Management of sickle cell disease in pregnancy. A British Society for Haematology Guideline

Abstract

This guideline was compiled according to the British Society of Haematology (BSH) process at https://b-s-h.org.uk/guidelines/proposing-and-writing-a-new-bsh-guideline/. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org This BSH guideline was developed and updated from a previous Royal College of Obstetricians and Gynaecologists (RCOG) Green-top guideline1 in accordance with the standard method of producing BSH guidelines. Medline, Embase, the Cochrane Database of Systematic Reviews, the Cochrane Control Register of Controlled Trials (CONTROL), the Database of Abstracts of Reviews and Effects (DARE), the ACP Journal Club and the Ovid database were searched for relevant randomised controlled trials, systematic reviews and meta-analyses between 2000 and August 2018. In all, 218 papers were identified. Search terms included: ‘sickle cell’, ‘hydroxycarbamide’, ‘antenatal’, ‘pregnancy’, ‘intrapartum’, ‘penicillin prophylaxis’, ‘ACE inhibitor’, ‘transfusion’, ‘ultrasound’, ‘Doppler’, ‘echocardiogram’, ‘anti-coagulation’, ‘prophylaxis’, ‘sickle cell and risk factors’, ‘preconceptual’ and ‘sickle cell crisis’ and included all relevant Medical Subject Headings (MeSH) terms and subheadings. The search was limited to humans and the English language. The National Library for Health and the National Guidelines Clearing House were also searched for relevant guidelines. Review of the manuscript was performed by the BSH Guidelines Committee, General Haematology Task Force, the BSH Guidelines Committee and the members of the sounding board of BSH. It was also placed on the members’ section of the BSH website for comment. It has also been reviewed by the Royal College of Obstetricians and Gynaecologists, Sickle Cell Society and BSH Obstetric Haematology Special Interest Group; these organisations do not necessarily approve or endorse the contents. The purpose of this guideline is to describe the management of sickle cell disease (SCD) in pregnancy in the UK. It will cover preconception screening and antenatal, intrapartum and postnatal management of women with the condition. It will not cover the management of women with sickle cell trait. Updates from the previous guideline1 include new information on pre-implantation genetic diagnosis (PGD), more comprehensive information on pre-conceptual screening and medication review, updated information on thromboprophylaxis, aspirin and vitamin D, changes to advice on antenatal care including frequency of ultrasonography (USS) scanning. It also includes reference to the most recent National Institute for Health and Clinical Excellence (NICE) and RCOG guidelines. SCD comprises a group of conditions caused by the inheritance of the abnormal haemoglobin sickle gene (HbS). The most severe form of SCD is homozygous SCD (HbSS) but SCD can also be due to compound heterozygous genotypes of HbS and another haemoglobin variant (e.g., HbC, HbDPunjab, HbE or β thalassaemia, see Table I). Sickle cell disease is one of the most common inherited condition worldwide, with over 300 000 children born with the condition each year globally, three-quarters of whom are born in Africa.3 The prevalence of SCD varies considerably across different ethnic communities, predominantly affecting people of African or African–Caribbean origin. Owing to population migration, SCD is now of increasing importance worldwide and there are increasing numbers of affected individuals in Europe and the United States. Within Europe, the UK has the largest population with the condition. In the UK it is estimated that there are 15 000 affected individuals, and approximately 300 infants born with the condition each year. The pathophysiology of SCD is the consequence of polymerisation of the abnormal sickle haemoglobin in low oxygen conditions leading to the formation of rigid and fragile sickle-shaped red cells. These cells are prone to increased breakdown, which causes haemolytic anaemia and the sickle-shaped red cells do not flow through blood vessels easily, causing blockage (vaso-occlusion) in small vessels, leading to most of the clinical features, including acute painful crises. Other complications of SCD include acute chest syndrome, pulmonary hypertension (PH), stroke, renal dysfunction, retinal disease, leg ulcers, cholelithiasis and avascular necrosis. SCD was previously associated with high childhood mortality, but now, in high-resource countries with neonatal screening and lifelong treatment, life expectancy is at least the mid-50s. With the majority of individuals born with SCD in the UK living to reproductive age and beyond, management of this condition in pregnancy is now more pertinent. There are approximately 110–200 pregnancies in women with SCD per year in the UK.4 Pregnancy in women with SCD is associated with higher risk of mortality and morbidity.4, 5 Data from a national study in the UK showed an increased risk of both sickle-related complications (acute pain, acute chest syndrome) and pregnancy-related complications [hypertension, venous thromboembolism (VTE) and urinary tract infections].4 A retrospective study has shown that pregnancy-related VTE in women with SCD appears to be 1·5–5 times greater than in the general population.6 Women with SCD were more likely to require blood transfusion or admission to the critical care unit. Women with SCD were more likely to deliver before 37 weeks of gestation and the babies were more likely to have a reduced birth weight. Whilst most of these complications were more common in women with HbSS than HbSC, both groups of women experienced an increased risk of complications. A systematic review and meta-analysis of studies in pregnancy in SCD confirmed these findings showing significant increases in maternal mortality, pre-eclampsia, stillbirth, preterm delivery and infants that are small for gestational age.5 Meta-regression demonstrated that increased relative risks were associated