Intravenous versus oral iron for anaemia among pregnant women in Nigeria (IVON): an open-label, randomised controlled trial.

BACKGROUND: Oral iron for anaemia in pregnancy is often not well tolerated, with poor adherence. Iron administered intravenously might address these tolerance and adherence issues. We investigated the effectiveness and safety of intravenous ferric carboxymaltose versus oral ferrous sulphate on anaemia and iron deficiency among pregnant women in Nigeria. METHODS: We did a multicentre, open-label, parallel, randomised controlled trial of pregnant women (aged 15-49 years) with haemoglobin (Hb) concentrations of less than 10 g/dL at 20-32 weeks' gestation from 11 primary, secondary, or tertiary health facilities in Nigeria (five in Lagos and six in Kano). Exclusion criteria included vaginal bleeding, blood transfusion or major surgery within the past 3 months, symptomatic anaemia, anaemia known to be unrelated to iron deficiency, clinically confirmed malabsorption syndrome, previous hypersensitivity to any form of iron, pre-existing maternal depression or other major psychiatric illness, immune-related diseases, such as systemic lupus erythematosus or rheumatoid arthritis, or severe allergic reactions. Participants were randomly assigned (1:1) by nurses and doctors using a web-based randomisation service to either receive a single dose of intravenous ferric carboxymaltose (20 mg/kg to a maximum of 1000 mg) or oral ferrous sulphate (200 mg; 65 mg elemental iron) three times daily until 6 weeks postpartum. The study was primarily unmasked. Primary outcomes were maternal anaemia (Hb <11 g/dL) at 36 weeks' gestation and preterm birth at before 37 weeks' gestation, with analysis by intention to treat in participants with available data. This study was registered at the ISRCTN registry on Dec 10, 2020 (ISRCTN63484804) and on ClinicalTrials.gov (NCT04976179) on April 7, 2021. FINDINGS: Between Aug 10, 2021, and Dec 15, 2022, 13 724 pregnant women were screened for eligibility. 12 668 were excluded due to ineligibility for inclusion, and 1056 provided consent to participate and were randomly assigned to either the intravenous or oral administration groups. 527 were assigned to the intravenous ferric carboxymaltose group and 529 were assigned to the oral ferrous sulphate group. 518 in the intravenous group were assessed at 36 weeks' gestational age and after 518 deliveries, and 511 completed the 6 weeks postpartum visit. 513 in the oral ferrous sulphate group were assessed at 36 weeks' gestational age and after 512 deliveries, and 501 completed the 6 weeks postpartum visit. No significant difference was found in anaemia at 36 weeks (299 [58%] of 517 in the intravenous group vs 305 [61%] of 503 in the oral group; risk ratio 0·95, 95% CI 0·85-1·06; p=0·36), nor in preterm birth (73 [14%] of 518 vs 77 [15%] of 513; 0·94, 0·70-1·26; p=0·66). There were no significant differences in adverse events. The most common adverse events were diarrhoea (in six participants) and vomiting (in three participants) in the oral group and fatigue (in two participants) and headache (in two participants) in the intravenous group. INTERPRETATION: Although the effect on overall anaemia did not differ, intravenous iron reduced the prevalence of iron deficiency to a greater extent than oral iron and was considered to be safe. We recommend that intravenous iron be considered for anaemic pregnant women in Nigeria and similar settings. FUNDING: Bill & Melinda Gates Foundation.

The effect of dates and honey extracts (phoenix dactylifera and apis mellifera) for increasing pregnant women's haemoglobin.

