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Hemolytic disease of the fetus and newborn: systematic literature review of the antenatal landscape.BMC Pregnancy and Childbirth Jan 2023Prevention of pregnancy-related alloimmunization and the management of hemolytic disease of the fetus and newborn (HDFN) has significantly improved over the past...
BACKGROUND
Prevention of pregnancy-related alloimmunization and the management of hemolytic disease of the fetus and newborn (HDFN) has significantly improved over the past decades. Considering improvements in HDFN care, the objectives of this systematic literature review were to assess the prenatal treatment landscape and outcomes of Rh(D)- and K-mediated HDFN in mothers and fetuses, to identify the burden of disease, to identify evidence gaps in the literature, and to provide recommendations for future research.
METHODS
We performed a systematic search on MEDLINE, EMBASE and clinicaltrials.gov. Observational studies, trials, modelling studies, systematic reviews of cohort studies, and case reports and series of women and/or their fetus with HDFN caused by Rhesus (Rh)D or Kell alloimmunization. Extracted data included prevalence; treatment patterns; clinical outcomes; treatment efficacy; and mortality.
RESULTS
We identified 2,541 articles. After excluding 2,482 articles and adding 1 article from screening systematic reviews, 60 articles were selected. Most abstracted data were from case reports and case series. Prevalence was 0.047% and 0.006% for Rh(D)- and K-mediated HDFN, respectively. Most commonly reported antenatal treatment was intrauterine transfusion (IUT; median frequency [interquartile range]: 13.0% [7.2-66.0]). Average gestational age at first IUT ranged between 25 and 27 weeks. weeks. This timing is early and carries risks, which were observed in outcomes associated with IUTs. The rate of hydrops fetalis among pregnancies with Rh(D)-mediated HDFN treated with IUT was 14.8% (range, 0-50%) and 39.2% in K-mediated HDFN. Overall mean ± SD fetal mortality rate that was found to be 19.8%±29.4% across 19 studies. Mean gestational age at birth ranged between 34 and 36 weeks.
CONCLUSION
These findings corroborate the rareness of HDFN and frequently needed intrauterine transfusion with inherent risks, and most births occur at a late preterm gestational age. We identified several evidence gaps providing opportunities for future studies.
Topics: Female; Humans; Pregnancy; Erythroblastosis, Fetal; Hydrops Fetalis; Hemolysis; Blood Transfusion, Intrauterine; Fetus
PubMed: 36611144
DOI: 10.1186/s12884-022-05329-z -
JAMA Network Open Oct 2023Sickle cell disease (SCD) is a monogenic disorder, yet clinical outcomes are influenced by additional genetic factors. Despite decades of research, the genetics of SCD... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Sickle cell disease (SCD) is a monogenic disorder, yet clinical outcomes are influenced by additional genetic factors. Despite decades of research, the genetics of SCD remain poorly understood.
OBJECTIVE
To assess all reported genetic modifiers of SCD, evaluate the design of associated studies, and provide guidelines for future analyses according to modern genetic study recommendations.
DATA SOURCES
PubMed, Web of Science, and Scopus were searched through May 16, 2023, identifying 5290 publications.
STUDY SELECTION
At least 2 reviewers identified 571 original, peer-reviewed English-language publications reporting genetic modifiers of human SCD phenotypes, wherein the outcome was not treatment response, and the comparison was not between SCD subtypes or including healthy controls.
DATA EXTRACTION AND SYNTHESIS
Data relevant to all genetic modifiers of SCD were extracted, evaluated, and presented following STREGA and PRISMA guidelines. Weighted z score meta-analyses and pathway analyses were conducted.
MAIN OUTCOMES AND MEASURES
Outcomes were aggregated into 25 categories, grouped as acute complications, chronic conditions, hematologic parameters or biomarkers, and general or mixed measures of SCD severity.
