case study for sickle cell anaemia

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Case Study: Sickle Cell Disease A 25-Year-Old in Transition

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A 25-year-old woman with a history of sickle cell disease (SCD) presents to the clinic for follow-up after a hospitalization for a vaso-occlusive pain crisis complicated by influenza A. She has a history of an acute ischemic stroke at age 5 years and has received monthly, simple red cell transfusions since the stroke. Her last transfusion was approximately four months prior. She is taking deferasirox 20 mg/kg daily but occasionally misses doses.

Laboratory results show the following:

Which of the following is the next best step in diagnosis

• Restart scheduled red blood cell transfusions
• Start prophylactic penicillin
• Discontinue transfusions and start hydroxyurea
• Order transcranial doppler ultrasonography (TCD) to assess risk of stroke
• Increase dose of deferasirox to 25 mg/kg/day

Explanation

The incidence of primary stroke in children with SCD is 0.6 to 0.8 events per 100 patient-years, with a cumulative incidence of 7.8 percent by age 14 years in the Jamaican cohort and 11 percent by age 20 years in the U.S. Cooperative Study of Sickle Cell Disease. Once stroke has occurred, the incidence of recurrent (secondary) stroke ranges from 47 to 93 percent in patients not started on regular transfusions. The Stroke Prevention Trial in SCD (STOP) randomized 130 high-risk children with SCD to either transfusion therapy (to maintain HbS 30%) or observation. These high-risk children had an increased blood flow in the internal carotid or middle cerebral artery by TCD. This study showed a 92 percent reduction in incidence of first stroke in transfused high-risk patients. A follow-up study, STOP2, randomly assigned 72 children whose TCD had normalized after 30 months of transfusion therapy to either ongoing or discontinued transfusions. The study was closed early due to a significant increase in abnormal TCD velocity and stroke risk for those who halted transfusion therapy.

The multicenter phase III TWiTCH trial evaluated children with SCA and abnormal TCD velocities without a history of stroke on chronic transfusions. Data showed that hydroxyurea at maximal tolerated dose was noninferior to chronic transfusions for maintaining TCD velocities as primary stroke prophylaxis (choice C). This patient has a history of ischemic stroke, so the results of TWiTCH do not apply to her.

The Stroke with Transfusions Changing to Hydroxyurea (SWiTCH) study was designed as a phase III multicenter trial to determine the efficacy of hydroxyurea/phlebotomy, compared with transfusions/chelation for children with SCA, stroke, and iron overload in secondary stroke prophylaxis. The primary endpoint was a composite of noninferiority for stroke prevention and superiority for reduction of liver iron content. The trial was terminated at the first scheduled interim analysis for futility for the composite endpoint, which required superiority of phlebotomy over iron chelation for reducing excess iron stores. The incidence of stroke on the hydroxyurea plus phlebotomy arm was higher (7 of 67 patients; 10.4%) than in the transfusion plus chelation arm (1 of 66 patients; 1.5%). These results, though not powered for inferiority, showed a trend towars increased stroke risk with transition to hydroxyurea. In patients with prior stroke, cessation of transfusion therapy is currently not recommended.

Whether chronic transfusion therapy can be stopped after a longer period of transfusions in a patient with a prior stroke remains unclear even though risk of recurrent stroke remains high in adolescence and young adulthood. In patients older than 16 years, TCD velocity criteria to determine stroke risk is not reliable (choice D).

In the Prophylaxis with Oral Penicillin in Children with Sickle Cell Anemia trial, children with SCA were randomly assigned to receive oral prophylactic penicillin or placebo PROPS 1986 ). The trial ended eight months early after the occurrence of 15 cases of pneumococcal sepsis, 13 in the placebo group and two in the penicillin group, showing an 84 percent reduction in pneumococcal sepsis with penicillin prophylaxis. The follow-up study, PROPS II, did not show an increased risk in pneumococcal infections with discontinuation of prophylactic penicillin after age 5 years. Therefore, prophylactic penicillin is not recommended in adults with SCA (choice B).

The trajectory of ferritin in this patient has not been established and an increase in oral iron chelation is not indicated at this time.

Case Study submitted by Marquita Nelson, MD, of University of Chicago, Chicago, IL.

• Hirst C, Owusu-Ofori S Prophylactic antibiotics for preventing pneumococcal infection in children with sickle cell disease . Cochrane Database Syst Rev. 2014 6:CD003427.
• Valadi N, Silva GS, Bowman LS, et al Transcranial Doppler ultrasonography in adults with sickle cell disease . Neurology. 2006 22:572-574.
• Ware RE, Davis BR, Schultz WH, et al Stroke with transfusions changing to hydroxyurea (SWiTCH) . Blood. 2012 119:3925-3932.
• Kumar N, Gross JB Jr, Ahlskog JE TCD with transfusions changing to hydroxyurea (TWiTCH): hydroxyurea therapy as an alternative to transfusions for primary stroke prevention in children with sickle cell anemia . Blood. 2015 126:3.

American Society of Hematology. (1). Case Study: Sickle Cell Disease A 25-Year-Old in Transition. Retrieved from https://www.hematology.org/education/trainees/fellows/case-studies/sickle-cell-disease-a-25-year-old-in-transition .

American Society of Hematology. "Case Study: Sickle Cell Disease A 25-Year-Old in Transition." Hematology.org. https://www.hematology.org/education/trainees/fellows/case-studies/sickle-cell-disease-a-25-year-old-in-transition (label-accessed May 14, 2024).

"American Society of Hematology." Case Study: Sickle Cell Disease A 25-Year-Old in Transition, 14 May. 2024 , https://www.hematology.org/education/trainees/fellows/case-studies/sickle-cell-disease-a-25-year-old-in-transition .

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A case study: Sickle cell anemia

Sickle cell anemia is a genetic disease with severe symptoms, including pain and anemia. The disease is caused by a mutated version of the gene that helps make hemoglobin — a protein that carries oxygen in red blood cells. People with two copies of the sickle cell gene have the disease. People who carry only one copy of the sickle cell gene do not have the disease, but may pass the gene on to their children.

The mutations that cause sickle cell anemia have been extensively studied and demonstrate how the effects of mutations can be traced from the DNA level up to the level of the whole organism. Consider someone carrying only one copy of the gene. She does not have the disease, but the gene that she carries still affects her, her cells, and her proteins:

• There are negative effects at the whole organism level Under conditions such as high elevation and intense exercise, a carrier of the sickle cell allele may occasionally show symptoms such as pain and fatigue.
• There are positive effects at the whole organism level Carriers of the sickle cell allele are resistant to malaria, because the parasites that cause this disease are killed inside sickle-shaped blood cells.

This is a chain of causation. What happens at the DNA level propagates up to the level of the complete organism. This example illustrates how a single mutation can have a large effect, in this case, both a positive and a negative one. But in many cases, evolutionary change is based on the accumulation of many mutations, each having a small effect. Whether the mutations are large or small, however, the same chain of causation applies: changes at the DNA level propagate up to the phenotype .

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Case history of a child with sickle cell anemia in India

A three years old male child, native of Jharkhand, Central India presented with mild pallor, icterus, and history of on and off abdominal and joint pains. On examination the child had mild splenomegaly. He had history of two prior hospital admissions. First at the age of 1 year, when he was diagnosed to have pneumonia and second, at the age of 3 years (3 months prior to coming to our institution) for fever, anemia and jaundice. He has had three transfusions till now, last transfusion was 3 months back. There is history of sibling death at 5 years of age due to fever and jaundice.

The hemogram showed anemia with leukocytosis. Red cell morphology (Figure 1) revealed severe anisopoikilocytosis with macrocytes, microcytic hypochromic red cells, target cells, many boat cells, sickled RBCs, polychromatic cells and occasional nucleated RBCs. Results of the automated blood cell counts showed Hb 7.7 g/dl, RBC 2.44 x 109/l, MCV 97.1 fl, MCH 31.4 pg, MCHC 32.3 g/dl, RDW 26.6%. There were occasional nucleated red cells and relative neutrophilia. Further to confirm HbS, a sickling test using freshly prepared 2% sodium meta-bisulphite was performed which was positive (Figure 2).

Hemoglobin HPLC on Bio-Rad Variant 2 showed raised fetal hemoglobin (HbF) and a variant peak in S window (71.9%) at retention time of 4.36 mins. Adult Hb (HbA) of 8.5% was noted (Figure 3). Figure 4 shows Cellulose acetate hemoglobin electrophoresis at alkaline pH (8.6), which showed a prominent band in S/D/G region and a faint band in F region. Investigations of the father showed also showed a variant peak in S window (32.9%) at retention time of 4.36 mins along with HbA (57.1%) on HPLC with Bio-Rad Variant II which is diagnostic of Sickle cell trait (Figure 5).

Sickle cell disease (SCD) is the most common symptomatic hemoglobinopathy caused as a result of inheritance of two copies of the sickle β-globin gene variant (βS). A single nucleotide substitution leading to replacement of glutamic acid by valine at position 6 of the β-globin polypeptide chain leads to formation of HbS which is responsible for disease manifestation.  SCD has a wide geographical distribution throughout major parts of Africa, the Middle East, India and in some regions of Mediterranean countries. In India, it is mainly concentrated in the central region including parts of Madhya Pradesh, Chattisgarh, Orissa, Maharashtra, Gujrat and Jharkhand. HbS has carrier frequencies varying from 5 to 35% and are especially seen amongst the scheduled tribes, scheduled castes and other backward castes.

Sickle cell mutation is believed to be originated five times in history spontaneously. This can be elucidated by five βS-globin haplotypes. These haplotypes include Senegal (SEN), Benin (BEN), Bantu or the Central African Republic (CAR), Cameroon (CAM) and Arab-Indian (ARAB). They enable us to understand the origin, evolution, migration and natural selection of genetic defects. They can be identified by specific restriction sites within the β-globin gene cluster. Different haplotypes are known to have different HbF levels. Senegal and Arab-Indian haplotypes have higher HbF levels when compared to other haplotypes. However, recently a study has investigated the origins of the sickle mutation by using whole-genome-sequence data to conclude that there might be single origin of sickle allele.

LEARNING POINTS

1.    Sickle cell disease (SCD) is the most common symptomatic hemoglobinopathy in the world, largely seen in parts of Africa, the Middle East, India and in some regions of Mediterranean countries.

2.    SCA is a monogenic disorder with an autosomal recessive inheritance. The parents are clinically asymptomatic and have normal blood counts. They are usually diagnosed incidentally or as a result of family studies in SCA patients.

3.    Neonates are asymptomatic due to high HbF, but symptoms begin to appear by six months of age. Many infants present with lethal complications at first presentation. This emphasizes the importance of newborn screening in these susceptible pre-symptomatic cases in endemic regions.

4.    SCA has a variable clinical course amongst different individuals depending upon various genetic determinants like βs haplotype, factors affecting HbF levels and co-inheritance of other disease modifying factors.

5.    Diagnosis mainly relies upon identification of HbS (by any of the following HPLC, Hb Electrophoresis, Iso-electric focusing or sickling test). Once HbS is identified, it has to be validated by alternative method.

6.    Treatment of sickle cell disease generally aims at relieving symptoms and preventing infections, sickle cell crises and long-term complications. Stem cell transplant is the only potential cure available presently.

HPLC pattern of the index case with sickle cell anemia showing HbS and HbF peaks.

Hemoglobin electrophoresis at alkaline pH. Black arrow shows the index case with HbS and HbF bands.

