Chronic kidney disease (CKD) is estimated to affect 3% of pregnant women in high-income countries,  which equates to between 15,000–20,000 pregnancies per year in England. The prevalence of CKD in pregnancy is predicted to rise in the future due to increasing maternal age and obesity.Although CKD is not a barrier to reproduction in most women, the risk of adverse pregnancy outcomes is increased in women with CKD including pre-eclampsia, fetal growth restriction, preterm delivery and accelerated loss of maternal renal function. CKD impacts on communication, decision-making, and the surveillance and management of women before, during, and after pregnancy.KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD). UK Renal Association Commentary available at: BMC Nephrology 2018; 19: 240.KDOQI Clinical Practice Guideline for Haemodialysis, 2015.KDIGO Clinical Practice Guideline for the Evaluation and Management of CKD, 2012KDIGO Clinical Practice Guideline for Glomerulonephritis, 2012KDIGO Guideline for the Care of Kidney Transplant Recipients, 2009.KDIGO Clinical Practice Guidelines for Nutrition in Chronic Renal Failure, 2008.NICE: Intrapartum Care for Women with Existing Medical Conditions or Obstetric Complications and their Babies [NG121], 2019.NICE: Urinary Tract Infection (Lower) Antimicrobial Prescribing [NG109], 2018NICE: Urinary Tract Infection (Recurrent) Antimicrobial Prescribing [NG112], 2018.NICE: Antenatal Care for Uncomplicated Pregnancies [CG62], 2008, updated 2017.NICE: Vitamin D supplement use in specific population groups [PH56], 2017NICE: Diabetes in Pregnancy: Management from Pre-conception to the Post-partum Period [NG3], 2015.NICE: Antenatal and postnatal mental health: clinical management and service guidance [CG192], 2014, updated 2018.NICE: Fertility: Assessment and Treatment for People with Fertility Problems, 2013.https://www.nice.org.uk/guidance/ph11/evidence/appendix-a-summary-of-evidence-from-surveillance-pdf-4671107966]NICE: Weight management before, during and after pregnancy [PH27], 2010 [additional data from 2017 surveillance available at: NICE: Hypertension in Pregnancy: Diagnosis and Management [CG107], 2011 (update awaited 2019).UK Renal Association Clinical Practice Guidelines: Undernutrition in Chronic Kidney Disease, June 2019RCOG: Thrombosis and Embolism During Pregnancy and the Puerperium, Reducing the Risk [Green-Top Guideline 37a], 2015.MBBRACE Confidential Enquiry into Maternal Deaths and Morbidity: lessons learned to inform maternity care www.european-renal-best-practice.org/content/erbp-documentsExisting guidance on the management of CKD in pregnancy includes the UK Consensus Group on Pregnancy in Renal Disease  and expert review. Neither Kidney Disease Outcomes Quality Initiative (KDOQI) or National Institute of Health and Care Excellence (NICE) have produced specific guidance on the management of renal disease in pregnancy. Published guidance containing information relevant to the care of women with CKD in pregnancy includes:The aim of this guideline is to improve the standard of, and to reduce regional variation in, the care of women with CKD in the UK who are pregnant, planning a pregnancy or post-partum.This guidance covers the care of women with CKD  who are planning a pregnancy, pregnant, or in the post-partum period. It also covers contraception and fertility for women with CKD.General practiceCommunity and hospital antenatal clinicsAntenatal, labour and postnatal wardsRenal out-patientsRenal wardsDialysis unitsThis guideline can be used in the following settings:The target audience and intended users of this guideline are nephrologists, obstetricians, obstetric physicians, midwives, renal nurses, pharmacists, specialist trainees in both nephrology and obstetrics, and women with CKD who are pregnant or considering pregnancy. Qualitative data on the experience of pregnancy and renal disease is provided in The clinical issues covered in this guideline are:3.1. Contraception3.2. Fertility3.3. Pre-pregnancy counselling and optimisation for pregnancy4.1Assessment of renal function in pregnancy4.2Antenatal care4.3Pre-eclampsia prophylaxis4.4Blood pressure management4.5Thromboembolism prophylaxis4.6Anaemia4.7Bone health4.8Renal biopsy4.9Peripartum care4.10Postnatal care5.1Renal transplantation5.2Dialysis5.3Lupus5.4Diabetic nephropathy5.5Urinary tract infection (UTI)5.6Congenital Abnormalities of the Kidney and Urinary Tract (CAKUT)Clinical issues that will not be covered are acute kidney injury and renal stone disease. In addition, fertility, contraception, teratogenicity and genetic implications in men with CKD will not be addressed.Literature searches were undertaken using Ovid Medline (1946 to 2018) using specific search terms related to each of the clinical issues covered in the guideline. Search terms are detailed in We recommend multidisciplinary teams  are established to offer advice and care for women with CKD who are pregnant or planning a pregnancy. All healthcare professionals caring for women with CKD should be able to access this MDT (1D).We recommend that low dose aspirin, low molecular weight heparin, labetalol, nifedipine, methyldopa, prednisolone, azathioprine, ciclosporin, tacrolimus and hydroxychloroquine are safe for use in pregnancy (1B).We recommend concentrations of calcineurin inhibitors  are checked throughout pregnancy and immediately postpartum, as blood concentrations may change (1C).We recommend that medications which interfere with calcineurin