RESULTS
The 571 included studies reported on 29 670 unique individuals (50% ≤ 18 years of age) from 43 countries. Of the 17 757 extracted results (4890 significant) in 1552 genes, 3675 results met the study criteria for meta-analysis: reported phenotype and genotype, association size and direction, variability measure, sample size, and statistical test. Only 173 results for 62 associations could be cross-study combined. The remaining associations could not be aggregated because they were only reported once or methods (eg, study design, reporting practice) and genotype or phenotype definitions were insufficiently harmonized. Gene variants regulating fetal hemoglobin and α-thalassemia (important markers for SCD severity) were frequently identified: 19 single-nucleotide variants in BCL11A, HBS1L-MYB, and HBG2 were significantly associated with fetal hemoglobin (absolute value of Z = 4.00 to 20.66; P = 8.63 × 10-95 to 6.19 × 10-5), and α-thalassemia deletions were significantly associated with increased hemoglobin level and reduced risk of albuminuria, abnormal transcranial Doppler velocity, and stroke (absolute value of Z = 3.43 to 5.16; P = 2.42 × 10-7 to 6.00 × 10-4). However, other associations remain unconfirmed. Pathway analyses of significant genes highlighted the importance of cellular adhesion, inflammation, oxidative and toxic stress, and blood vessel regulation in SCD (23 of the top 25 Gene Ontology pathways involve these processes) and suggested future research areas.
CONCLUSIONS AND RELEVANCE
The findings of this comprehensive systematic review and meta-analysis of all published genetic modifiers of SCD indicated that implementation of standardized phenotypes, statistical methods, and reporting practices should accelerate discovery and validation of genetic modifiers and development of clinically actionable genetic profiles.
Topics: Humans; Fetal Hemoglobin; alpha-Thalassemia; Anemia, Sickle Cell; Genotype; Genetic Variation
PubMed: 37851445
DOI: 10.1001/jamanetworkopen.2023.37484 -
The Cochrane Database of Systematic... Sep 2022Sickle cell disease (SCD) is one of the most common inherited diseases worldwide. It is associated with lifelong morbidity and a reduced life expectancy. Hydroxyurea... (Review)
Review
BACKGROUND
Sickle cell disease (SCD) is one of the most common inherited diseases worldwide. It is associated with lifelong morbidity and a reduced life expectancy. Hydroxyurea (hydroxycarbamide), an oral chemotherapeutic drug, ameliorates some of the clinical problems of SCD, in particular that of pain, by raising foetal haemoglobin (HbF). This is an update of a previously published Cochrane Review.
OBJECTIVES
The aims of this review are to determine through a review of randomised or quasi-randomised studies whether the use of hydroxyurea in people with SCD alters the pattern of acute events, including pain; prevents, delays or reverses organ dysfunction; alters mortality and quality of life; or is associated with adverse effects. In addition, we hoped to assess whether the response to hydroxyurea in SCD varies with the type of SCD, age of the individual, duration and dose of treatment, and healthcare setting.
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Haemoglobinopathies Register, comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We also searched online trial registries. The date of the most recent search was 17 February 2022.
SELECTION CRITERIA
Randomised and quasi-randomised controlled trials (RCTs and quasi-RCTs), of one month or longer, comparing hydroxyurea with placebo or standard therapy in people with SCD.
DATA COLLECTION AND ANALYSIS
Authors independently assessed studies for inclusion, carried out data extraction, assessed the risk of bias and assessed the quality of the evidence using GRADE.