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• Case report
• Open access
• Published: 23 August 2013

A 19-year-old man with sickle cell disease presenting with spinal infarction: a case report

• April Edwards 1 ,
• E Leila Jerome Clay 2 , 3 ,
• Valerie Jewells 4 ,
• Stacie Adams 5 ,
• Regina D Crawford 6 &
• Rupa Redding-Lallinger 2  

Journal of Medical Case Reports volume  7 , Article number:  210 ( 2013 ) Cite this article

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Introduction

Vasculopathy of the large vessels commonly occurs in sickle cell disease, and as a result cerebral infarction is a well characterized complication of this condition. However, spinal infarction appears to be rare. Spinal infarct is infrequent in the non-sickle cell population as well, and accounts for only about 1 percent of all central nervous system infarcts.

Case presentation

In the present work, we report the case of a 19-year-old African-American man with sickle cell disease who experienced an anterior spinal infarct and subsequent quadriplegia. He was incidentally noted to be a heterozygote for factor V Leiden. We also reviewed the literature and found two previous cases of spinal cord infarction and sickle hemoglobin. Our literature search did not demonstrate that heterozygocity for factor V Leiden plays an important role in spinal cord infarction.

Conclusions

The paucity of cases associated with sickle hemoglobin does not allow us to postulate any particular risk factors with sickle cell disease that might predispose patients to spinal cord infarction. Our patient’s case raises the question as to whether spinal cord infarction is being missed in individuals with sickle cell disease and neurologic symptoms.

Peer Review reports

Cerebral infarction is the most common neurologic complication that occurs with sickle cell disease (SCD); it can be either overt or silent and it can be associated with significant morbidity [ 1 ]. Overt stroke in SCD was first characterized in 1923, and histopathologic studies later revealed large vessel narrowing with superimposed thrombosis as the underlying cause [ 2 , 3 ]. Though cerebral infarction is the most frequent neurological complication, a number of other potentially devastating central nervous system (CNS) sequelae have also been described. These include: intra-cranial hemorrhage, isolated neuropathies, transverse myelitis, auditory and ocular manifestations, and spinal cord involvement [ 1 ]. In the spinal cord there has been a description of cord compression by extramedullary hemopoietic tissue in addition to rare case reports of spinal cord infarction [ 1 , 4 – 6 ].

In the non-sickle cell disease population it appears that spinal infarct is much less frequent than cerebral infarction as well, and accounts for only about 1 percent of all CNS infarcts [ 7 ]. Of those with spinal infarction, most appear to be from traumatic or surgical etiologies than other organic causes [ 7 , 8 ]. Aortic disease is a frequent culprit with many case reports detailing adverse sequelae following surgical repair of aneurysms, but also aortic thrombosis, and aortic dissection [ 8 ]. Other non-traumatic, non-surgical etiologies of spinal cord infarct include: global hypotension and/or arterial insufficiency, often after cardiac arrest; transient ischemic attacks; fibrocartilagenous emboli; arterial vascular malformations; syphilitic arteritis and adjacent spinal disease [ 8 – 10 ]. In a 2006 study, Novy et al . noted that 12 of their 27 patients with spinal infarct had pre-existing spinal disease including compression fractures, spondylolisthesis, chronic arachonoiditis and chronic cervical disk protrusion, and of those 12 patients, 11 had an infarct at the level of their pre-existing disease [ 7 ]. However, the cause of spinal infarct is frequently cryptogenic [ 11 ].

There is considerable evidence that sickle cell disease represents a hypercoagulable state [ 12 – 15 ]. It appears that nearly every component of hemostasis is altered to some degree in SCD [ 15 ]. Studies have indicated that in sickle cell disease there is increased platelet activation and aggregation, increased levels of D-dimer and fibrinogen and fibrin-fibrinogen complex while there are simultaneously decreased factors V, VII, VIIa and proteins C and S [ 13 ]. There is good evidence that there is externalization of phosphatidylserine (a phospholipid normally found in the inner monolayer of red blood cells) in SCD, which is thought to play a significant role in promoting macrophage recognition in erythrophagocytosis and thus triggering a signal for the coagulation process [ 13 , 14 ]. Increased phosphatidylserine exposure is also thought to be associated with increased tissue factor expression [ 14 ]. However, it remains unclear how or to what extent those abnormalities contribute to disease complications such as cerebral and spinal infarcts.

Because cerebral infarcts occur only in a subset of the sickle cell population, it has been postulated that there may be identifiable features of this subgroup that exacerbate the hypercoagulable state of sickle cell disease. In the search for possible characteristics of this subpopulation, some have begun to explore factors that predispose the general population to coagulation abnormalities and thrombophilia. Specifically, there have been case reports of persons with SCD who developed CNS infarcts and were found to have the factor V Leiden, a prothrombin gene variant, a methylenetetrahidrofolate reductase gene mutation, or some combination of those mutations [ 16 – 18 ]. These studies were conducted in Brazil and Israel; notably the prevalence of the factor V Leiden and the prothrombin gene variant are known to be very low in African-Americans [ 19 ]. Also, there have been a few single nucleotide polymorphisms (SNPs) in persons with SCD that have been found to be associated with increased stroke risk: ANXA2, TGFBR3, and TEK were noted in a study including these SNPs [ 20 ]. However, further validation is needed before these can be used to prospectively guide recommendations for molecular genetic testing or treatment [ 20 ]. There is no known identifiable thrombophilic abnormality that predicts cerebral infarction in sickle cell disease.

On the morning of admission, our patient, a 19-year-old African-American man with sickle cell anemia, felt himself to be in his usual state of health, although he had just been discharged the previous day from a hospitalization for acute chest syndrome. He ate breakfast and spent the day watching television. However, at approximately 5:45 p.m. when he used the bathroom, he noticed that he could not pull up his trousers due to weakness in his left arm. As he walked out of the bathroom, he noted that he was having difficulty walking because of weakness in his right leg. As his mother was helping him to his bed, his left leg also became weak. He began experiencing ‘shocking’ pains on both sides of his neck, which were unlike his usual pain, and also noted that he had an erection. These events transpired rapidly, within about six minutes, at which point his family called Emergency Medical Services (EMS) and our patient was transported to our hospital.

On arrival at our hospital, he was alert and oriented and cranial nerves II to XII were intact. He had flaccid paralysis of the bilateral upper extremities and the left lower extremity, and normal tone with 5 out of 5 strength in the right lower extremity. He had areflexia in the biceps, triceps, and brachioradialis bilaterally, hyper-reflexia at the left patella, and sustained clonus at the left Achilles. Sensation was intact throughout. The results of the rest of his physical examination were normal.

Relevant medical history included asthma, recurrent acute chest syndrome (>10 episodes), and intermittent attempts at hydroxyurea treatment with poor compliance over the previous 10 years. Following the identification of silent cerebral infarcts, he was treated for the three years between 2005 and 2008 with exchange transfusions to maintain hemoglobin S < 30 percent; during this time he did very well. At 10 days prior to presentation, he was hospitalized with an acute chest syndrome. During that hospitalization he had an initial PO 2 of 76, a hemoglobin (Hb)/hematocrit (Hct) nadir of 5.8/17, and was found to have a methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. He was treated with antibiotics and a transfusion. His discharge hemoglobin was 6.6 and oxygen saturation 96 percent. He was without symptoms at the time of discharge.

Admission laboratory test data included a white blood cell count of 12 × 10 3 /uL Hb 8.7g/dL, Hct 26 percent, platelets 449 × 10 3 cells/mm 3 with a hemoglobin electrophoresis of HbA 86 percent, HbS 7 percent, and HbC 7 percent. He had a lumbar puncture that demonstrated unremarkable cerebrospinal fluid findings and no evidence of IgG oligoclonal bands. The results of peripheral blood and urine cultures were negative. A chest X-ray showed patchy consolidation in the right upper lobe suspicious for pneumonia. The results of computed tomography (CT) angiography of the head and neck were unremarkable. Given concern for spinal cord involvement, 1.5T T1, T2, and fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) studies of the brain and cervical spine was performed showing an abnormal T2/FLAIR signal in the cervical spinal cord, which was thought at that time likely to be due to artifact. Later the initial MRI was read to also show swelling of the cord in the same area. He was admitted to the neurologic intensive care unit where he received an exchange transfusion with no significant improvement in his symptoms; subsequent hemoglobin electrophoresis showed HbA 85 percent, HbS 9 percent. While in the intensive care unit (ICU) he experienced episodes of hypotension that were initially managed with vasopressors. After his blood pressure stabilized he was transitioned to fludrocortisone and midodrine. He never had respiratory insufficiency. Two days after admission he had a repeat MRI, which showed T2 hyperintense signal extending from C2 through to C7 (Figure  1 A). In addition, diffusion-weighted imaging demonstrated restricted diffusion consistent with a focus of infarction in addition to cord edema and swelling in the gray and white matter of the right side of the cord. There was associated enlargement of the spinal cord consistent with edema from the anterior spinal infarct. A hypercoagulability investigation performed during his hospitalization included a polymerase chain reaction (PCR) study that demonstrated that he was heterozygous for the factor V Leiden 1691 G>A mutation. Other studies performed were for factor VIII, fibrinogen, functional anti-thrombin, lupus anti-coagulant, anti-cardiolipin, all of which were within normal limits. His erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were both elevated, and proteins C and S were found to be low but within the expected range for someone with sickle cell disease. He was anti-coagulated with a heparin drip during his stay in the acute care facility, but this was discontinued on discharge. A monthly exchange transfusion regimen was instituted with the goal of keeping his hemoglobin S level < 30 percent.

A,B T2 hyperintense signal extending from C2 to C7 with edema of the gray and white matter of the cord. The arrows point to the edema. As with all infarcts, the area of infarct is bright on B1000 and dark on apparent diffusion coefficient sequences.

Although initially there was almost complete paralysis of his extremities, over the four days he spent in the neurologic ICU, our patient demonstrated slow but steady progress in regaining some motor function of his affected limbs. He was transferred from the ICU to the wards on day five and began working with physical and occupational therapy. On day 10, he was transferred to a rehabilitation facility, where he made gradual but steady progress in regaining motor function. He was discharged home after three weeks.

Five months after the acute onset of paralysis, he had some residual left arm and leg weakness and spasticity, but was able to walk unassisted and perform most activities of daily living without assistance. A repeat MRI scan showed a persistence of slight T2 signal abnormality in the cervical cord, consistent with previous spinal cord infarction. There was no spinal cord atrophy (Figure  2 ). Our patient continued to make progress, regaining much of his strength and function, and was maintained on a regimen of monthly scheduled exchange transfusions.

A,B Follow-up magnetic resonance imaging study demonstrating no spinal cord atrophy with residual signal from myelomalacia, months after infarct. Arrows point to the decrease in edema.

At 18 months post-infarct he presented with complaints of three hours of generalized weakness, worse in his lower extremities in association with a pain crisis. His symptoms of weakness had largely resolved by the time he arrived at our Emergency Department. On examination he had 4 out of 5 strength in his left lower extremity and 5 out of 5 in right lower extremity, and 3 out of 5 grip strength bilaterally with a slightly unsteady gait; these findings were not substantially different from his post-spinal cord infarction baseline. His hemoglobin S was 51.5 percent at that time. Repeat imaging studies of his brain and spine at that time were unchanged from his prior studies. He was admitted and had an exchange transfusion achieving a post-transfusion HbS of 8.3 percent. He was given daily low-dose (81mg) aspirin. Currently, at 20 months post-spinal cord infarction, his condition is unchanged.