with genotype (HbSS versus HbSC) and low gross national income. Although women with HbSC experience fewer adverse outcomes than women with HbSS, they are still susceptible to increased painful crises during pregnancy, antenatal admission and and these women have the of and care for with There are fewer on pregnancy outcomes in women with or but evidence that these be and of pregnancy and be care for women with SCD and be of the comprehensive review from and this in This include of reproductive of to preconception and review of be and Women with SCD have a is a of a β variant (e.g., HbC, β will have a risk of to in each pregnancy of a with a Women with SCD be reproductive diagnosis or by an and this be Women are not of the of and do not have the to or in A review in a showed that over a over all of a birth of per This was higher than the previously birth This that there were significant to and a of of children with SCD found that been of to that of and relevant in a A comprehensive review is of of pregnancy and and review of complications be of this The outcomes of the most recent review be in is of importance include of renal and complications in to of with SCD during and are by and from with the of and disease in to pregnancy, women have blood and screening with and urinary or Women with in renal or be to be in women with a blood of of medication the and are all increased in SCD and has been used a for and screening for A is associated with increased mortality and increased risk of A small study has shown that of women a but this was not associated with Women pregnancy have screening with this has not been performed in the previous year and at they have of Other significant previous also be for of disease this clinical Other complications of SCD that screening and to on pregnancy are in Table A review of be performed to is for with SCD in of haemolytic anaemia that at increased risk of is also in all women to and be 5 be pregnancy and during pregnancy both to the risk of and to also for the increased during is common in with SCD and and for are is for all and women in the women with SCD be vitamin per national for and it be to vitamin levels to with SCD are and are at risk of in from and is of in children with but there is randomised evidence in In of and increased risk of women with SCD or this they are not also be reviewed and updated per national and this include and this has not been the previous The to during pregnancy be with women of management and can be during pregnancy these are not be used with before weeks and weeks of gestation to the risk of of the be with to a of standard care be reviewed and be to that are used in SCD including or for renal dysfunction, and The recent Guidelines that women with disease are have a for by the strength of for and the of pregnancy and that are in of In these women renal and be at least women will be to pregnancy this has been shown to the of acute painful and acute chest in individuals with severe clinical of SCD and is the for SCD in the is in and in pregnancy has been in a previous BSH This in women are due to and severe sickle with red cell be an women do it be There are in the of women in pregnancy both for SCD and for and of these have it pregnancy adverse on the have been that for women with severe disease and the risks of include increased risk of acute chest and the risks of This is for women are not to blood transfusion of red cell or previous severe haemolytic transfusion these a between the the and the to pregnancy to with information the risks and of pregnancy to to the for for be the in is A clinical is retrospective on during pregnancy Pregnancy and are not during pregnancy due to a of they be in the and be a is to Women with be with and to to at high risks of complications. there is evidence of this be to is in but it women be to to and can be including and are not for during pregnancy and be to or pregnancy is confirmed Although these are not for in the UK at the of they be at and women have been these from It is that has a affected is a or is affected by a significant is of this and and be information can be on the Sickle Cell website which includes information the that can The of the screening is to that screening are by weeks of pregnancy by care or that diagnosis can be diagnosis or be in pregnancy to to of an affected pregnancy diagnosis can be performed from weeks of gestation and is associated with a low risk of are diagnosis of in the maternal but this is not the of this to be that increased to have women preconception all of the in the section on preconception care including review of for red cell and during be but be the of antenatal care is for and of general and complications. on antenatal care for the is by of complications care and between is to and for transfusion and and management of SCD complications including acute and management of be The frequency of will on and the of complications but a is per for clinical blood blood and to These are in Table general advice and not Review and Clinical to assess SCD complications renal and complications Review women are 5 and and oxygen and blood for and advice SCD and pregnancy Review and blood renal and group and red cell not previously performed aspirin vitamin not on this for VTE and Review management per review and per antenatal guideline and of and and of and and group and Review VTE risk and of and and at weeks or and of and to aspirin to delivery information and advice and of delivery each be for information and and of and The and be and that the of acute crises (e.g., for increased be with and be be used with before weeks and weeks of gestation to of the be to women with it not be for women can to and sickle cell and women with be to advice be and to admission and gestation in women with SCD increases the risk of acute and acute these pregnancies require and increased Women with SCD have an increased risk of hypertension and 37 is at from weeks of gestation for women at high risk of they have