MAIN RESULTS
We included nine RCTs recruiting 1104 adults and children with SCD (haemoglobin SS (HbSS), haemoglobin SC (HbSC) or haemoglobin Sβºthalassaemia (HbSβºthal) genotypes). Studies lasted from six to 30 months. We judged the quality of the evidence for the first two comparisons below as moderate to low as the studies contributing to these comparisons were mostly large and well-designed (and at low risk of bias); however, the evidence was limited and imprecise for some outcomes such as quality of life, deaths during the studies and adverse events, and the results are applicable only to individuals with HbSS and HbSβºthal genotypes. We judged the quality of the evidence for the third and fourth comparisons to be very low due to the limited number of participants, the lack of statistical power (both studies were terminated early with approximately only 20% of their target sample size recruited) and the lack of applicability to all age groups and genotypes. Hydroxyurea versus placebo Five studies (784 adults and children with HbSS or HbSβºthal) compared hydroxyurea to placebo; four recruited individuals with only severe disease and one recruited individuals with all disease severities. Hydroxyurea probably improves pain alteration (using measures such as pain crisis frequency, duration, intensity, hospital admissions and opoid use) and life-threatening illness, but we found no difference in death rates (10 deaths occurred during the studies, but the rates did not differ by treatment group) (all moderate-quality evidence). Hydroxyurea may improve measures of HbF (low-quality evidence) and probably decreases neutrophil counts (moderate-quality evidence). There were no consistent differences in terms of quality of life and adverse events (including serious or life-threatening events) (low-quality evidence). There were fewer occurrences of acute chest syndrome and blood transfusions in the hydroxyurea groups. Hydroxyurea and phlebotomy versus transfusion and chelation Two studies (254 children with HbSS or HbSβºthal also with risk of primary or secondary stroke) contributed to this comparison. There were no consistent differences in terms of pain alteration, death or adverse events (low-quality evidence) or life-threatening illness (moderate-quality evidence). Hydroxyurea with phlebotomy probably increased HbF and decreased neutrophil counts (moderate-quality evidence), but there were more occurrences of acute chest syndrome and infections. Quality of life was not reported. In the primary prevention study, no strokes occurred in either treatment group but in the secondary prevention study, seven strokes occurred in the hydroxyurea and phlebotomy group (none in the transfusion and chelation group) and the study was terminated early. Hydroxyurea versus observation One study (22 children with HbSS or HbSβºthal also at risk of stoke) compared hydroxyurea to observation. Pain alteration and quality of life were not reported. There were no differences in life-threatening illness, death (no deaths reported in either group) or adverse events (very low-quality evidence). We are uncertain if hydroxyurea improves HbF or decreases neutrophil counts (very low-quality evidence). Treatment regimens with and without hydroxyurea One study (44 adults and children with HbSC) compared treatment regimens with and without hydroxyurea. Pain alteration, life-threatening illness and quality of life were not reported. There were no differences in death rates (no deaths reported in either group), adverse events or neutrophil levels (very low-quality evidence). We are uncertain if hydroxyurea improves HbF (very low-quality evidence).
AUTHORS' CONCLUSIONS
There is evidence to suggest that hydroxyurea may be effective in decreasing the frequency of pain episodes and other acute complications in adults and children with sickle cell anaemia of HbSS or HbSβºthal genotypes and in preventing life-threatening neurological events in those with sickle cell anaemia at risk of primary stroke by maintaining transcranial Doppler velocities. However, there is still insufficient evidence on the long-term benefits of hydroxyurea, particularly with regard to preventing chronic complications of SCD, or recommending a standard dose or dose escalation to maximum tolerated dose. There is also insufficient evidence about the long-term risks of hydroxyurea, including its effects on fertility and reproduction. Evidence is also limited on the effects of hydroxyurea on individuals with the HbSC genotype. Future studies should be designed to address such uncertainties.
Topics: Acute Chest Syndrome; Adult; Anemia, Sickle Cell; Antisickling Agents; Child; Hemoglobin, Sickle; Humans; Hydroxyurea; Pain; Stroke
PubMed: 36047926
DOI: 10.1002/14651858.CD002202.pub3 -
Heliyon Nov 2021Treatment for polycystic ovary syndrome (PCOS) usually initiates with a series of lifestyle modifications such as diet, weight loss, and exercise.
BACKGROUND
Treatment for polycystic ovary syndrome (PCOS) usually initiates with a series of lifestyle modifications such as diet, weight loss, and exercise.
AIMS
We, therefore, conducted this meta-analysis to systematically review and evaluate the possible benefits of LGD on a range of anthropometric, clinical, and biochemical parameters in women with PCOS.