Spinal cord infarct is infrequent compared to cerebral infarction in the general population, and most commonly occurs as a result of a dissecting aortic aneurysm or aortic surgery [ 7 , 8 ]. In persons with sickle hemoglobin, significant spinal cord infarction appears to be an even more rare neurologic complication. To the best of our knowledge, there are only two reported cases of other persons, both now deceased, detailing this pathology [ 4 , 5 ]. Of note, the radiographic findings from our patient have been previously presented in a radiology journal with emphasis on the diffusion-weighted images, but in this report we describe the clinical details and our patient’s subsequent course [ 6 ].

There is a case report from 1970 of a 59-year-old Jamaican woman with presumed sickle cell trait who deteriorated over the course of several years to near complete paraplegia and who was subsequently found to have a slightly swollen spinal cord in the cervical region and atrophic thoracic and lumbar spine cord segments on autopsy [ 4 ]. The authors noted that her vasculature and neural tissue was otherwise without the stigmata of significant atherosclerotic or degenerative disease, and while no thrombosed vessels were found in relation to the areas of necrosis in her spinal cord, there were however, many arteries and veins distended with abnormally shaped sickle red cells [ 4 ]. A 1980 case report describes a 19-year-old African-American man with sickle cell disease who developed sudden-onset quadriplegia and in post-mortem studies was found to have multiple, old, focal and confluent infarcts involving the cortex and subcortical white matter in the brain, and also of the cervical, thoracic, and upper lumbar spinal cord [ 5 ]. There are no data from these case reports in the literature concerning other potential risk factors including any thrombophilic abnormalities, as these were not commonly looked for in 1970 and 1980.

From the available reports that have looked for an association between factor V Leiden and complications of sickle cell disease, there is no evidence of an obvious relationship [ 16 , 21 , 22 ]. Kahn et al. studied a cohort of 82 patients with different sickle cell states, 19 of whom had had a stroke [ 21 ]. Only one of the 82 was heterozygous for factor V Leiden (there were no homozygotes), and this was not a patient who had experienced a stroke, priapism or any other vascular-type disorder [ 21 ]. Andrade et al. similarly examined a cohort of 73 patients with sickle cell disease in Brazil, of whom five had a stroke [ 16 ]. One of the five was a heterozygote for factor V Leiden; of the patients who had not experienced a stroke, none were positive for the factor V Leiden mutation. Interestingly, that patient had a sister who also had sickle cell anemia and stroke, but the sister did not carry the factor V Leiden mutation. We conclude that our patient’s heterozygosity for factor V Leiden did not contribute to the occurrence of the spinal cord infarction.

Our patient has severe sickle cell disease as manifested by multiple bouts of recurrent acute chest syndrome and the presence of a silent cerebral infarction. As a comorbidity which predisposes to more severe disease, he also has asthma. However, he would not be considered to be very unusual in having this degree of illness. Therefore, the question arises as to why he developed the rare complication of spinal cord infarction. It occurred during the recovery from an episode of acute chest syndrome, which is known to be a time period of increased risk for cerebral infarction, but this is clearly not a full explanation given the frequency of acute chest syndrome and the rarity of spinal cord infarction. His hypoxemia had resolved when the spinal cord infarction occurred, and his worsened anemia had been corrected. In addition, his sickle hemoglobin percentage was quite low. Although our review of the literature does not suggest that his infarct can be explained by the factor V Leiden heterozygosity, he was not tested for any of the other genetic variants that have been recently found to be associated with stroke in SCD such as ANXA2, TGFBR3, and TEK. It is possible that a combination of factor V Leiden heterozygosity and another mutation may increase his risk for this complication. However, in order to determine risk factors for this complication, its true incidence in SCD must be known.

It is possible that spinal cord infarction may occur more commonly than previously recognized in sickle cell disease and is missed or misdiagnosed as cerebral infarction. Although in our patient’s case there were clear findings suggestive of spinal cord involvement, some presentations could be more subtle, and many clinicians may not think of the spinal cord when a patient with sickle cell presents with neurologic deficits. We hope that this report may lead others who care for people with sickle cell disease to be vigilant to the possibility of central nervous system infarction involving the spinal cord.

Written informed consent was obtained from the patient for publication of this manuscript and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

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This manuscript was prepared during the corresponding author’s training and was supported by the T32 NIH grant PHS GRANT 5T32 HL 7149–35.

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E Leila Jerome Clay & Rupa Redding-Lallinger

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E Leila Jerome Clay

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Valerie Jewells

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AE reviewed our patient’s case, data and figures, and was a major contributor in writing the manuscript. ELJC reviewed our patient’s case and data, completed subsequent drafts of the manuscript and was a major contributor in writing the manuscript. VJ provided the radiological findings, figures and interpretations. SA was involved during the initial presentation of our patient’s case. RDC was involved during the initial presentation of our patient’s case. RR-L reviewed our patient’s case, data, co-ordinated the authors and was a major contributor in writing the manuscript. All authors read and approved the final manuscript.

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Edwards, A., Clay, E.L.J., Jewells, V. et al. A 19-year-old man with sickle cell disease presenting with spinal infarction: a case report. J Med Case Reports 7 , 210 (2013). https://doi.org/10.1186/1752-1947-7-210

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Literature review, preconception care, maternal health, conflict-of-interest disclosure, off-label drug use, evidence-based management of pregnant women with sickle cell disease in high-income countries.

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Eugene Oteng-Ntim , Panicos Shangaris; Evidence-based management of pregnant women with sickle cell disease in high-income countries. Hematology Am Soc Hematol Educ Program 2022; 2022 (1): 408–413. doi: https://doi.org/10.1182/hematology.2022000378

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Globally, patients living with sickle cell disease are now surviving to reproductive age, with life expectancy approaching 50 years in most countries. Thus, reproductive options are now essential for patients living with the condition. However, it can be associated with maternal, delivery, and fetal complications. Outcomes may vary depending on the level of expertise and resources. In this piece we provide an optional guideline for managing sickle cell disease in pregnancy. The therapeutic option of serial exchange prophylactic transfusion has been offered in the context of a clinical trial (TAPS2).

Understand the maternal delivery and fetal complications associated with SCD and pregnancy

Learn about the management options available for SCD and pregnancy

Review the evidence and the research approaches to addressing transfusion management in pregnancy

A 28-year-old woman of African background, known to have sickle cell disease (SCD), presented to the clinic during her second pregnancy at 8 weeks' gestation. Her husband was a carrier of SCD, and thus this pregnancy was conceived through preimplantation genetic diagnosis (PGD) to avoid the 50% chance of having offspring with SCD. Her first pregnancy was complicated by preeclampsia, necessitating delivery at 36 weeks by cesarean. During that pregnancy she had an acute painful episode close to delivery and, as a result, had an exchange blood transfusion before the cesarean. The baby weighed 2.34  kg. During the second pregnancy, she was started on aspirin at 150  mg/d, folic acid, penicillin at 250  mg twice daily, and thromboprophylaxis in the form of dalteparin from 28 weeks onward. She declined to go on any trials, including the TAPS2 trial (transfusion for pregnant women with SCD). The pregnancy progressed well with normal serial growth scans and minimal manifestation of SCD. Therefore, we recommended delivery at 38 weeks' gestation. Still, a day before the delivery date she had a severe acute painful episode with significant anemia that required a top-up transfusion. After she was stabilized, a decision was made for a planned cesarean due to her previous cesarean. The baby weighed 2.20  kg. The mother and her baby did well post delivery without further concerns.

This review was written in accordance with the American Society of Hematology processes. The level of evidence was based on the grade nomenclature—ie, grading of recommendations, assessment, development, and evaluation ( http://www.gradeworkinggroup.org ). It was also based on a guideline by the British Society of Haematology and updated according to a Royal College of Obstetricians and Gynaecologists Green Top guideline. 1 , 2  

A series of databases were searched, including Medline, Embase, the Cochrane Library, and others for randomized controlled trials, systematic reviews, and meta-analyses between 2000 and 2021. In all, over 220 papers were identified. The search terms included “sickle cell,” “antenatal,” “pregnancy,” “intrapartum,” “hydroxycarbamide,” “penicillin prophylaxis,” “risk factors,” “preconception,” and “sickle cell crises.” 1  

This article describes how SCD is managed during pregnancy in the Western World, particularly in the United Kingdom. It aims to cover preconception screening and antenatal, intrapartum, and postnatal management of women with SCD. It does not cover the management of women who are sickle cell carriers. Instead, it reviews comprehensive information on preconception screening, medications, PGD, thromboprophylaxis, aspirin and vitamin D, and serial ultrasound scans.

SCD consists of a group of conditions caused by the inheritance of an abnormal sickle hemoglobin (HbS) gene. The most common is homozygous SCD, but there are other compound heterozygous types, one of the unusual being HbS—for example, HbSC ( Table 1 ). SCD is the most common inherited condition worldwide, with well over 300 000 children born with the disease each year, 75% of whom are born in Africa. 1   In the UK and France, there are estimated to be 12 000 to 15 000 affected individuals, 3   and in the UK, approximately 260 children are born with the condition each year. The pathophysiology of SCD is a result of HbS in low oxygen conditions giving rise to rigid and fragile sickle-shaped red cells. 3   This leads to an increase in the breakdown of these cells, resulting in anemia and the sickle-shaped red cells polymerizing and causing the clinical features of acute pain, significant anemia, shortness of breath, and fatigue. The polymerization/vaso-occlusion can result in end-organ damage, such as acute chest syndrome, pulmonary hypertension, stroke, renal dysfunction, retinal disease, and leg ulcers. These manifestations result in reduced life expectancy. In Western countries and some developing countries, patients live up to their mid-50s. Still, as most are living to reproductive age, management of this condition in pregnancy becomes more relevant. Pregnancy in women with the condition is associated with a high risk of mortality, estimated to be up to 2%, and morbidity. 4   Pregnancy-related conditions such as hypertension and venous thromboembolism are significantly increased, as confirmed in other observational studies. 4 , 5   During pregnancy, patients are more likely to require blood transfusions and admission to the critical care unit. The babies of mothers with SCD are more likely to be born preterm, before 37 weeks' gestation, and thus there is a high need for neonatal intensive care admission, as well as an increased risk of reduced birth weight and stillbirth. These risks may be more pronounced in HbSS than in HbSC. Although even rarer, HbS beta-zero also behaves like HbSS.

