnosis ratio (61 and 39 percent, respectively) for alpha thalassemia variants compared with NGS combined with gap-PCR aimed to detect deletions known to be responsible for 80 percent of the molecular causes of alpha thalassemia .
APPROACH TO FETAL AND PREIMPLANTATION DIAGNOSIS
Fetal diagnosis — Fetal diagnostic testing should be offered to pregnant individuals at risk of having a fetus with hemoglobinopathy after counseling regarding the risks, limitations, and benefits of testing. After this counseling, the at-risk individual should be able to make an informed decision on whether to proceed with fetal genetic testing and should understand how the results of genetic testing will impact their reproductive choices. The decision to proceed with fetal diagnosis of hemoglobinopathies is influenced by the ethical considerations and the cultural and social background of the individual and their family. It is estimated that 50 to 70 percent of parents with sickle cell trait or thalassemia trait who have received genetic counseling will request fetal testing [26,27].
•Chorionic villus sampling, amniocentesis – DNA-based testing for Hb S and C and alpha and beta thalassemia can be performed during the first trimester of pregnancy on villi obtained by chorionic villus sampling (CVS, which is typically done at 10 to 12 weeks of gestation) or on cells in amniotic fluid obtained by amniocentesis (typically performed at ≥15 weeks of gestation). These procedures are discussed in detail separately. (See "Chorionic villus sampling" and "Diagnostic amniocentesis".)
•Celocentesis (investigational) – Celocentesis (ultrasound-guided aspiration of celomic fluid) is an investigational technique for very early prenatal diagnosis of hemoglobinopathy when in utero intervention is being considered. Recent advances in genomic techniques have enabled reliable results from the small number of fetal cells that are available as early as 7 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 . 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. Diagnostic accuracy appears to be >99 percent in limited small series.
●Noninvasive screening – Noninvasive screening is an alternative to an invasive procedure for diagnostic testing, but the sensitivity and specificity have not been established.
•Cell-free DNA – Use of noninvasive prenatal screening (NIPS) for monogenic autosomal recessive diseases by assessment of cell-free DNA in the maternal circulation is commercially available. However, it is considered investigational because the methodology has more challenges than aneuploidy screening for the common trisomies and sex chromosome aneuploidies and because of the lack of adequate validation studies [29-31]. It should be performed at ≥10 weeks of gestation to ensure an adequate fetal fraction. (See "Prenatal screening for common aneuploidies using cell-free DNA".)
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 NIPS and distinguished from the maternally inherited pathogenic allele. This may involve inclusion of other family members for molecular tracking of the pathogenic allele. If NIPS is performed, it is a screening test; positive findings must be confirmed by diagnostic testing performed on a fetal/placental sample obtained via an invasive procedure (CVS, amniocentesis discussed above) before undertaking any interventions. Given its limitations, some parents and providers might choose to perform interventional diagnostic testing even with a negative NIPS, particularly in cases where the couple had prior affected children.
•Sonographic markers – Ultrasound markers can also be used to screen fetuses of couples at risk, in particular for alpha thalassemia major . The cardiothoracic ratio, placental thickness, and middle cerebral artery peak systolic velocity (MCA-PSV) are most commonly used. The cardiothoracic ratio appears to be most effective for detecting fetal alpha thalassemia major during early gestational weeks. An affected fetus is suggested by 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) after 15 weeks . Other ultrasound markers can be used but are beyond the scope of this topic and require highly trained staff .
Hydrops in the setting of parents known to be alpha thalassemia carriers is likely related to alpha thalassemia major. In these cases, a consensus statement is recommended using percutaneous umbilical cord blood sampling to obtain fetal blood for hemoglobin electrophoresis and measurement of the levels of γ-globin tetramers (Hb Bart's) to confirm the diagnosis .
Preimplantation diagnosis — Preimplantation genetic testing for monogenic disorders (PGT-M) to identify affected and unaffected embryos in vitro has been performed successfully in couples who are thalassemia heterozygotes [36,37] or sickle cell heterozygotes or homozygotes [38,39]. Diagnostic accuracy is >99 percent. This procedure can only be performed in conjunction with in vitro fertilization (IVF). Nevertheless, some couples choose to undergo IVF with PGT and transfer of embryos unlikely to be affected by hemoglobinopathy, thereby avoiding the need to consider termination or potentially morbid in-utero and postnatal therapy of an affected pregnancy. Confirmatory prenatal diagnostic testing is recommended. (See "Preimplantation genetic testing".)
●When 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 (table 3).
•(See "Overview of the clinical manifestations of sickle cell disease".)
•(See "Overview of the management and prognosis of sickle cell disease".)
•(See "Hemoglobin variants including Hb C, Hb D, and Hb E".)
•(See "Public health issues in the thalassemic syndromes".)
•(See "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance".)