METHODS
We performed a systematic search through major indexing databases, including Scopus, Pubmed/Medline, ISI web of science, Embase, Cochrane central, and CINAHL (1966-April 30, 2021) using key concepts of PCOS.
RESULTS
Of 935 initial publications, 542 remain after duplicates removal. Then, 141 records were removed at the title and abstract screening level. After excluding 392 literatures, we finally included 8 articles. The final selected studies included 412 overweight and obese individuals with PCOS (207 cases in LGID group and 205 patients in comparators) with a mean age of 21-32 years. Measured emotional health (3 studies, 132 participants, SMD: -1.97; 95%CI:-3.54, -0.40, = 0.01, = 89%) and body hair (3 studies, 132 participants, SMD: -0.40; 95%CI:-0.46, -0.35, < 0.0001, = 0%), were found to be significantly lower in women in LGD vs control diet groups. Moreover, infertility (3 studies, 132 participants, SMD: 1.45; 95%CI: 0.30, 2.61, = 0.01, = 79%) was significantly higher in women in LGD vs control diet groups.
CONCLUSION
The present meta-analysis has shown that LGD may play a significant role in reducing the risk and improving the clinical and biochemical features of PCOS. So far the evidences for choosing the best dietary modalities for PCOS are not strong to make a definite recommendation.
PubMed: 34820542
DOI: 10.1016/j.heliyon.2021.e08338 -
American Journal of Obstetrics &... Sep 2023This study aimed to review the diagnostic criteria for mirror syndrome and describe its clinical presentation. (Review)
Review
OBJECTIVE
This study aimed to review the diagnostic criteria for mirror syndrome and describe its clinical presentation.
DATA SOURCES
Databases from PubMed, Scopus, Cochrane Library, ClinicalTrials.gov, and CINAHL were inquired for case series containing ≥2 cases of mirror syndrome from inception to February 2022.
STUDY ELIGIBILITY CRITERIA
Studies were included if they reported ≥2 cases of mirror syndrome and included case reports, case series, cohort studies, and case-control studies.
STUDY APPRAISAL AND SYNTHESIS METHODS
The studies' quality and risk of bias were independently assessed. Data were tabulated using Microsoft Excel and summarized using narrative review and descriptive statistics. This systematic review was conducted according to the Preferred Reporting Item for Systematic Reviews and Meta-Analyses statement. All eligible references were assessed. Screening of records and data extraction were independently performed, and a third author resolved disagreements.
RESULTS
Of 13 citations, 12 studies (n=82) reported diagnostic criteria for mirror syndrome: maternal edema (11/12), fetal hydrops (9/12), placental edema (6/12), placentomegaly (5/12), and preeclampsia (2/12); 12 studies (n=82) described the clinical presentation of mirror syndrome as maternal edema (62.2%), hypoalbuminemia (54.9%), anemia (39.0%), and new-onset hypertension (39.0%); 4 studies (n=36) reported that hemodilution was present in all patients; 8 studies (n=36) reported the etiology of fetal hydrops, with the most common being structural cardiac malformations (19.4%), alpha thalassemia (19.4%), Rh isoimmunization (13.9%), and nonimmune hydrops fetalis (13.9%); and 6 studies (n=47) reported maternal complications, 89.4% of which were major: postpartum hemorrhage (44.7%), hemorrhage requiring blood transfusion (19.1%), intensive care unit admission (12.8%), heart failure (10.6%), pulmonary edema (8.5%), and renal dysfunction (8.5%). In 39 cases, the reported fetal outcomes were stillbirth (66.6%) and neonatal or infant death (25.6%). The overall survival rate among continued pregnancies was 7.7%.