Significant maternal SCD genotype

Discussions about pregnancy and conception care for women with SCD should take place between the health care provider and the patient. This should be part of a patient's comprehensive annual review and include fertility planning, which should begin in pediatrics services where appropriate. Reproductive options, partner screening, the optimization of health before conception, the use of preconception folic acid supplementation, and any potentially teratogenic medications should be discussed. Preconception clinics should be available and easily accessible, ensuring that vaccination regimes are up to date. 3  

Genetic screening

When a woman has SCD and the father of the baby is a carrier of the Hb beta chain variant, the risk of offspring having SCD is 50%; thus, women with SCD should receive counseling about their reproductive choices and the likelihood of having a child with SCD as well as the option of PGD. This is so important in the United Kingdom, where it is paid for, particularly for mothers without an unaffected offspring. Also, the choices regarding prenatal diagnosis and future noninvasive prenatal testing need to be discussed. 6 , 7  

To a large extent, most women are unaware of the possibility of PGD and hence do not have the opportunity to consider it. 8   For example, a review conducted in a London tertiary referral center showed that 60 at-risk couples over 5 years had 74 cycles of PGD, and the take-home baby rate was 63% per couple, a significant increase in the take-home baby rate compared to 5 years earlier. Therefore, the national guidelines recommend that as part of the annual review, all women with SCD should be encouraged to engage in preconception partner testing. 1  

Particularly relevant preconception investigations should incorporate renal function, echocardiography, and liver function, as well as medications and therapies. Blood pressure and urinary protein should be monitored in the form of albumin creatinine ratio or protein creatinine ratio. Abnormal renal and liver function should be investigated, excluding nonsickle causes. Hypertensive medications should be considered in women with blood pressure higher than 130/80  mm Hg, and appropriate antihypertensives should be prescribed based on the National Institute for Health and Care Excellence guidelines (eg, nifedipine, labetalol, or methyldopa). Pulmonary hypertension, ventricular ectopics, and early cardiac deaths are increased in SCD; hence, echocardiography is very pertinent in the preconception period. 8  

A raised tricuspid regurgitation velocity is associated with increased mortality. Hence, women planning a pregnancy should have echocardiography performed at least within a year of trying to conceive, and pregnancy is contraindicated in those with raised pulmonary hypertension or tricuspid regurgitation velocity. 1 , 9  

Other complications of SCD that merit screening and optimization before embarking on pregnancy are summarized in Table 2 . We recommend that a specialist review women before conception to optimize health and screening for disease complications and that preconception clinics are available and accessible. 3  

Preconception screening and optimization of complications in SCD

Preconception medication review

After a thorough review of medications prior to conception, folic acid supplementation should be 5 mg/d, as recommended, particularly if preparing for pregnancy, as this significantly improves or prevents neural tube defects. Vitamin D deficiency is common in pregnancy, and hence we suggest at least 400 IU/d and no more than 4000 IU/d. 10   Because of the hyposplenism associated with SCD, it is important to highlight vaccinations for meningococcal, pneumococcal, and Haemophilus influenzae , as well as penicillin prophylaxis to reduce the frequency of pneumonia and bacterial infections. 1 , 11  

The optimal analgesia during pregnancy should be discussed and the appropriate medications prescribed. Paracetamol and codeine-containing analgesics can be offered during pregnancy. If these are not ablating the pain, then nonsteroidal anti- inflammatory drugs in the form of ibuprofen can be used between 12 and 30 weeks but should be considered with caution before 12 weeks and avoided after 30 weeks. 12 .13 Opioid intake should be assessed, with referral to the chronic pain team if needed. 1 , 13 , 14   SCD pregnant patients are at risk of developing opioid related disorders, such as opioid type dependence, non-dependent opioid abuse, and accidental poisoning by opioids, four times more than their non-SCD counterparts. 15  

Medications that may be teratogenic, such as angiotensin-converting enzyme inhibitors and hydroxycarbamide, should be reviewed and discontinued prior to pregnancy, and this also goes for crizanlizumab. The teratogenic effects of these agents have been demonstrated in animal studies. It is crucial to advise that these medications be stopped since the evidence in human studies is negligible.

Iron chelators are often not recommended in pregnancy due to the lack of a safety profile, and they should be stopped. Iron overload should be appropriately assessed with liver and cardiac magnetic resonance imaging before conception to highlight those at high risk of iron-related complications. If there is evidence of iron overload, it should be treated before conception. Cardiac iron overload is unusual in SCD, but if present, it would be essential to regress the chelate before pregnancy. New medications such as voxelator, crizanlizumab, and glutamine are not approved in pregnancy and should be discontinued before conception. However, these medications may be approved at some point, and thus women may have been prescribed these from overseas. 1  

The recommendation is that folic acid be given before conception and throughout pregnancy. Women should also be given vitamin D as per national recommendations for all pregnant women. 16   Daily antibiotic prophylaxis is recommended for the prevention of pneumococcal pneumonia, 1 , 5 , 11   and vaccinations should be updated as per national recommendations for SCD. These should include the COVID-19 vaccine as well as the flu vaccination.

Antenatal care/antenatal hemoglobinopathy screening

Women whose partners are carriers or are affected by significant hemoglobinopathies must be aware of this and receive the appropriate counseling. In addition, partner status should be documented. The objective of the screening program is to ensure that screening tests for important prenatal diagnoses are offered between 8 and 10 weeks of pregnancy by the primary care or maternity services.

Prenatal diagnosis in the form of chorionic villus sampling or amniocentesis should be offered as early as possible in pregnancy to ensure early access to termination of an affected pregnancy if the woman chooses.

Prenatal diagnosis can be performed from 11 weeks, with the risk of miscarriage quoted to be approximately 1%. Current studies are ongoing with regard to utilizing free fetal DNA and next generation sequencing. 6  

All of the actions outlined in the preconception section should be followed for women who become pregnant without preconception care, including vaccination advice and the assessment of end-organ damage, red cell antibodies, iron status, and transfusion status.

The challenge in the antenatal period of SCD is the prevention of general and SCD-specific complications. 6 , 14 , 17-20   Preventing SCD-specific complications requires multidisciplinary care, with the involvement of obstetricians, midwives, and hematologists interested in SCD. Good communication is fundamental to patient safety, and hospital protocols for transfusion indications and the detection and management of SCD complications, including infection and acute pain, and the management of labor should be available.

At the antenatal appointments, information and education regarding acute pain episode prevention measures, such as the avoidance of infection, the need to rest, and the need to stay well hydrated, are crucial. In addition, women's housing and work circumstances should be reviewed and appropriate interventions made to reduce the potential of triggering an acute pain episode.

Medication compliance, as well as ensuring patients have the appropriate medications, is pertinent. Early pregnancy assessment for hyperemesis and instruction about the importance of proper hydration may prevent sickle cell acute pain episodes and avoid hospital admission. Low-dose aspirin should be taken at 150  mg/d, from 12 weeks onward until 36 weeks, to prevent preeclampsia and hypertension in pregnancy. 1 , 21   The available evidence suggests that low-dose aspirin reduces the incidence of preeclampsia by 50% to 80%. 9   Identifying high blood pressure and proteinuria allows for timely intervention to save lives. The need for thromboprophylaxis to start at 28 weeks and continue for 6 weeks postnatally for those whose risk factor is only SCD and at booking for those with additional risk factors is very important. 1  

Serial growth scans every 4 weeks are recommended, and those with extremely low levels of pregnancy-associated plasma protein (under 0.5) will require 2 weekly scans from 20 weeks onward, as the risks in those with low pregnancy- associated plasma protein are even more heightened, especially for those with SCD. 1-3 , 21  

Blood transfusion during pregnancy

Transfusions are needed to correct severe anemia, reduce sickle cell complications, reduce the extent of sickling, and maintain oxygen supply to the fetus. 22 , 23   However, this must be weighed against the side effects of transfusion, including the risk of alloimmunization and delayed hemolytic reaction.

The type of blood selected for the transfusion of women with SCD should be cytomegalovirus negative, HbS negative, and a standard Rh cell matched line as per previous British Society of Haematology recommendations. In addition, a full transfusion history should be taken prior to transfusion and communicated with the transfusion laboratory and the national transfusion database to ensure no historical autoantibodies are present. 22  

Patients with antibodies need to be referred for fetal red cell antibody titers to prevent hemolytic disease in the newborn. There is a fundamental question about whether to offer exchange blood transfusions prophylactically throughout pregnancy, but there is currently insufficient evidence to recommend serial prophylactic exchange blood transfusions. 22  

A phase 2 clinical trial is currently ongoing ( ClinicalTrials.gov Identifier: NCT03975894), and so far, 34 patients have been recruited out of the 40 women needed for the feasibility study. The transfusions commence between 6 and 18 weeks 0 days' gestation. The transfusions commence between 6 and 18 weeks of gestation and are repeated every 6 to 10 weeks until the end of pregnancy, aiming to maintain HbS% or combined HbS/HbC% below 30%. They are continued throughout pregnancy and are to be stopped at the end of pregnancy. 24   A previous randomized controlled trial over 20 years ago showed a significant reduction in vaso-occlusive crises in the prophylactic transfusion arm. There was no clear difference in other outcomes, but the small numbers may explain this. The Cochrane Review concluded that there were no clear clinical benefits of prophylactic exchange blood transfusions over standard care and that appropriate randomized controlled trials are needed. 22 , 24  

A recent systematic review by Malinowski et al demonstrated that prophylactic transfusion was associated with a reduction in maternal mortality, vaso-occlusive crises, pulmonary complications, pyelonephritis, perinatal mortality, neonatal death, and preterm birth. 25  

There was no difference in rates of pulmonary infection, acute chest syndrome, or preeclampsia, and they concluded that prophylactic transfusion might have a positive impact on severe maternal and neonatal outcomes. Still, the evidence comes from a very small sample size, and a further randomized controlled trial is needed. Clearly, the risks and benefits of prophylactic transfusion should be discussed with patients, hematologists, and obstetricians in early pregnancy. Factors to consider would include genotype, phenotype, previous obstetric history before pregnancy, and alloimmunization. 22  

We recommend that women who are already on long-term serial exchange transfusion continue it during pregnancy. Those on hydroxycarbamide (hydroxyurea) should be advised to stop and be considered for prophylactic transfusion if they experience worsening sickle symptoms afterward.

A recent study demonstrated that the use of hydroxyurea up to the time of conception does not seem to have an adverse effect on the fetus and may be considered safe. Women who continue taking hydroxyurea during pregnancy may be at an increased risk of fetal demise or their fetus being small for gestational age. There was no increase in birth defects when hydroxyurea was used during pregnancy. 26  

A recent report from the Boston Birth Cohort showed that children exposed to maternal SCD are at risk of attention deficit hyperactivity disorder, even though the authors stated that more studies are needed to confirm these results. In addition, maternal anemia and opioid use constitute risks, and regular red cell transfusions can be used to prevent fetal exposure to maternal anemia as well as reduce pain and limit opioid use. 27  

The standard of care is to give a transfusion only if the patient is symptomatic. There is no evidence of optimal Hb levels or HbS percentages before delivery by cesarean.

Pain management

All pregnant women with SCD should have a prospective pain management plan that has been developed and discussed with the multidisciplinary team. 6   There should be a low threshold to refer the woman to a tertiary unit or secondary care, particularly if simple analgesics in the form of paracetamol and dihydrocodeine are not working, and women who are febrile should be referred to secondary or tertiary care in a timely fashion. When admitted to the hospital with pain after trying dihydrocodeine or paracetamol, they may require admission, and either the oral, subcutaneous, or intravenous forms of morphine or diamorphine can be considered, depending on the woman's preference and the local expertise. Pethidine should be avoided because of the risk of associated seizures or toxicity. 1  

Women with an acute pain episode at presentation should be assessed rapidly, and any precipitating factors should be treated quickly. A complete set of observations using the modified obstetric early warning chart, including systolic and diastolic blood pressure, respiratory rate, temperature, oxygen saturation, and pain score, should be documented and repeated every 1 to 2 hours.

Women should be cared for in units with experience in SCD and high-risk pregnancy. Senior obstetricians, hematologists, obstetric anesthetists, obstetric physicians, specialist nurses, and midwives should meet as a multidisciplinary team. Care should be considered and planned by the group and discussed with the woman and her family.

Fluid balance and fluid status should be carefully documented, and dehydration should be simultaneously avoided, ensuring fluid overload. The oxygen saturation should be above 94%. When it is below 94%, blood gasses should be performed, and acute chest syndrome, pulmonary hypertension, and pulmonary embolus should be excluded. 1  

Suppose the oxygen saturation is not recovering with facial oxygen? In that case there should be early recourse to transfer to intensive care if satisfactory oxygen saturation cannot be maintained using a face mask or nasal cannula. The woman should be assessed for infection, including urine culture and microscopy. A chest x-ray should be indicated if the woman has abnormalities on the chest examination or significant hypoxia.