aspirin Although there is evidence that aspirin the risk of in women with in of increased risk that women with SCD and be aspirin from evidence that aspirin the risk of be at for is of antenatal care for all women and blood and the of be at each Women with or renal will require more and be with a pregnancy Women with SCD have a low blood an in blood be A blood of be on recent Society of for all with This is than for women In women with it is to from the complications of be performed per the A of studies an increased risk of and babies that are small for gestational age in the of women with be for of to of delivery and to mortality and in of the times increased risk of A levels are performed in the and the is of the more has been used in women with SCD to severe anaemia and sickle-related complications. It also pregnancy complications by the of in the maternal and and blood flow and oxygen to the These be the of transfusion including the risk of and risk of haemolytic transfusion The of blood for transfusion of women with SCD be and and in with previous BSH A transfusion be from the at the or and include with the transfusion and national transfusion database to there are with be to the red cell or screening for haemolytic disease of the for of A in the management of women with SCD the to blood transfusion during is to blood by the clinical for for acute anaemia or acute complications. The is to blood this is used include or transfusion be at gestation transfusion be and is there a or that be This has been in a previous BSH guideline and a recent There is evidence to transfusion over standard care and there is evidence that transfusion will during pregnancy it is not the of transfusion will the risks of transfusion (e.g., The recent that there was evidence to a of transfusion than standard A clinical is the of blood transfusion in women with SCD In one randomised including women and in the women standard care or transfusion with or transfusion to and In the standard care of women There was a significant in crises in the transfusion risk but in outcomes mortality, mortality or severe maternal this be by the small numbers included in the There was from the A Cochrane not randomised and that there were clinical of transfusion over standard There have been on outcomes of transfusion in pregnancy and a meta-analysis has on the previous randomised clinical and studies This meta-analysis demonstrated that transfusion was associated with a in maternal mortality, pulmonary mortality, neonatal and preterm There was in pulmonary acute chest syndrome, urinary tract pre-eclampsia, infants that are small for gestational age or have a low birth weight. The were low for most of the outcomes and they that transfusion on severe maternal and neonatal outcomes but the evidence from a small of There has been a at outcomes of women with HbSC and women transfusion with women transfusion on or transfusion but numbers were small and were it is not to the of transfusion in women with Women are on transfusion on this during pregnancy at the Women on will be to this to and transfusion be they experience a of sickle they or they have a severe the of transfusion are not to the standard care is to transfusion on There is evidence to or be used for care and most evidence from the care of with The randomised of transfusion used an of an for transfusion and this was used in previous RCOG for a higher during pregnancy this will on and of Women with severe sickle complications (e.g., acute chest syndrome, or be with transfusion in with There is evidence the or to A randomised at in with HbSS showed that transfusion to was associated with reduced sickle acute chest section was not included in this and the complications were due to general Women with anaemia from transfusion to Pregnancy is associated with an increased of acute painful in both HbSS and to a HbSC In a UK acute was the most common affecting of women with or severe crises or in of women with HbSS and of women with HbSC painful crises were also higher in the HbSS in of HbSS and of HbSC women There are a of for the increased of including increased and in pregnancy and are which is common in pregnancy, to increased and red cell the in pregnancy to and the increased risk of for urinary or which can a sickle by delivery or is a and can the risks of and significant which can all to a higher of women with SCD with causes of acute or A is to the is for and not be women have a management for in the of a that have been developed and with the and the and with all with care including general and This be at and reviewed at There be a low for a to care and all women with that not with are have or chest or of of be to There are randomised controlled the management of painful in women with of acute in women national to women with to for evidence of of for the be in the with and or or be used with in the and weeks of gestation due to the risk of of the a will to be to the The for the management of acute that be of in a and the be controlled of There is evidence to women be severe pain, or can be by the or on the and be of the risk of and in with a with sickle be for complications and A of a including and blood oxygen and be and With of and be at Women be for in an with experienced with in women with on and the gestation of the and the of it be to on a a an or in a or critical care and the and care be and by this group and with the and be and be and be to and be reviewed at least in a with renal disease or with is a be and oxygen the or review be due to the risk of acute chest and pulmonary and oxygen be There be to care oxygen be with oxygen or Women with or chest be an The be for and and A chest be performed the has on chest or is per the guideline be the is or there is a high clinical of blood cell are in women and in SCD and do not necessarily be for women with SCD are to with painful there is a Other be to the adverse of to or to and be the painful most women are to but this be by the previous In an of the gestation