CONCLUSION
The diagnostic criteria of mirror syndrome differed considerably among studies. Mirror syndrome clinical presentation overlapped with preeclampsia. Only 4 studies discussed hemodilution. Significant maternal morbidity and fetal mortality were associated with mirror syndrome. Further research is warranted to elucidate the pathogenesis of mirror syndrome to better guide clinicians in identifying and managing the condition.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Edema; Hydrops Fetalis; Placenta; Pre-Eclampsia; Syndrome; Systematic Reviews as Topic
PubMed: 37385374
DOI: 10.1016/j.ajogmf.2023.101067 -
Blood Reviews May 2023Complementary and alternative medicine (CAM) is a popular alternative to opioid and other analgesics in sickle cell disease (SCD). We review the effectiveness,... (Review)
Review
BACKGROUND
Complementary and alternative medicine (CAM) is a popular alternative to opioid and other analgesics in sickle cell disease (SCD). We review the effectiveness, prevalence, and factors associated with CAM use in the pediatric SCD population.
METHODS
The review protocol was created based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A literature search was conducted in MEDLINE, Embase, Cochrane Library, PubMed, and Web of Science.
RESULTS
Twenty-four studies were examined. The prevalence of CAM use in pediatric patients with SCD ranged from 36 to 84.5%. Common inpatient CAM interventions were yoga, virtual reality, and acupuncture, which decreased pain scale scores. Outpatient CAMs were consisted of cognitive behavioral therapy, massage therapy, and guided-imagery, which increased pain tolerability and decreased pain scale scores.
CONCLUSIONS
CAM modalities can decrease pain scale scores. However, the impact of specific CAM modalities on emergency department visits, hospitalizations, and school absences were inconclusive.
Topics: Child; Humans; Complementary Therapies; Pain; Anemia, Sickle Cell
PubMed: 36775794
DOI: 10.1016/j.blre.2023.101052 -
Journal of Clinical Medicine Dec 2021In the last half century, the life expectancy of beta-thalassemia patients has strikingly increased mostly due to regular blood transfusions and chelation treatments.... (Review)
Review
In the last half century, the life expectancy of beta-thalassemia patients has strikingly increased mostly due to regular blood transfusions and chelation treatments. The improved survival, however, has allowed for the emergence of comorbidities, such as hearing loss, with a non-negligible impact on the patients' quality of life. This thorough review analyzes the acquired knowledge regarding hearing impairment in this hereditary hemoglobinopathy, aiming at defining its prevalence, features, course, and possible disease- or treatment-related pathogenic factors. Following PRISMA criteria, we retrieved 60 studies published between 1979 and 2021. Diagnostic tools and criteria, forms of hearing impairment, correlations with beta-thalassemia phenotypes, age and sex, chelation treatment and laboratory findings including iron overload, were carefully searched, analyzed and summarized. In spite of the relatively high number of studies in the last 40 years, our knowledge is rather limited, and large prospective studies with homogeneous diagnostic tools and criteria are required to define all the aforementioned issues. According to the literature, the overall prevalence rate of hearing impairment is 32.3%; age, sex, and laboratory findings do not seem to correlate with hearing deficits, while the weak relationship with clinical phenotype and chelation treatment seems to highlight the presence of further yet to be identified pathogenic factors.
PubMed: 35011846
DOI: 10.3390/jcm11010102 -
Frontiers in Medicine 2021This systematic review aimed to provide an overview of the clinical profile and outcome of COVID-19 infection in patients with hemoglobinopathy. The rate of COVID-19...
This systematic review aimed to provide an overview of the clinical profile and outcome of COVID-19 infection in patients with hemoglobinopathy. The rate of COVID-19 mortality and its predictors were also identified. A systematic search was conducted in accordance with PRISMA guidelines in five electronic databases (PubMed, Scopus, Web of Science, Embase, WHO COVID-19 database) for articles published between 1st December 2019 to 31st October 2020. All articles with laboratory-confirmed COVID-19 cases with underlying hemoglobinopathy were included. Methodological quality was assessed using the Joanna Briggs Institute (JBI) critical appraisal checklists. Thirty-one articles with data on 246 patients with hemoglobinopathy were included in this review. In general, clinical manifestations of COVID-19 infection among patients with hemoglobinopathy were similar to the general population. Vaso-occlusive crisis occurred in 55.6% of sickle cell disease patients with COVID-19 infection. Mortality from COVID-19 infection among patients with hemoglobinopathy was 6.9%. After adjusting for age, gender, types of hemoglobinopathy and oxygen supplementation, respiratory (adj OR = 89.63, 95% CI 2.514-3195.537, = 0.014) and cardiovascular (adj OR = 35.20, 95% CI 1.291-959.526, = 0.035) comorbidities were significant predictors of mortality. Patients with hemoglobinopathy had a higher mortality rate from COVID-19 infection compared to the general population. Those with coexisting cardiovascular or respiratory comorbidities require closer monitoring during the course of illness. More data are needed to allow a better understanding on the clinical impact of COVID-19 infections among patients with hemoglobinopathy. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020218200.