Antibiotics should be prescribed appropriately. 1   In addition, thromboprophylaxis should be prescribed for women with SCD, as alluded to above.

National Institute for Health and Care Excellence guidelines on the management of acute painful episodes should be followed. Nonsteroidal anti-inflammatory drugs may be used cautiously in the first trimester and avoided after 30 weeks' gestation. Between 12 and 30 weeks, it is appropriate to use a nonsteroidal. 13  

Management of acute chest syndrome.

Acute chest syndrome is a significant complication of SCD characterized by fever and/or respiratory symptoms and new pulmonary infiltrate shown on chest x-ray. Patients should be observed closely. Essential investigations for diagnosis and prognosis should ensure a timely chest x-ray and full blood count, as well as arterial blood gas analysis. Low oxygen saturation or severe hypoxia mandate a timely transfer to the intensive care unit, as this may save lives. A differential diagnosis in the form of pulmonary embolus and severe pneumonia and in this current environment, COVID-19 pneumonitis, should be excluded by chest computed tomography. 20 , 28-30   Prompt pain relief and treatment of bacterial and viral infections save lives. Assessment for either exchange blood transfusion or top-up transfusion may improve the acute situation. Involving the critical care team early when a diagnosis of acute chest syndrome is made avoids deterioration of the patient, as the timely use of noninvasive or invasive ventilation with transfusion may be protective for the patient.

The management of both thrombotic and hemorrhagic stroke could be necessary in SCD in pregnancy, and timely diagnosis saves lives. 1 , 14 , 17-19   Patients who present with acute neurological impairment or the suspicion of acute stroke require urgent brain imaging, with a referral to a stroke unit, a neurologist, and a hematologist. Rapid exchange blood transfusion can decrease long-term neurological damage, and the role of thrombolysis should be discussed with a specialist neurologist and the obstetrician. 17  

Acute anemia with SCD may be attributable to parvovirus B19, and a rapid top-up transfusion significantly saves lives. However, all causes of anemia should be appropriately investigated because they sometimes may not be SCD related but are due to bleeding, be it antenatally, intrapartum, or postnatally. Sometimes, either obstetric related or indeed in countries where malaria is endemic, they could also be due to malaria. 1 , 18  

Intrapartum care

With increased perinatal mortality, particularly during the latter stages of pregnancy in patients with SCD and given the risk of abruption and unexplained stillbirth due to placental abnormalities, we recommend the need to offer induction of labor between 38 and 40 weeks. Thus, appropriate delivery planning, including the time, mode, and place of delivery with multidisciplinary input, could make a difference in improving outcomes. The mode of delivery depends on obstetric complications; otherwise, supporting a vaginal delivery or cesarean incorporating the patient's choice is very pertinent. 1 , 14 , 18  

Optimal intrapartum care in the form of good analgesia, the avoidance of dehydration, regular monitoring of oxygen saturation, and the avoidance of protracted labor is recommended. An antenatal review by the anesthetist to provide the appropriate planning to avoid a general anesthetic is pertinent to the care of patients with SCD. In addition, continuous electronic fetal monitoring is needed, given the increased risk of unexplained stillbirth or adverse perinatal outcomes. Epidural analgesia is safe and effective and should be available for women with SCD.

Postpartum care

It is important for clinicians to remain vigilant because the risk of a sickle cell acute pain episode increases during this time, with almost 25% of women having an acute pain episode post delivery. 1 , 14   Ensuring hydration and oxygenation with early mobilization helps minimize acute pain episodes and complications. The use of nonsteroidal anti-inflammatory drugs, as well as paracetamol and codeine sulfate, can be used. Infants should be monitored for sedation, breathing difficulties, and weight gain. Breastfeeding should be encouraged. Antithrombotic stockings should be provided and low-molecular-weight heparin should be administered in women with SCD post delivery. 1 , 14  

Contraceptive advice should be given after delivery, but while breastfeeding, estrogen-based contraceptives are contraindicated. Otherwise, all forms of contraceptives are advisable. If oral, a progesterone-only pill such as Cerazette or injectable forms such as Depo-Provera or implants and intrauterine devices can be considered. Using copper devices may increase the risk of infection; thus, using prophylactic antibiotics around the time of insertion is very important. 1  

In conclusion, most women with SCD in developed countries have pregnancies with good maternal and infant outcomes. Patients who have reached reproductive age require preconception and pregnancy advice and a discussion about reproductive options. It is essential to be aware that pregnancy and delivery provide an added risk for the woman and the fetus; thus, the need for protocolized management plan from each unit incorporating the multidisciplinary team's advice is vital.

The multidisciplinary team should include an obstetrician with expertise in the management of high-risk pregnancies, a team of midwives, and a hematologist. If in an area of low SCD prevalence, a link to a specialist center or hemoglobinopathy coordinating center is pertinent. 1 , 14 , 18 , 19   It is essential to highlight the need for well-designed clinical trials in this area to ascertain optimal pregnancy treatment options ( Table 3 ).

Research agenda

Eugene Oteng-Ntim: no competing financial interests to declare.

Panicos Shangaris: no competing financial interests to declare.

Eugene Oteng-Ntim: nothing to disclose.

Panicos Shangaris: nothing to disclose.

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Harris KM , Preiss L , Varughese T, et al. Examining Mental Health, Education, Employment, and Pain in Sickle Cell Disease. JAMA Netw Open. 2023;6(5):e2314070. doi:10.1001/jamanetworkopen.2023.14070

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Examining Mental Health, Education, Employment, and Pain in Sickle Cell Disease

• 1 Program in Occupational Therapy, Washington University in St Louis School of Medicine, St Louis, Missouri
• 2 Department of Surgery, Division of Public Health Sciences, Washington University in St Louis School of Medicine, St Louis, Missouri
• 3 RTI International, Research Triangle Park, North Carolina
• 4 School of Medicine, University of Missouri at Columbia, Columbia
• 5 Department of Pediatrics, Pediatric Hematology/Oncology, and Cancer Center, Hematology Program, Yale University School of Medicine, New Haven, Connecticut
• 6 School of Medicine, Department of Pediatrics, Division of Hematology, University of California, San Francisco
• 7 School of Nursing, Duke University, Durham, North Carolina
• 8 Department of Hematology, St Jude Children’s Research Hospital, Memphis, Tennessee
• 9 Department of Medicine, Division of Hematology and Oncology, College of Medicine, University of Illinois at Chicago, Chicago
• 10 Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York
• 11 College of Medicine, Department of Public Health Sciences, Medical University of South Carolina, Charleston
• 12 Department of Emergency Medicine, Augusta University, Medical College of Georgia, Augusta
• 13 Department of Pediatrics, Division of Pediatric Hematology/Oncology, St Louis Children’s Hospital, Washington University in St Louis, School of Medicine, St Louis, Missouri

Question   What is the association of educational attainment, employment status, and mental health with pain episode frequency and severity among individuals with sickle cell disease (SCD)?

Findings   In this cross-sectional analysis of 2264 individuals with SCD, 47.8% reported frequent pain (ie, ≥ 4 pain crises in 12 months). Although educational attainment and income were not significantly associated with increased pain episode frequency or severity, age, sex, and depression were associated with SCD-related pain.

Meaning   Pain is complex, and these findings suggest that screening patients with SCD for depression and other mental health challenges is warranted, especially among those experiencing higher pain episode frequency and severity.

Importance   Pain related to sickle cell disease (SCD) is complex and associated with social determinants of health. Emotional and stress-related effects of SCD impact daily quality of life and the frequency and severity of pain.

Objective   To explore the association of educational attainment, employment status, and mental health with pain episode frequency and severity among individuals with SCD.

Design, Setting, and Participants   This is a cross-sectional analysis of patient registry data collected at baseline (2017-2018) from patients treated at 8 sites of the US Sickle Cell Disease Implementation Consortium. Data analysis was performed from September 2020 to March 2022.

Main Outcomes and Measures   Electronic medical record abstraction and a participant survey provided demographic data, mental health diagnosis, and Adult Sickle Cell Quality of Life Measurement Information System pain scores. Multivariable regression was used to examine the associations of education, employment, and mental health with the main outcomes (pain frequency and pain severity).

Results   The study enrolled a total of 2264 participants aged 15 to 45 years (mean [SD] age, 27.9 [7.9] years; 1272 female participants [56.2%]) with SCD. Nearly one-half of the participant sample reported taking daily pain medication (1057 participants [47.0%]) and/or hydroxyurea use (1091 participants [49.2%]), 627 participants (28.0%) received regular blood transfusion, 457 (20.0%) had a depression diagnosis confirmed by medical record abstraction, 1789 (79.8%) reported severe pain (rated most recent pain crises as ≥7 out of 10), and 1078 (47.8%) reported more than 4 pain episodes in the prior 12 months. The mean (SD) pain frequency and severity t scores for the sample were 48.6 (11.4) and 50.3 (10.1), respectively. Educational attainment and income were not associated with increased pain frequency or severity. Unemployment (β, 2.13; 95% CI, 0.99 to 3.23; P  < .001) and female sex (β, 1.78; 95% CI, 0.80 to 2.76; P  < .001) were associated with increased pain frequency. Age younger than 18 years was inversely associated with pain frequency (β, −5.72; 95% CI, −7.72 to −3.72; P  < .001) and pain severity (β, 5.10; 95% CI, −6.70 to −3.51; P  < .001). Depression was associated with increased pain frequency (β, 2.18; 95% CI, 1.04 to 3.31; P  < .001) but not pain severity. Hydroxyurea use was associated with increased pain severity (β, 1.36; 95% CI, 0.47 to 2.24; P  = .003), and daily use of pain medication was associated with both increased pain frequency (β, 6.29; 95% CI, 5.28 to 7.31; P  < .001) and pain severity (β, 2.87; 95% CI, 1.95 to 3.80; P  < .001).

Conclusions and Relevance   These findings suggest that employment status, sex, age, and depression are associated with pain frequency among patients with SCD. Depression screening for these patients is warranted, especially among those experiencing higher pain frequency and severity. Comprehensive treatment and pain reduction must consider the full experiences of patients with SCD, including impacts on mental health.