Objectives: To examine the effect of date fruit extract and honey in increasing haemoglobin levels in pregnant women. METHODS: The quasi-experimental study was conducted from July to August 2022 in Rumbai Pesisir Subdistric, Pekanbaru, Indonesia, and comprised anaemic pregnant women with haemoglobin levels <11gm/dl who were not consuming iron tablets or blood boosters. They were given honey and date extracts 2 tablespoons twice daily for two weeks. Haemoglobin level was checked at baseline and then at the end of each week of intervention. Data was analysed using SPSS version 20 and quantitative method by using bivariate analysis. RESULTS: Of the 50 women, 59(98%) were aged 20-35 years, and 1(2%) was aged >35 years. Besides, 21(42%) women were in the second trimester, 17(34%) in third, and 12(24%) in the first trimester of pregnancy. The increase in haemoglobin levels post-intervention was highly significant (p=0.0001). CONCLUSIONS: Date fruit extract and honey increased haemoglobin level of pregnant women.

Immune thrombocytopenia and pregnancy: challenges and opportunities in diagnosis and management.

INTRODUCTION: Immune thrombocytopenia (ITP) affecting pregnancy is a diagnostic and often a therapeutic challenge. AREAS COVERED: We review the current diagnostic criteria for ITP in pregnancy and the potential utility of laboratory tests. We discuss the impact of ITP on pregnancy outcomes and the effects of pregnancy on patients living with chronic ITP.  We describe the criteria for intervention, the evidence supporting first-line treatment approaches and the therapeutic decisions and challenges in cases refractory to steroids and IVIG. We review the evidence supporting the potential use of thrombopoietin receptor agonists for refractory thrombocytopenia. Finally, we describe the diagnostic, prognostic, and treatment approaches to neonatal ITP and considerations regarding breastfeeding. We searched the terms 'immune thrombocytopenia' and 'pregnancy' on PubMed to identify the relevant literature published before 31 December 2023, including within cited references. EXPERT OPINION: Decreased platelet production may play a role in pregnancy-related ITP exacerbation. Putative mechanisms include placental hormones, such as inhibin. Although IVIG and prednisone usually suffice to achieve hemostasis for delivery, second-line agents are sometimes required to allow for neuraxial anesthesia. There is growing evidence supporting the use of romiplostim during pregnancy; however, its risk of venous thromboembolism warrants further evaluation.

Hemostatic management of von Willebrand disease during childbirth with a plasma-derived von Willebrand factor/factor VIII concentrate.

BACKGROUND: Females with von Willebrand disease (VWD) do not show the same increases in von Willebrand factor and factor (F)VIII levels during pregnancy as females without VWD and are at higher risk of excessive bleeding associated with childbirth. Data on hemostatic management for childbirth in VWD patients are limited. OBJECTIVES: To evaluate the dosing, efficacy, and safety of plasma-derived von Willebrand factor/FVIII (wilate) for prevention of excessive bleeding associated with childbirth in females with any type of VWD. METHODS: Data for females with VWD who received wilate for hemostatic coverage for childbirth during 2 prospective clinical studies were analyzed. RESULTS: Ten females with VWD and a mean age at enrolment of 29.6 years were treated with wilate to prevent excessive bleeding associated with childbirth. Two patients had type 1, 4 had type 2 (2 2A, 1 2B, and 1 2M), and 4 had type 3 VWD. Of the 10 deliveries, 5 were by cesarean section. Patients received a mean of 9.5 infusions of wilate over 6.8 exposure days, with a mean total dose of 234 IU/kg per delivery and 25 IU/kg per infusion. Hemostatic management for all deliveries was rated excellent or good, with no excessive bleeding during delivery and no postpartum bleeding during the period of wilate treatment in any patient. Two patients experienced 8 possible or probable treatment-related adverse events; all were mild or moderate and resolved. No thromboembolic events were observed. CONCLUSION: The results of this case series indicate that wilate provided effective hemostatic cover for childbirth in females with VWD during delivery and postpartum.

Rituximab as a treatment for refractory immune thrombocytopenia during pregnancy.