of the is before the for weeks and is not to be by scanning. weeks be performed in to not performed in the chest is an of SCD affecting to of women with It is by and a new pulmonary on chest be for this and all have a guideline that includes the for diagnosis and include chest and blood blood be in with low oxygen severe is a of and The diagnosis is which be in with a chest and chest is and includes for causes be including blood for and and and for management will include and of or transfusion be in the A transfusion in or severe disease but transfusion will be there are of clinical or a of to The critical care be in the care of with severe clinical or in a to or an of acute chest the be blood transfusion the of stroke, both and is associated with and this diagnosis be in with SCD with acute is a and and to the and blood transfusion can The of be with a and In women with it is to disease due to SCD from anaemia in women with SCD be to with in SCD causes a red cell and an by a a be in with an acute anaemia with is with blood transfusion and the be With there is the risk of to the a review by a is to assess Women with SCD can anaemia to or causes of anaemia to the causes of anaemia in SCD include in women with a Pregnancy is a risk for VTE for women but this risk is in women with In a recent the risk of VTE and were increased to a The prevalence of VTE was greater in women with complications acute chest and to these but was in with more severe In this study and of VTE were in the antenatal and to the higher of in women with chest or acute chest and the in a high of for is these Women of VTE be according to RCOG Green-top The of and during Pregnancy and the There are randomised controlled to the of systematic review and increased mortality, during the of pregnancy, in due to the complications of The risks of stillbirth, pre-eclampsia, and acute sickle cell are increased and A birth be in with the to include of of for and that be to the increased risk of and pre-eclampsia, delivery between and weeks is to complications and associated adverse Whilst studies delivery the of delivery for women with recent studies UK of delivery the of with the for the section on 5 section increases the risk of and VTE birth not be for women with SCD in the of risk or Women with SCD are more at risk of section of the increased complications pre-eclampsia, and the for avascular of the can to and and in women with severe a to the risk of intrapartum SCD a management for to with of of oxygen and of a form the of the intrapartum management of a with General risks the and be Women be review by an in the of pregnancy to these be of the risk of to a with There are randomised controlled the of birth for women with SCD but women be to birth in that are to both the complications of SCD and Obstetricians to be of the increased frequency of sickle cell and in the intrapartum and of the increased risk of painful with This is to and in this the be is the be section be is not and delivery is not is not or is be a to venous is to the be to the The for oxygen is increased during the intrapartum and the of to in the is during blood be and oxygen oxygen is or in is not by but of be A The have a low to There are randomised controlled during for women with SCD but during is is of the increased of stillbirth, and Sickle cell in be per the for is and and be for women in It is for to the risk of sickle cell increased with of women a delivery and more common general and be and be for are in the and can be used during and infants are at risk from the adverse of not be during and and can be used but be at the for the and be for and be in women the is at high risk of SCD the is a affected or for SCD be be to there is experience in the of SCD in care be per the guideline on postnatal are in the in the form of is the is in and for weeks Women be the on and the of to be the risks of an pregnancy, is an in the care of women with SCD and advice be to the care all have and the of be the and of There is with that the risk of or sickle be A retrospective study of women with of which were showed a increased risk of associated with for risk there was significant A systematic review found of on the frequency of sickle crises or adverse and on associated with sickle evidence the are that be used with risk by risk The updated of the the the and the have not been shown to have and there is evidence of clinical study showed to an in painful has been found to painful and an of in has been associated with in women with with clinical by of With the be for the weeks but most women will see reduced The The is due to the increased risk of blood but it is still that the the are in women with SCD but than of The majority of women with SCD in the UK will reproductive age and of and pregnancy form of Pregnancy is a of increased risk for women with SCD with increased of maternal and complications. each have a for the management of women with This an that has for the care of women with including an with in pregnancies and a with a low prevalence of SCD be to a or for care and and all in care in the care of women with The majority of the in this are of low the limited and of clinical in this and are on they are likely to be updated clinical evidence There is a for clinical in this to The to for in the The BSH General Haematology Task members at the of this guideline were and The to the BSH sounding and the BSH Guidelines Committee for in this to and for the of the BSH Obstetric Special Interest The BSH the during the of this have a of to the BSH and Task which be on The have and for is by the and is also a and of Health The members of the group have of to of the group will the group new evidence that the strength of the in this or it The will be reviewed by the relevant Task and the search will be to search for new evidence that have been The will be and from the BSH website it new are an will be on the BSH website the advice and information in this are to be and at the of to the the the for the of this