Sickle cell disease (SCD) is a chronic hemolytic anemia that causes organ damage and disproportionately affects individuals of African descent. 1 Frequent acute vaso-occlusive crises (VOCs) result in chronic inflammation and can lead to acute chest syndrome, severe anemia, and end-organ damage. 2 - 4 Chronic organ dysfunction is often progressive and experienced by most individuals with SCD at some point throughout the life course. 5 - 8 Complications of SCD can affect educational outcomes and life opportunity for those affected. Cognitive deficits are common and lead to youth with SCD having a lower and often declining intelligence quotient. 9 , 10 Lower academic performance, lower test scores, and grade failure are also associated with cognitive deficits. 11 , 12 Poor educational outcomes increase students’ risk of dropping out of high school, which, in turn, leads to lower earning potential in adulthood, higher unemployment and incarceration rates, higher poverty, and, ultimately, early death. 13 - 16

Although individuals with SCD experience a variety of complications, pain is a hallmark of the disease and often leads to increased health care utilization and hospitalizations, impacting overall quality of life (QoL). 2 Pain is complex and does not exist in isolation. SCD-related complications and hospitalizations are associated with social determinants of health, such as socioeconomic status, depression, health literacy, and educational outcomes. 17 - 20 Pain level, frequency, and effect on overall QoL can be impacted by both family-level and neighborhood-level socioeconomic status. 17 The chronic yet unpredictable nature of the pain and other adverse effects of SCD often leads to increased individual and family stress. These emotional and stress-related effects of the disease may impact daily QoL and frequency and severity of pain. 21 Mental health is related to opioid use for SCD-related pain and can be seen in stress and negative coping behaviors experienced by individuals with SCD. 22 Rates of depression among individuals with SCD are approximately 3 times higher than those among the general population (26.0% vs 9.5%), 23 , 24 with depressive symptoms impacting pain frequency, health care utilization, health care–related QoL (HRQoL) and stigma (both depression-related and SCD-related stigma). Individuals with SCD, especially young adults, experience greater risk for health-related stigma. 25 , 26 Stigma (both perceived and internalized) is associated with disease-related complications of SCD, including pain and health care utilization (ie, frequent emergency department visits and hospitalizations). Specifically, stigma is associated with higher patient-reported disease severity and pain, higher health care utilization, lower QoL, loneliness, and less pain reduction as a result of hospital treatment. 27 , 28 SCD-related stigma also has social consequences, including impacts on psychological well-being (including anxiety and depression) or exacerbated pain (perhaps as a result of poor management), and can create challenges in patient-physician relationships. 26

The pathways through which SCD affects opportunity and life outcomes are relatively clear, but the impact that these outcomes in turn have on SCD symptoms and symptom severity is less defined. Although studies 17 , 18 have found that hospital admission frequency may have a limited impact on academic outcomes in youth with SCD, we do know that pain is a factor associated with hospitalizations, stress, and social impacts. Few studies have explicitly examined the associations of SCD-related pain with educational, socioeconomic, and mental health outcomes. To our knowledge, no definitive models exists to clearly define these associations. This study fills this gap because our primary objective was to explore the associations of educational attainment, employment status, and mental health with pain episode frequency and severity in individuals with SCD.

The Sickle Cell Disease Implementation Consortium (SCDIC) is a National Heart, Lung, and Blood Institute–funded 6-year, 2-phase, multisite, implementation science research study that includes a needs assessment, interventions, and the development of a longitudinal registry of patients with SCD. 29 Participants for this cross-sectional study were recruited from the 8 clinical centers of the SCDIC: University of Illinois at Chicago (Chicago, Illinois), Duke University (Durham, North Carolina), Washington University School of Medicine (St Louis, Missouri), Mount Sinai School of Medicine (New York, New York), St Jude Children’s Research Hospital (Memphis, Tennessee), Augusta University (Augusta, Georgia), Medical University of South Carolina (Charleston, South Carolina), and UCSF Children’s Hospital Oakland (Oakland, California). 29 These 8 clinical centers provide services to many of their region’s patients with SCD including those in both urban and rural areas. Participant data from the SCDIC longitudinal registry from all 8 consortium sites were included in the analysis. Registry data included information tracked through the electronic medical record, as well as surveys completed by participants at their medical visit examining the physical, social, and emotional impact SCD has on patients. 30 Data included in this sample were collected at baseline, from 2017 to 2018. Each participating center obtained institutional review board approval for all study activities and data collection. Informed consent was obtained through signed consent forms. This report follows Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guidelines for observational studies.

Measures included in the participant survey include the Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me), a tool examining HRQoL specifically for patients with SCD. 21 , 31 - 33 The ASCQ-Me measures HRQoL in 7 different areas: emotional impact, pain impact, sleep impact, social functioning impact, stiffness impact, pain episodes, and a SCD medical history checklist. 21 , 32 Each area is assessed using a 5-item questionnaire, with the exception of the SCD medical history checklist, which uses a 9-item questionnaire. The 5 items examining pain episodes can be used to measure pain episode frequency and severity. 33 Responses to the first 2 questions, “In the past 12 months how many sickle cell pain attack (crises) did you have?” and “When was your last pain attack (crisis)?” were used to create a composite pain episode frequency score. The following 3 questions—“Using any number from 0-10, where 0 is no pain and 10 is the worst imaginable pain, how severe was your pain during your last pain attack (crisis)?” “How much did your last pain attack (crisis) interfere with your life?” and “About how long did your most recent pain attack (crisis) last?”—were used to create a composite pain episode severity score. Scores from these questions yield a raw score between 0 and 11 for pain episode frequency and 0 and 22 for pain episode severity, which can then be converted to standardized t scores for use in the analysis. The t scores have a mean of 50 and SD of 10. In the pain episode domain, lower t scores indicate lower pain frequency and severity.

Participants provided demographic information, including self-identifying race and sex. Information on race is included as a demographic characteristic but was not included in the analysis. In addition to demographic and disease characteristics (ie, educational and employment characteristics and SCD genotype), the survey examined patient experiences, disease management, and QoL. 30 Educational attainment response options included less than high school, some high school, high school graduate or general educational development (GED), some college, college graduate, some graduate school, and graduate or professional degree. For the purposes of analysis, high school graduate or GED and some college were combined to create high school graduate, GED, and some college; and some graduate school and graduate or professional degree were combined to create graduate school. Employment status response were categorized as employed, unemployed, or not employed by choice. Medical record abstraction (MRA) was used to identify and merge relevant data elements for participants, including medical diagnoses of anxiety and depression. 30 Both the MRA data element for diagnosis of depression and patient self-report of current or prior treatment for depression were examined for this analysis. Given similarities in the findings across measures of depression, results of analyses examining self-reported treatment for depression are reported here. It is important to note that while engaged in the study, some community participants had not been seen by a SCD physician as an outpatient in more than 2 years. These participants were unaffiliated with the local site and, thus, did not have MRA data available for inclusion in the analysis.

Data analysis was performed from September 2020 to March 2022. Descriptive statistics, including means, SDs, and ranges for continuous variables and frequencies for categorical variables, were used to describe the study sample, patient characteristics, experiences, and HRQoL. Multivariable regression analysis was used to examine the associations of educational attainment, employment status, and mental health with the frequency and severity of pain episodes for individuals with SCD, and to test the hypothesis that, after controlling for age, sex, and treatment (hydroxyurea and pain medication use), individuals with a history of anxiety or depression, lower educational attainment, and periods of unemployment experience more frequent and severe pain crises. In addition to continuous composite measures of pain episode frequency and severity from the ASCQ-Me, separate analyses examining dichotomous variables for pain episode frequency and severity were examined. In the absence of documented guidelines or consistent definitions for more or less severe or frequent pain in SCD, this study used methods previously used by Rizio et al 34 to determine more severe and less severe pain or frequent pain episodes. Participants were stratified into 2 groups on the basis of pain frequency and severity scores on the ASCQ-Me measures: those with 3 or fewer pain episodes in the prior 12 months (compared with those with 4 or more pain episodes) and those with pain severity scores at least one-half SD above the mean. Multivariable logistic regression was used to examine associations of these categorical variables with educational attainment, employment status, mental health. To ensure best model fit, backward elimination (significance was set at 2-tailed P  < .05) was used for all regression analyses. All analyses were conducted using SAS software version 9.4 (SAS Institute).

A total of 2264 participants from all 8 consortium sites were included in this analysis ( Table 1 ). The mean (SD) participant age was 27.9 (7.9) years (range, 15-45 years); however, nearly 70% of the sample (1541 participants) were aged 18 to 34 years, and less than 10% (209 participants) were younger than 18 years. More than one-half of the sample identified as female (1272 participants [56.2%]), 43.8% (992 participants) identified as male, and 95.5% (2112 participants) identified as Black. Seventy-two percent (1633 participants) had a diagnosis of sickle cell anemia (SCA) which includes the 2 most severe genotypes of SCD (1545 patients [68.3%] with hemoglobin [Hb] SS, the most severe form of SCD, and 88 patients [3.9%] with HbSβ 0 thalassemia). More than one-half of the participants (1733 participants [78.0%]) reported their highest level of education as a high school diploma or lower. Most were unemployed (1408 participants [63.9%]), although 513 (23.3%) of those who were not employed reported being not employed by choice, and 1083 participants (54.0%) reported an average annual household income less than $25 000.

Nearly one-half of all patients (1057 participants [47.0%]) reported taking pain medication every day for SCD-related pain, and most were taking some form of disease-modifying therapy (hydroxyurea, 1091 participants [49.2%]; regular blood transfusion, 627 participants [28.0%]). One-third of all participants either self-reported or had medical record reports of current or prior treatment for depression (723 participants [33.0%]), and 13.7% had a diagnosis of anxiety noted in their medical record (309 participants). Cross-tabulations examining self-reports of depression (537 participants) and diagnosis of depression in the medical record (457 participants) suggest that one-half of those self-reporting treatment for depression had a diagnosis of depression in the medical record (271 participants [50.5%]), and more than one-half of those with a diagnosis of depression in the medical record also self-reported treatment for depression (271 participants [59.3%]). Mean (SD) pain frequency and severity t scores were 48.6 (11.4) and 50.3 (10.1), respectively. A majority of participants (1789 participants [79.8%]) rated their pain as a 7 or higher on a scale of 1 to 10, and nearly one-half of the sample reported more than 4 pain episodes in the prior 12 months (1078 participants [47.8%]) and pain episodes lasting 4 or more days (1114 participants [49.7%]).

Regression results for pain episode frequency can be found in Table 2 . The β values indicating the degree of change in the outcome variable are provided, along with 95% CIs and P values. In the full model, educational attainment and income were not significantly associated with increased pain episode frequency; however, employment status as unemployed was associated with increased pain episode frequency (β, 2.13; 95% CI, 0.99 to 3.26; P  < .001). Individuals in the sample who were unemployed had pain episode frequency scores that were, on average, 2.13 points higher than those for employed individuals. Female sex was associated with increased pain episode frequency (β, 1.78; 95% CI, 0.8 to 2.76; P  < .001), as was age, with all age groups showing lower means than the reference group of 25 to 34 years (age <18 years, β, −5.72; 95% CI, −7.72 to −3.72; P  < .001; age 18-24 years, β, −1.76; 95% CI, −2.99 to −0.52; P  = .005; age ≥35 years, β, −2.46; 95% CI, −3.71 to −1.21; P  < .001). Female participants had pain frequency scores, on average, 1.78 points higher than those for male participants, whereas individuals younger than 18 years, those aged 18 to 24 years, and those aged 35 years and older had lower pain frequency scores than those aged 24 to 35. Controlling for age and sex, self-report of current or prior treatment for depression was associated with increased pain episode frequency (β, 2.18; 95% CI, 1.04 to 3.31; P  < .001), as was hydroxyurea use (β, 1.15; 95% CI, 0.19 to 2.12; P  = .02) and daily use of pain medication (β, 6.29; 95% CI, 5.28 to 7.31; P  < .001). Among those who reported current or prior treatment for depression, those who also reported hydroxyurea use (mean [SE], 1.15 [0.49] points) and daily use of pain medication (mean [SE], 6.29 [0.52] points) had higher pain frequency scores than those who did not report such use. Regression models examining medical record–confirmed diagnosis of depression yielded consistent results for pain frequency ( Table 3 ).