Immune thrombocytopenia (ITP) is most common in women during their reproductive years. When a low platelet count occurs for the first time during pregnancy, the differential diagnosis includes pregnancy-specific conditions. Although ITP is the most common cause of thrombocytopenia early in pregnancy, pregnancy-related thrombocytopenia develops mainly in late gestation. As maternal and neonatal outcomes are usually favourable, ITP per se is not a contraindication for pregnancy. We report the case with a literature review of patient with ITP, whose diagnosis was established in early pregnancy. This condition was refractory to first-line treatments, such as high-dose steroids and intravenous immunoglobulin and other splenectomy-sparing approaches, as rituximab, having the control been reached on the third trimester after splenectomy. Although not effective in this case, we still believe that rituximab should be considered before surgery during pregnancy.

Consensus recommendations for optimising the diagnosis and treatment of paroxysmal nocturnal haemoglobinuria in Singapore.

Introduction: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare haematologic disease characterised by intravascular haemolysis, thrombophilia and bone marrow failure. There is a lack of established clinical guidance on the screening, diagnosis and manage-ment of PNH in Singapore. A relatively low level of awareness among healthcare professionals regarding PNH manifestations further contributes to diagnostic delays. Additionally, limited access to complement inhibitors, like eculizumab, may delay treatment and impact patient outcomes. Method: Nine haematologists from different institu-tions in Singapore convened to formulate evidence-based consensus recommendations for optimising the diagnosis and management of patients with PNH and improving access to novel treatments. The experts reviewed the existing literature and international guidelines published from January 2010 to July 2023, focusing on 7 clinical questions spanning PNH screening, diagnostic criteria, investigations, treatment and monitoring of subclinical and classic disease, PNH with underlying bone marrow disorders, and PNH in pregnancy. A total of 181 papers were reviewed to formulate the statements. All experts voted on the statements via 2 rounds of Delphi and convened for an expert panel discussion to finetune the recommendations. Results: Sixteen statements have been formulated for optimising the screening, diagnosis and management of PNH. Upon confirmation of PNH diagnosis, individuals with active haemolysis and/or thrombosis should be considered for anti-complement therapy, with eculizumab being the only approved drug in Singapore. Conclusion: The current recommendations aim to guide the clinicians in optimising the screening, diagnosis and management of PNH in Singapore.

A new effect of intravenous iron treatment in pregnancy: contraction in nonstress test and timing of labor.

OBJECTIVE: The aim of this study was to elucidate the cause and results of contractions occurring in term pregnant women receiving intravenous iron therapy. METHODS: During 2019-2020, 136 pregnant women beyond 35 weeks of gestation, who received intravenous iron treatment due to iron deficiency anemia, were included through retrospective screening. Iron deficiency anemia was defined as having hemoglobin levels <10 g/dL and ferritin levels <15 ng/mL, and the pregnant women underwent nonstress test before and after treatment. RESULTS: The average treatment week for the pregnant women was 36.82±0.74, and the presence of regular contractions in post-treatment follow-up nonstress tests was 72.1% (n=98). The average week of birth was 38.48±1.60. Pregnant women with contractions who had previous cesarean were found to have a mean delivery week of 36.82±0.67, which was statistically significant earlier than for nulliparous and multiparous women (p<0.001). CONCLUSION: In pregnant women with iron deficiency anemia who were beyond 35 weeks, temporary regular contractions may be observed in the nonstress test following intravenous iron replacement. We think that this effect may lead to early term birth in pregnant women with a history of cesarean section. It needs to be confirmed by further prospective studies and animal studies.

Management of Primary Immune Thrombocytopenia: Turkish Modified Delphi-Based Consensus Statement for Special Considerations