PubMed: 34722593
DOI: 10.3389/fmed.2021.757510 -
British Journal of Haematology Jun 2023Hyperhaemolysis syndrome (HHS), a severe form of delayed haemolytic transfusion reaction most commonly described in patients with sickle cell disease (SCD), involves... (Review)
Review
Hyperhaemolysis syndrome (HHS), a severe form of delayed haemolytic transfusion reaction most commonly described in patients with sickle cell disease (SCD), involves destruction of both donor and recipient red blood cells (RBCs). As the epidemiology and underlying pathophysiology have yet to be definitively elucidated, recognition can be challenging. We systematically reviewed PubMed and EMBASE to identify all cases of post-transfusion hyperhaemolysis and characterized the epidemiological, clinical and immunohaematological characteristics and treatments of HHS. We identified 51 patients (33 females and 18 males), including 31 patients with SCD (HbSS, HbSC and HbS/β-thalassaemia). The median haemoglobin nadir (3.9 g/dL) occurred a median of 10 days post-transfusion. 32.6% and 45.7% of patients had a negative indirect anti-globulin test and a negative direct anti-globulin test, respectively. The most common therapies included corticosteroids and intravenous immune globulin. 66.0% of patients received ≥1 supportive transfusion, which was associated with a longer median hospital stay/time to recovery (23 days vs. 15 days; p = 0.015) compared to no supportive transfusion. These findings illustrate that HHS that often results in marked anaemia 10 days post-transfusion is not restricted to patients with haemoglobinopathies, and additional transfused RBCs may be associated with a longer time-to-recovery.
Topics: Male; Female; Humans; Transfusion Reaction; Anemia, Sickle Cell; Blood Transfusion; Erythrocytes; Hemoglobin SC Disease; Syndrome
PubMed: 37074146
DOI: 10.1111/bjh.18825 -
The Journal of Maternal-fetal &... Oct 2022Mirror syndrome is a rare disease associated with high fetal mortality of up to 67.2%. It is thought to be underdiagnosed and is often associated with preeclampsia.... (Review)
Review
INTRODUCTION
Mirror syndrome is a rare disease associated with high fetal mortality of up to 67.2%. It is thought to be underdiagnosed and is often associated with preeclampsia. Mirror syndrome is characterized by "triple edema": generalized maternal, placental, and fetal edema.
OBJECTIVE
This comprehensive review aims to thoroughly summarize the existing data and provide a broad update on the topic to help accurate diagnosis and encourage further research.
METHODS
A comprehensive search of several databases (Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, and Daily, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus) was conducted.
RESULTS
The last systematic review of mirror syndrome cases was conducted in 2016 and included 113 patients. Much is still unknown about the pathophysiology of the disease and it remains underdiagnosed.
CONCLUSIONS AND RELEVANCE
Mirror syndrome is likely more prevalent than current data suggests for it is often misdiagnosed as pre-eclampsia. The differential of Mirror syndrome should be considered in anomalous presentations of pre-eclampsia as intervention may save the fetus and improve maternal symptoms. It is important to further the study on the pathophysiology of the disease to better understand, diagnose and potentially treat it, to avoid its high morbidity and mortality.
Topics: Edema; Female; Humans; Hydrops Fetalis; Placenta; Pre-Eclampsia; Pregnancy; Syndrome; Systematic Reviews as Topic
PubMed: 33722118
DOI: 10.1080/14767058.2020.1844656