Like pain episode frequency, educational attainment and income were not significantly associated with increased pain episode severity ( Table 2 ). Employment status, however, was associated with pain episode severity for individuals who were unemployed (β, 1.07; 95% CI, 0.03 to 2.11; P  = .04). Individuals in the sample who were unemployed had pain episode severity scores that were, on average, 1.07 points higher than those for individuals who were employed. Age was inversely associated with pain severity for individuals younger than 18 years (β, −5.10; 95% CI, −6.70 to −3.51; P  < .001) and aged 18 to 24 years (β, −1.11; 95% CI, −2.20 to −0.02; P  = .04). Individuals younger than 18 years and aged 18 to 24 years had lower pain severity scores (by 5.1 points and 1.11 points, respectively) than individuals aged 24 to 35 years. Female sex was associated with pain severity (β, 2.13; 95% CI, 1.24 to 3.02; P  < .001). Female participants had pain severity scores, on average, 1.78 points higher than those for male participants. Although depression was not retained in the full models for pain severity, hydroxyurea use (β, 1.36; 95% CI, 0.47 to 2.24; P  = .003) and daily use of pain medication (β, 2.87; 95% CI, 1.95 to 3.80; P  < .001) remained associated with increased pain episode severity. Those reporting hydroxyurea use and daily use of pain medication also had higher pain severity scores (mean [SE], 1.36 [0.45] and 2.87 [0.47] points, respectively) than those not reporting such use. Depression was also dropped from final regression models examining medical record–confirmed diagnosis of depression, yielding consistent results.

Logistic regression results examining more frequent pain (≥4 VOCs in 12 months) revealed that age younger than 18 years (odds ratio [OR], 0.50; 95% CI, 0.33-0.76; P  = .001) and older than 35 years (OR, 0.65; 95% CI, 0.51-0.84; P  = .001) remained inversely associated with pain frequency, and female sex was associated with more frequent pain (OR, 1.26; 95% CI, 1.03-1.54; P  = .02). Participants younger than 18 years and older than 35 years were less likely than individuals aged 18 to 35 years to have more than 4 VOCs in 12 months (50% and 65%, respectively), and female participants were just over 25% more likely than male participants to have more than 4 VOCs in 12 months. Controlling for age and sex, employment status as unemployed (OR, 1.66; 95% CI, 1.32-2.08; P  < .001) and self-reported treatment for depression (OR, 1.55; 95% CI, 1.23-1.95; P  < .001) were both associated with more frequent pain. Participants who were unemployed or who self-reported treatment for depression were more than 1.5 times more likely than participants who were employed or did not report depression to have more frequent pain (>4 VOCs in 12 months). Individuals taking daily pain medication were 2.56 times more likely than those not taking pain medication to experience more frequent pain (OR, 2.56; 95% CI, 2.10-3.14; P  < .001). Similarly, age younger than 18 years (OR, 0.56; 95% CI, 0.35-0.86; P  = .008) and lower annual household income ($25 000-$50 000, OR, 0.73; 95% CI, 0.57-0.95; P  = .02) were inversely associated with more severe pain, and female sex (OR, 1.44; 95% CI, 1.18-1.76; P  < .001) and employment status as unemployed (OR, 1.40; 95% CI, 1.11-1.78; P  = .005) were both associated with more severe pain ( Table 4 ). Younger participants (aged <18 years) and those with lower household incomes ($25 000-$50 000 annually) were less likely than older participants and those with higher incomes to have more severe pain, and female and unemployed participants were 1.5 times more likely than male and employed participants to have more severe pain.

The overall findings of this cross-sectional study suggest that, in terms of education and employment, SCD-related pain does not discriminate. It does not matter how educated one is, and neither educational attainment nor income was associated with pain episode frequency or severity. Age and sex were, however, associated with both pain episode frequency and severity, with adolescents and young adults experiencing both less frequent and less severe pain episodes compared with older adults and female participants experiencing more frequent and severe pain episodes compared with male participants. Regardless of indicator (self-report or medical record), depression was significantly associated with pain episode frequency but not pain severity. This finding is particularly important considering the disproportionate impact SCD has on individuals of African descent, the stigma Black youth with SCD encounter when they seek care for VOCs, and the current climate and limitations to treatment for pain. 26 When stratifying participants with more frequent and more severe pain, regressions yielded consistent results with 2 key differences: employment status as unemployed was associated with both more frequent and more severe pain, and annual household income greater than $25 000 but less than $50 000 was inversely associated with more severe pain.

These findings are consistent with other research 35 , 36 in this area demonstrating that intensity of pain and emotion-focused coping were associated with a reduced QoL for youth participants, and that negative feelings including stress were associated with experiences of pain crises among participants. A prior interview study 37 among youth with SCD and their caregivers examining the impact of life-limiting conditions such as SCD found that pain was described as multidimensional, affecting many facets of participants life, including their psychosocial well-being. Prior studies 36 , 37 also found that fear of death and stigma were particularly palpable for youth and young adult participants, particularly during periods of intense pain. Future research to build on this body of work, including continued data collection with a focus on depression symptoms, diagnosis, and treatment, as well as additional analyses examining causation, is warranted.

This study has limitations that should be addressed. Although we cannot make statements of causality given the cross-sectional design of this study, the findings do highlight a consistent association between depression and pain for patients with SCD. This association remains for both patient-reported depression and diagnoses of depression documented in the medical record. Although patient reports of depression are not the best measure, the medical record alone is insufficient. The inconsistencies revealed in these measures suggest that the medical record underreports depression among individuals with SCD. The absence of MRA for unaffiliated or community participants may further suppress the reported prevalence of depression among this population. Taken together, this indicates that our overall understanding, diagnosis, and documentation of depression and treatment for depression are suboptimal. 38

The findings of this cross-sectional study suggest that pain interventions cannot ignore screening for depression and other mental health challenges among patients with SCD. Without proper screening and assessments for depression, we might overestimate other factors and overlook key factors or outcomes in this population. Further investigation is needed to both understand depression among this population and its association with SCD-related pain. Better screening for depression and the development of interventions are critical. Pain is complex. We cannot treat SCD-related pain with medications only; rather, we must begin to consider and incorporate holistic or comprehensive approaches to reducing pain. To do so, we must consider the full experiences of patients with SCD.

Accepted for Publication: March 21, 2023.

Published: May 18, 2023. doi:10.1001/jamanetworkopen.2023.14070

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2023 Harris KM et al. JAMA Network Open .

Corresponding Author: Kelly M. Harris, PhD, CCC-SLP, Program in Occupational Therapy, Washington University in St Louis School of Medicine, 660 S Euclid Ave, MSC 8505-45-1, St Louis, MO 63110 ( [email protected] ).

Author Contributions: Ms Preiss had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Harris, Treadwell, Glassberg, Melvin, King.

Acquisition, analysis, or interpretation of data: Harris, Preiss, Varughese, Bauer, Calhoun, Treadwell, Masese, Hankins, Hussain, Glassberg, Gibson, King.

Drafting of the manuscript: Harris.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Preiss.

Obtained funding: Treadwell, Hankins, Glassberg, Melvin, Gibson, King.

Administrative, technical, or material support: Harris, Bauer, Calhoun, Masese, Melvin, King.

Supervision: Harris, Glassberg, King.

Conflict of Interest Disclosures: Dr Treadwell reported receiving grants from National Heart, Lung, and Blood Institute (NHLBI) during the conduct of the study and personal fees from Global Blood Therapeutics and Wolters Kluwer Health outside the submitted work. Dr Hankins reported receiving grants from NHLBI, Centers for Disease Control and Prevention, and Health Resources and Services Administration during the conduct of the study and personal fees from GBT and Forma Therapeutics outside the submitted work. Dr Glassberg reported receiving grants from National Institutes of Health (NIH) during the conduct of the study and personal fees from GBT, CSL Behring, Novartis, Sanius Health, and Roche outside the submitted work. Dr Melvin reported receiving grants from NIH/NHLBI outside the submitted work. Dr Gibson reported receiving grants from NIH during the conduct of the study. Dr King reported receiving grant K24 HL148305 from NHLBI outside the submitted work. No other disclosures were reported.

Funding/Support: Funding supporting study design and conduct, data collection and management, and data analysis and interpretation was provided by NIH/NHLBI grant 5U01HL133994-03S1 (to Dr King, Principal Investigator) and US federal government cooperative agreements HL133948, HL133964, HL133990, HL133996, HL133994, HL133997, HL134004, HL134007, and HL134042 from the NHLBI and the National Institute on Minority Health and Health Disparities.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See the Supplement .

Additional Contributions: We thank and acknowledge the study participants. RTI International and the Sickle Cell Disease Implementation Consortium assisted with study coordination, data collection, and management. Seth Howdeshell, MD, MPHS (University of Iowa), performed data management and was not compensated for this work. We thank Regina Abel, PhD (deceased), who assisted with study conceptualization, data collection, and analysis.

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Sickle Cell Disease: Case Study with Clinico-Pathological Aspect

G. K. Sawke¹ and C. B. S. Dangi²

¹Department of Pathology, People’s College of Medical Sciences and Research Centre, Bhopal India.

²Human Genetic Lab. CSRD, People’s Group, Bhanpur Road, Bhopal India.

Corresponding Author E-mail: [email protected]

Sickle cell disease is an autosomal recessive inherited disorder of red blood cells. It has also been called a ‘molecular’ disease because it results from the mutation of one aminoacid in haemoglobin molecule. This article reports a case of homozygous sickle cell disease in an adolescent patients with complications. It also advocates for further study on various clinicopathological aspects of the disease and urge for alertness on the part of health care professionals regarding a holistic approach to the management.

Sickle cell disease(SCD); Autosomal; Haemoglobin.  

Introduction

Sickle cell disease (SCD) is an hereditary hemolytic anemia . People with sickle cell disease have red blood cells that contain mostly hemoglobin S, an abnormal type of hemoglobin. Hemoglobin – is the main substance of the red blood cell. It helps red blood cells carry oxygen from the air in our lungs to all parts of the body. Normal red blood cells contain hemoglobin A. Hemoglobin S and hemoglobin C are abnormal types of hemoglobin. Normal red blood cells are soft ,round and biconcave and can squeeze through tiny blood vessels. The basic molecular lesion in Hb S is the single point mutation in one aminoacid out of 146 in haemoglobin molecule. There is substitution of valine for glutamic acid at six residue position of beta globin .

Sickle-cell anaemia is the name of a specific form of sickle-cell disease in which there is homozygosity for the mutation that causes HbS. Sickle-cell anaemia is also referred to as “HbSS”, “SS disease”, “haemoglobin S” or permutations thereof. In heterozygous people, who have only one sickle gene and one normal adult hemoglobin gene, it is referred to as “HbAS” or “sickle cell trait”. Other, rarer forms of sickle-cell disease include sickle-haemoglobin C disease (HbSC), sickle beta-plus-thalassaemia (HbS/β + ) and sickle beta-zero-thalassaemia (HbS/β 0 ). These other forms of sickle-cell disease are compound heterozygous states in which the person has only one copy of the mutation that causes HbS and one copy of another abnormal haemoglobin allele.

An 11 years girl patient refered to Centre for Scientific Research and  Development(CSRD) of people’s group for advance haematology investigations.

Patient has significant skeletomuscular pain off and on, abdominal discomfort with pain and fever off and on. She was recently operated for cholecystectomy for gallstones.There was history of hip surgery nine years ago. No history of jaundice, or any other chronic illness was present. On examination pallor++, and mild spleenomagaly was found.

Patient’s investigation profile revealed Haemoglobin 7 gms%, Total WBC count within normal limits,differential WBC count ;neutrophilia, haematocrit 20.7%, RBCs indices within normal limits except RDW 15%. Normal platelets count and coagulation profile. Serum Iron studies and Vitamin B12 & Red cell folate were within normal range.Coomb’s test, G6PD, and Malaria antigen tests were negative. Liver function tests show mild increase in total and indirect bilirubin . Blood glucose, urea, serum creatinin, electrolytes were normal.

Patient’s abdominal ultrasonography report shows cholelithiesis and mild spleenomagaly.