Objective: Primary immune thrombocytopenia (ITP) is an acquired disorder of platelets with a complex and unclear mechanism of increased immune destruction or impaired production of platelets. While the management of ITP is evolving, there is still a need for guidance, particularly in certain circumstances such as pregnancy, emergencies, or patients requiring co-medications. We aimed to determine the tendencies of hematologists in Türkiye in the event of such special considerations. Materials and Methods: Applying a modified Delphi method, the Turkish National ITP Working Group, founded under the auspices of the Turkish Society of Hematology, developed a questionnaire consisting of statements regarding pregnancy, emergencies, and circumstances requiring co-treatment with antiaggregants or anticoagulants. A total of 107 hematologists working in university or state hospitals voted for their agreement or disagreement with the statements for two sequential rounds. Results: The participating hematologists reached an agreement on starting treatment for pregnant patients with platelets of less than 30x109/L and delivery either vaginally or by cesarean section being safe at platelet counts above 50x109/L. For emergencies and the rescue management of ITP, the panel agreed against the use of high-dose corticosteroids alone, preferring combinations with transfusions or intravenous immunoglobulin. For patients who require interventions, platelet counts of >50x109/L were regarded as safe for low-risk procedures as well as co-treatment with antiplatelets or anticoagulants. Conclusion: As the National ITP Study Group, we have observed the need to increase the practice guidance regarding patients with primary ITP requiring additional treatments including invasive interventions and co-treatments for coagulation. Decisions on the management of ITP during pregnancy should be individualized. There is a lack of consensus on the thresholds of platelet counts as well as co-morbidities and co-medications. This lack of consensus may be due to variations in practices.

A meta-analysis of ferric carboxymaltose versus other intravenous iron preparations for the management of iron deficiency anemia during pregnancy.

Objective: We conducted a meta-analysis of randomized clinical trials evaluating the clinical effects of ferric carboxymaltose therapy compared to other intravenous iron in improving hemoglobin and serum ferritin in pregnant women. We also assessed the safety of ferric carboxymaltose vs. other intravenous iron. Data source: EMBASE, PubMed, and Web of Science were searched for trials related to ferric carboxymaltose in pregnant women, published between 2005 and 2021. We also reviewed articles from google scholar. The keywords "ferric carboxymaltose," "FCM," "intravenous," "randomized," "pregnancy," "quality of life," and "neonatal outcomes" were used to search the literature. The search was limited to pregnant women. Selection of studies: Studies related to ferric carboxymaltose in pregnancy were scanned. Observational studies, review articles, and case reports were excluded. Randomized studies in pregnant women involving ferric carboxymaltose and other intravenous iron formulations were shortlisted. Of 256 studies, nine randomized control trials were selected. Data collection: Two reviewers independently extracted data from nine selected trials. Data synthesis: The final effect size for increase in hemoglobin after treatment was significant for ferric carboxymaltose vs. iron sucrose/iron polymaltose (standard mean difference 0.89g/dl [95% confidence interval 0.27,1.51]). The final effect size for the increase in ferritin after treatment was more for ferric carboxymaltose vs. iron sucrose/iron polymaltose (standard mean difference 22.53µg/L [-7.26, 52.33]). No serious adverse events were reported with ferric carboxymaltose or other intravenous iron. Conclusion: Ferric carboxymaltose demonstrated better efficacy than other intravenous iron in increasing hemoglobin and ferritin levels in treating iron deficiency anemia in pregnant women.

The Experience of Anaemia and Ingesting Oral Iron Supplementation in Pregnancy: A Qualitative Study.

INTRODUCTION: The objective of this study was to understand the experience of iron deficiency anaemia requiring oral iron in pregnancy and the factors affecting compliance with oral iron supplementation. Participants' understanding regarding the possible consequences of anaemia in pregnancy was also explored. Feedback on a proposed randomised controlled trial of daily versus alternate day oral iron in pregnancy was sought. MATERIALS & METHODS: Following ethical approval, fourteen semi-structured one-to-one interviews were carried out using an interview tool with open-ended questions. Recruitment was carried out through social media and from an antenatal out-patient setting. Interviews were audio-recorded, transcribed and analysed thematically. RESULTS: Fatigue emerged as a predominant and troubling symptom. Awareness was often highlighted through friends/family and from healthcare professionals, particularly in first pregnancies. Knowledge surrounding the potential short-term and long-term adverse consequences of untreated anaemia however was limited. Gastro-intestinal side-effects, a previous experience of poor tolerance and forgetfulness all negatively impacted compliance with oral iron supplementation in pregnancy. Routine, a perceived improvement in fatigue with supplementation and reduced dose frequency recurred as themes which positively affected compliance. Pregnancy as a motivating factor recurred as a theme in analysis. The role of diet was felt to be important. Knowledge of iron-rich foods and absorption aids and inhibitors was good, but practice on optimal ingestion of oral iron supplementation varied. Feedback on trial acceptability was positive with the benefit of extra supportive care noted. Incorporating study visits with routine care was advised in view of time constraints. This area of research was perceived as important. CONCLUSION: In order to successfully reduce the rates of iron deficiency anaemia in pregnancy, it is crucial that all factors affecting compliance with oral iron are considered. Providing women with the important information on the possible consequences of sub optimally treated anaemia may help to improve this public health issue.