●As discussed above, most cases of confirmed fetal hemoglobinopathy do not require an alteration in pregnancy care, as fetal hemoglobinopathy typically has no adverse effects on the fetus, mother, or course of pregnancy. Alpha thalassemia major, typically a result from homozygous alpha thalassemia with the loss of all four alpha globin chains, is an exception as it usually causes hydrops fetalis and, in the absence of any intervention, causes fetal death during the late-second through mid-third trimester of pregnancy. Fetal hydrops can also lead to a preeclampsia-like syndrome called maternal mirror syndrome. (See "Nonimmune hydrops fetalis", section on 'Mirror syndrome'.)
One intervention for fetuses with alpha thalassemia major 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 . (See "Alpha thalassemia major: Prenatal and postnatal management".)
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 [41,42]. For severe hemoglobinopathies, advances in medical technology may lead to more curative interventions, such as stem cell transplantation, gene therapy, and gene editing [43,44], and could influence parents' decision-making. (See "Intrauterine fetal transfusion of red cells" and "Hematopoietic cell transplantation for transfusion-dependent thalassemia".)
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 (see "Patient education: Sickle cell trait (The Basics)") and (see "Patient education: Sickle cell disease (The Basics)") and (see "Patient education: When your child has sickle cell disease (The Basics)").
SUMMARY AND RECOMMENDATIONS
●Definitions – Hemoglobinopathies are conditions caused by genetic variants that result in absent or decreased globin chain production (thalassemia syndromes) or hemoglobin (Hb) structural variants (S, C, and E are most common) or combinations of these variants. (See 'Epidemiology of carrier state and disease' above.)
●Parental carrier screening – Preconception/prenatal hemoglobinopathy screening is a routine part of preconception/prenatal care. Our approach is shown in the algorithm (algorithm 1). The goal is to identify individuals/couples at high risk of having a child with a clinically important inherited hemoglobinopathy. Typically, the pregnant or potentially pregnant member of the couple is screened first, but both members can be screened concurrently if time and gestational age is an issue. Screening results allow the couple 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. (See 'Screening goals and potential benefits' above and 'Approach to screening' above.)
●Prenatal (fetal) diagnosis – If the fetus is at risk of having an inherited hemoglobinopathy, DNA-based testing for fetal hemoglobinopathies can be performed during the first trimester on cells obtained by chorionic villus sampling (CVS; 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 but is typically followed by fetal testing for confirmation. (See 'Approach to fetal and preimplantation diagnosis' above.)
●Postdiagnostic counseling – 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 'Postdiagnostic management' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Brigitta U Mueller, MD, who contributed to earlier versions of this topic review.
6 : The changing profile of homozygous beta-thalassemia: demography, ethnicity, and age distribution of current North American patients and changes in two decades.
11 : Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates.
15 : Hemoglobin H hydrops fetalis syndrome resulting from the association of the - -SEA deletion and the alphaQuong Szealpha mutation in a Chinese woman.
16 : Preconception carrier screening and prenatal diagnosis in thalassemia and hemoglobinopathies: challenges and future perspectives.
17 : Preconception carrier screening and prenatal diagnosis in thalassemia and hemoglobinopathies: challenges and future perspectives.
19 : Hemoglobinopathy Evaluation in Routine Carrier Testing: Results to Inform Guidelines and Protocols
20 : Hemoglobinopathy Evaluation in Routine Carrier Testing: Results to Inform Guidelines and Protocols
21 : Joint SOGC-CCMG Opinion for Reproductive Genetic Carrier Screening: An Update for All Canadian Providers of Maternity and Reproductive Healthcare in the Era of Direct-to-Consumer Testing.
22 : EMQN Best Practice Guidelines for molecular and haematology methods for carrier identification and prenatal diagnosis of the haemoglobinopathies.
23 : The Evolving Role of Next-Generation Sequencing in Screening and Diagnosis of Hemoglobinopathies.
24 : Next-generation sequencing improves thalassemia carrier screening among premarital adults in a high prevalence population: the Dai nationality, China.
25 : Combined use of gap-PCR and next-generation sequencing improves thalassaemia carrier screening among premarital adults in China.
31 : Noninvasive Prenatal Test forβ-Thalassemia and Sickle Cell Disease Using Probe Capture Enrichment and Next-Generation Sequencing of DNA in Maternal Plasma.
34 : Fetal hemoglobin Bart's hydrops fetalis: pathophysiology, prenatal diagnosis and possibility of intrauterine treatment.
38 : Live birth following preimplantation genetic testing to prevent sickle cell disease in a low resource setting: A case report.
40 : Outcomes of haemoglobin Bart's hydrops fetalis following intrauterine transfusion in Ontario, Canada.
43 : A systematic review of quality of life in sickle cell disease and thalassemia after stem cell transplant or gene therapy.
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