In CSRD patient’s blood samples were investigated for haemoglobin electrophoresis (HPLC). Haemoglobin chromatography revealed high value of fetal haemoglobin(Hb F)-30.7% (normal <1.5%), low value of haemoglobin adult(Hb A) 3.4% (normal range 83.24-90.79%), and very high concentration of haemoglobin sickle(Hb S) 62.9% which is normally absent.  With these findings diagnosis of Haemoglobin ‘S’ homozygous state was considered and haemoglobin electrophoresis (HPLC) of parents and siblings were advised.

Following the patients tests, her parents and brother’s investigations performed. Both the parents and brother’s reports showed haemoglobin S heterozygous state. Patient was advised to consult haematologist in tertiary care hospital for advance treatment and management .

If one parent has sickle-cell anaemia (SS) and the other has sickle-cell trait (AS), there is a 50% chance of a child’s having sickle-cell disease (SS) and a 50% chance of a child’s having sickle-cell trait (AS). When both parents have sickle-cell trait (AS), a child has a 25% chance (1 of 4) of sickle-cell disease (SS). In our case both the parents are haemoglobin S heterozygous(AS),hence the patient is (SS) and her brother is (AS).

Clinical expression of the patients with sickle cell disease(SCD) is variable. Some patients need a lot of care while others need only routine check-ups.

The new therapies for treating SCD, hydroxyurea, a ribonuclease   reductase inhibitor, is most promising. Hydroxyurea was initially developed because of its ability to increase fetal haemoglobin production, but it has other beneficial effects too. Other new therapies being evaluated include butyrates and decitabine.[8] Bone marrow transplantation of children has shown cure in some patients. [9] Both bone marrow transplantation and hydroxyurea therapy are expensive modalities.

Finding financial resources for such expensive therapies for SCD have been difficult, especially in developing countries like India. For the optimal management of SCD patients, a comprehensive care centre with multidisciplinary team is required. Early diagnosis of patients by screening programme is very important. Diagnosed patients should be referred to centre for periodic evaluation. Parents should be given genetic counseling and support. Presently patient is maintaining normal routine  life with  proper clinical management.

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Iron absorption in adults with sickle cell anemia: a stable-isotope approach

• Original Contribution
• Published: 09 May 2024

Cite this article

• Juliana Omena¹   ORCID: orcid.org/0000-0003-4639-1898 1   na1 ,
• Flávia Fioruci Bezerra¹   ORCID: orcid.org/0000-0002-6594-4323 1   na1 ,
• Vanessa Monteiro Voll¹   ORCID: orcid.org/0000-0002-0939-0071 1 ,
• Bernardo Ferreira Braz 2 , 3 ,
• Ricardo Erthal Santelli   ORCID: orcid.org/0000-0001-9812-6098 2 , 3 ,
• Carmen Marino Donangelo   ORCID: orcid.org/0000-0002-4243-4179 4 ,
• Gustavo Federico Jauregui 5 ,
• Andrea Soares Ribeiro 6 ,
• Cláudia dos Santos Cople Rodrigues   ORCID: orcid.org/0000-0001-9497-556X 1 &
• Marta Citelli   ORCID: orcid.org/0000-0003-1380-3729 1  

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Iron absorption in sickle cell anemia (SCA) remains unclear and studies in adults with SCA are scarce. The aim of this study was to evaluate the iron absorption SCA adults and its association with iron status and hepcidin concentration.

SCA patients ( n  = 13; SCA total ) and control participants ( n  = 10) ingested an oral stable iron isotope ( 57 Fe). Iron absorption was measured by inductively coupled plasma mass spectrometry (ICP-MS) 14 days after isotope administration. Patients with ≥ 1000 ng/mL serum ferritin were considered to present iron overload (IO) (SCAio+; n  = 3) and others classified without IO (SCAio-; n  = 10).

Iron absorption in the control group ranged from 0.3 to 26.5% (median = 0.9%), while it varied from 0.3 to 5.4% in SCAio+ (median = 0.5%) and from 0.3 to 64.2% in the SCAio- (median = 6.9%). Hepcidin median values were 14.1 ng/mL (3.0–31.9 ng/mL) in SCAio-, 6.2 ng/mL (3.3–7.8 ng/mL) in SCAio + and 6.2 ng/mL (0.6–9.3 ng/mL) in control. Iron absorption was associated with ferritin level ( r = − 0.641; p  = 0.018) and liver iron concentration (LIC; r = − 0.786; p  = 0.036) in the SCA total group.

Our data suggest that SCAio- individuals may be at risk of developing primary IO. Simultaneously, secondary IO may induce physiological adaptation, resulting in reduced iron absorption. Further studies evaluating intestinal iron absorption using larger sample sizes should be conducted to help establish a safe nutrition approach to be adopted and to ensure the security of food-fortifying public policies for these patients.

Trial registration

This trial was registered at www.ensaiosclinicos.gov.br (Identifier RBR-4b7v8pt).

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Data availability.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors express their gratitude to the volunteers who participated in this study. They would also like to acknowledge the excellent technical assistance provided by Isis Rodrigues, Viviane F.Meneses, Clarice M. Carvalho, Elizabeth Pereira, Verônica Barbosa, and Valdilene L. Souza.

This study was supported by the Ministry of Health (process # 777022/2012); Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (process # 408401/2017-6); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) (Finance Code 001); Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (process # E-26-010.100930/2018 and E-26/200.963/2022).

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Flávia Fioruci Bezerra and Vanessa Monteiro Voll have contributed equally to this work.

Authors and Affiliations

Nutrition Institute, Rio de Janeiro State University, São Francisco Xavier Street, 524, 12144F, Maracanã, Rio de Janeiro, 20550-900, Brazil

Juliana Omena¹, Flávia Fioruci Bezerra¹, Vanessa Monteiro Voll¹, Cláudia dos Santos Cople Rodrigues & Marta Citelli

Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

Bernardo Ferreira Braz & Ricardo Erthal Santelli

National Institute of Science and Technology of Bioanalytics (INCTBio), Campinas, Brazil

School of Nutrition, University of the Republic, Montevideo, Uruguay

Carmen Marino Donangelo

Radiology Department, Pedro Ernesto University Hospital, Rio de Janeiro, Brazil

Gustavo Federico Jauregui

Hematology Department, Pedro Ernesto University Hospital, Rio de Janeiro, Brazil

Andrea Soares Ribeiro

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MC, JO, FFB, and CSCR designed the research; JO, MC, and VMV conducted the research; JO, VMV, MC, BFB and RES conducted the laboratory analysis; FFB and CMD helped to interpret the data and provided critical suggestions and comments; GFJ and ASR conducted the MRI procedures; JO, FFB and MC performed the statistical analysis, wrote the manuscript, and had primary responsibility for the final content. All authors read, contributed and approved the final manuscript. None of the authors declared any personal or financial conflict of interest.

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Correspondence to Juliana Omena¹ or Marta Citelli .

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The study was conducted in accordance with the Declaration of Helsinki principles. The Ethical Committee of Hemorio (419/17; 2.788.659) and Pedro Ernesto University Hospital (2.695.418) approved the study protocol. Written informed consent was obtained from each participant.

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Omena¹, J., Bezerra¹, F.F., Voll¹, V.M. et al. Iron absorption in adults with sickle cell anemia: a stable-isotope approach. Eur J Nutr (2024). https://doi.org/10.1007/s00394-024-03417-8

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• Cells collected from 1st SCD patient receiving gene therapy Lyfgenia

After collection, stem cells are treated then infused via stem cell transplant

by Andrea Lobo, PhD | May 9, 2024

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Bluebird Bio has announced it’s completed collecting cells from the first sickle cell disease (SCD) patient receiving the gene therapy Lyfgenia (lovotibeglogene autotemcel), following its recent approval in the U.S.

The cells were collected at Children’s National Hospital in Washington D.C., which is part of the company’s national network of qualified treatment centers . The. centers are selected based on their expertise in cell and gene therapy, transplant, and SCD, and they receive specialized training on how to administer Lyfgenia.

“We are thrilled to be the first center in the country to commercially collect cells from a person living with sickle cell disease and are proud to be the trailblazers in using this new approach,” David Jacobsohn, MD, chief of the division of Blood and Marrow Transplantation at Children’s, said in a company press release . “The recent approval of gene therapies to treat patients with sickle cell is an enormous breakthrough in patient care and a silver lining to families witnessing their children’s struggles with this condition.”

Meanwhile, Minaris Regenerative Medicine , a global cell and gene therapy manufacturer, has announced the first commercial run of Lyfgenia at its facility in Allendale, New Jersey.

“The commencement of commercial manufacturing for Lyfgenia represents an important step for the cell and gene therapy industry as it will allow many patients fighting sickle cell disease to benefit from this new, potentially curative medicine,” Hiroto Bando, PhD, Minaris’ CEO, said in a separate press release .

SCD is caused  by mutations in the  HBB gene that lead to an abnormal form of hemoglobin, the protein in red blood cells that carries oxygen through the body, being produced. Defective hemoglobin tends to form clumps and causes red blood cells to acquire a sickle-like shape, which are prone to getting stuck inside blood vessels, restricting blood flow and reducing oxygen delivery to tissues. This can lead to episodes of acute pain known as vaso-occlusive crises (VOCs).

Casgevy gene therapy conditionally approved in EU for SCD and TDT

How does lygenia gene therapy work.

Lyfgenia is a one-time gene therapy approved last year by the U.S. Food and Drug Administration for SCD patients, ages 12 and older, with a history of vaso-occlusive events (VOEs), including VOCs and other sickle cell-related complications. It’s designed to provide patients with a modified HBB  gene that produces a form of hemoglobin, called HbA T87Q , which is resistant to clumping.

The treatment involves collecting patients’ hematopoietic stem cells, or blood cell precursors, and treating them with Lyfgenia before infusing them back into the patient via a stem cell transplant . Before the transplant, patients must undergo a round of chemotherapy to eliminate faulty blood stem cells.

After the transplant, red blood cells generated from the engineered stem cells should produce the anti-sickling hemoglobin, limiting red blood cell sickling and potentially reducing the frequency and severity of VOEs.

Lyfgenia’s approval was based on efficacy data from 36 patients, ages 12-50, who entered the completed Phase 1/2 HGB-206 trial (NCT02140554) , where all received the gene therapy.

Of 32 patients evaluated for the trial’s main efficacy goals, 30 (94%) had no severe VOEs and 28 (88.2%) had no VOEs after the treatment.

Safety data obtained for 54 patients who initiated the process of cell collection showed the most common side effects were inflammation of the lips, mouth, and throat, and low levels of blood cells.

The company is also conducting the Phase 3 HGB-210 trial (NCT04293185) , which is evaluating the efficacy of the gene therapy in about 35 SCD patients, ages 2-50. The trial is ongoing.

A long-term safety and efficacy follow-up study, LTF-307 (NCT04628585) is also underway. It’s open to SCD patients treated with Lyfgenia in previous clinical studies sponsored by the company. The study will follow the participants for 13 additional years.

“Seeing people living with sickle cell disease receive gene therapy in the real world is a vision that has fueled Bluebird for more than 10 years,” said Andrew Obenshain, Bluebird’s president and CEO. “This historic moment comes nearly a century after sickle cell disease was the first genetic disorder to be characterized at the molecular level and almost a decade after Bluebird initiated clinical development for Lyfgenia. We are grateful to the patients, caregivers, researchers, and clinicians whose work made this milestone possible, and look forward to continued partnership with the sickle cell disease community.”

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