Current obstetric outcomes in Jamaican women with sickle hemoglobinopathy - a balance of risks for aspirin?

OBJECTIVES: Sickle cell disease (SCD) occurs in 2.8 % of our Jamaican antenatal population with homozygous HbSS being most associated with adverse maternal and perinatal outcomes. METHODS: A retrospective comparative analysis of HbSS, HbSC and HbSßThal pregnancy outcomes at the University Hospital of the West Indies (UHWI) between January 2012 and December 2022 was conducted. RESULTS: Of 120 patients (138 pregnancies), obesity occurred in 36 % (20/56) of the 'non-HbSS' group, i.e. HbSßThal (55 %, 5/9) and HbSC (32 %, 15/47) combined vs. 9.7 % of the HbSS (8/82). HbSS patients had more crises requiring transfusions, acute chest syndrome (ACS), maternal 'near-misses' (OR=10.7, 95 % 3.5-32.3; p<0.001), hospitalizations (OR 7.6, 95 % CI 3.4-16.9; p<0.001), low birth weight (LBW) neonates (OR 3.1, 1.1-8.9; p=0.037) and preterm birth (OR=2.6, 1.2-5.8; p=0.018) compared to HbSC and HbSßThal. Low dose aspirin was prescribed in 43 %. Logistic regression showed those NOT on aspirin (n=76) had more miscarriages (22 v. 2 %), were LESS likely to have a live birth (75 v. 95 % (0.2, 0.04-0.57, p=0.005)), but surprisingly had fewer painful crises (28 v. 46 % (0.5, 0.03-0.9, p=0.03)). CONCLUSIONS: HbSS women had a 10-fold excess of maternal near-misses. Additional research may further clarify the effects of aspirin on pregnancy outcomes as related to SCD genotypes.

Successful management of refractory immune-mediated thrombotic thrombocytopenic purpura during pregnancy and delivery using the anti-VWF nanobody caplacizumab.

Pregnancy is a potential trigger of acute thrombotic thrombocytopenic purpura (TTP). The management of pregnancy-associated immune-mediated TTP (iTTP) can be challenging, especially when it is refractory to standard treatment. Caplacizumab, a nanobody to von Willebrand factor (VWF) blocking its A1 domain, is a valuable new therapeutic option. Its use is, however, not approved during pregnancy and breastfeeding. We describe the successful off-label administration of caplacizumab during pregnancy and delivery in a patient with refractory iTTP. The favourable outcome without significant thrombotic or haemorrhagic complications indicates that caplacizumab may be an effective and safe treatment option in refractory iTTP during pregnancy.

Clinical outcome post treatment of anemia in pregnancy with intravenous versus oral iron therapy: a systematic review and meta-analysis.

Oral iron therapy is often the most common way of treating anaemia; however intravenous iron is considered effective due to rapid iron replenishment. We have dearth of evidence on clinical outcomes post treatment of anaemia. We have searched studies published in English in PubMed, Cochrane, Scopus, ProQuest, and Google Scholar. Our study analysed the clinical outcomes amongst neonates and mother and the adverse events post treatment and assessed the mean change in maternal haemoglobin concentration in both the groups. Forest plots for the clinical outcomes are presented. From a total of 370 studies, 34 Randomized and quasi experimental studies comparing clinical outcomes post-treatment of anaemia in pregnancy were included for quantitative evidence synthesis. Pooled results of maternal clinical outcomes using random effect model [OR: 0.79 (95% CI 0.66; 0.95); 10 outcomes; 17 studies] showed statistically significant difference among both the groups [Moderate quality evidence]; however no significant difference [OR: 0.99 (95% CI 0.86; 1.14); 7 outcomes; 8 studies] have been observed for neonatal complications [Low quality evidence]. The study found that pregnant women receiving IV iron were significantly less likely to experience adverse events as compared with those receiving oral iron [OR 0.39;  (95% CI 0.26-0.60)]; 34 studies; 13,909 women; [Low quality evidence]. Findings from meta-regression analysis showed that IV iron is more likely to reduce maternal complications by 21% compared to oral iron. Increase in odds of adverse maternal outcomes was observed due to increase in gestational age and publication year but no effect for the type of drug used. IV iron increases Hb more and at a higher pace than oral iron. Intravenous iron is more likely to avert adverse maternal outcomes and adverse reactions. However, there is no conclusive evidence on its effectiveness on individual maternal outcome or neonatal outcome/s. Protocol registered with PROSPERO CRD42022368346).

Assessment-based management of placenta-mediated pregnancy complications: Pragmatism until a precision medicine approach evolves.

The management of pregnant women with thrombophilia and a history of gestational vascular complications remains debatable. Treatment of the latter is often based on clinical outcome rather than disease mechanism. While the use of venous thromboembolism prophylaxis in pregnancy is recommended for those at increased risk, the ability of anticoagulant and/or antiplatelet agents to lower the risk of placenta-mediated complications in this clinical setting remains controversial. The available guidelines are inconsistent in some situations, which reflects the limited evidence base. This review critically discusses risk assessment models (RAMs) and management strategies of women with thrombophilia and pregnancy complications, using clinical vignettes. RAMs, taking into account obstetric and thrombotic history as well as thrombophilia status, could drive a precision medicine approach, based on disease mechanism, and guide individual therapeutic interventions in high-risk clinical settings.

Association of lupus anticoagulants with risk factors for obstetric complications and adverse gestational outcome.

BACKGROUND: Lupus anticoagulant (LA) may be a cause of poor obstetric outcome. OBJECTIVE: To search the association of LA with risk factors for obstetric complications and adverse gestational outcome. METHODS: This retrospective cohort was consisted of 2 groups of pregnancies with poor obstetric history; 1) LA (+) gestations (Study Group, n= 20) and 2) LA (-) gestations (Control Group, 78). All patients were admitted to a special antenatal care program and were examined in terms of risk factors for thrombotic events, placenta-related obstetric complications, and poor gestational outcomes. Patients were administered low-dose low-molecular-weight heparin (LMWH), low-dose salicylic acid and low-dose corticosteroid (if necessary) within the framework of a prophylaxis protocol in addition to their already existing medications. RESULTS: We have shown that adverse gestational outcome was 1.7-fold more frequent in LA (+) pregnancies with poor obstetric history (p= 0.039, 70% vs. 41%). Higher rates of autoimmune diseases and hereditary thrombophilia were observed among LA (+) patients compared to LA (-) gestations (35% vs. 10.3%, p< 0.012 and 55% vs. 19.2%, p< 0.003, respectively). To identify the effectiveness of low-dose LMWH prophylaxis protocol, we compared gestational outcomes and demonstrated that the miscarriage rate was significantly decreased to half in current pregnancies compared to the previous gestations (73.6% vs. 35%, p= 0.003). CONCLUSIONS: Autoimmune diseases and hereditary thrombophilia are more frequent in LA (+) pregnancies, and these women are prone to obstetric problems. Low-dose LMWH and salicylic acid prophylaxis are critical in the management of LA (+) pregnant women.