inhibitor metabolism  are avoided in pregnant and post-partum women taking tacrolimus or ciclosporin whenever possible (1D).We recommend mycophenolate mofetil, methotrexate and cyclophosphamide are not taken in pregnancy as they are teratogenic (1B).We recommend mycophenolate mofetil is stopped before pregnancy, as use in pregnancy is associated with an increased risk of spontaneous miscarriage and fetal abnormality. A 3-month interval is advised before conception to allow conversion to a pregnancy-safe alternative and ensure stable disease/kidney function (1C).We recommend that, when other treatment options exist, rituximab is avoided in pregnancy due to the risk of neonatal B cell depletion and unknown long-term outcomes (1D).We recommend sirolimus and everolimus are avoided in pregnancy due to insufficient safety data (1D).We suggest the benefits of eculizumab in pregnancy for organ threatening disease are likely to outweigh risk (2D).2 and stable renal function during pregnancy (1D).We recommend metformin can be used in pregnancy for women with a pre-pregnancy eGFR>30mls/min/1.73mWe recommend immunosuppressive treatment is not increased routinely in the peripartum period and that dose changes are based on clinical indications and blood concentrations (1D).We recommend women can breastfeed whilst taking prednisolone, hydroxychloroquine, azathioprine, ciclosporin, tacrolimus, enalapril, captopril, amlodipine, nifedipine, labetalol, atenolol and low molecular weight heparin (1C).We recommend advice on safe and effective contraception is offered to all women of reproductive age with CKD (1D).We recommend safe and effective contraception is offered to women of reproductive age who are taking teratogenic medication, have active glomerulonephritis, are within one year of renal transplantation or acute graft rejection, and for any woman who does not wish to conceive (1D).We recommend that the progesterone only-pill, a progesterone subdermal implant, and the progesterone intra-uterine system are safe and effective for women with CKD (1C).We recommend that progesterone-only emergency contraception is safe for women with CKD (1C).We suggest fertility preservation is considered for women of reproductive age who require treatment with cyclophosphamide (2C).We suggest women who have had previous treatment with cyclophosphamide have early investigation of infertility (2D).We recommend women with CKD are referred for pre-pregnancy counselling before receiving assisted reproduction (1D).We recommend single-embryo transfer is performed to reduce risk of complications associated with multifetal pregnancies in women with CKD (1C).We suggest women with CKD considering pregnancy are offered pre-pregnancy counselling by a multidisciplinary team including a consultant obstetrician and nephrologist or expert physician (2D).We recommend women with CKD are advised there is an increased risk of complications in pregnancy including pre-eclampsia, preterm birth, fetal growth restriction, and neonatal unit (NNU) admission, and that they are more likely to require caesarean delivery (1C).We recommend women with known or suspected inheritable renal diseases are offered genetic counselling including inheritance risk, prognosis, and intervention options including pre-implantation genetic diagnosis (1C).stabilising disease activity in advance of pregnancy on minimised doses of pregnancy-appropriate medications (1B).optimising blood pressure control (< 140/90 mmHg) on pregnancy-appropriate medications (1B).optimising glycaemic control in women with diabetes mellitus (1A) (see section 5.4).minimising risk of exposure to teratogenic medications (1C) (see section 2).making a treatment plan in the event of hyperemesis or disease exacerbation/relapse during pregnancy (1D).We recommend pre-pregnancy counselling for the optimisation of maternal and neonatal outcomes in women with CKD, which may include:We recommend women with CKD who are taking angiotensin converting enzyme inhibitors have a plan for discontinuation/conversion guided by the strength of indication for renin-angiotensin blockade and the likelihood of pregnancy confirmation in the first trimester (1B).We recommend angiotensin receptor antagonists are discontinued in advance of pregnancy (1D).We suggest women with CKD stages 4 and 5 contemplating pregnancy are offered pre-dialysis education (2D).We recommend renal function in pregnancy is assessed using serum creatinine concentrations as estimated GFR (eGFR) is not valid for use in pregnancy (1C).We recommend women with CKD have formal quantification of proteinuria in pregnancy (1D).We recommend quantification of proteinuria is undertaken by protein:creatinine ratio (uPCR) or albumin:creatinine ratio (uACR). Twenty-four hour urine collection for quantification of protein is not required (1B).We suggest pregnant women with CKD who have not had pre-pregnancy counselling by the MDT are referred to the MDT and receive the same counselling and optimisation as for women attending pre-pregnancy (2D).We recommend pregnant women with CKD receive routine antenatal care, in addition to specialist input (1D).We recommend pregnant women with CKD be referred for assessment by a consultant obstetrician (1D).We recommend pregnant women with CKD have access to usual trisomy screening with specialist interpretation of high-risk results (1C).We recommend women with CKD exposed to teratogenic drugs in the first trimester are referred to a specialist fetal medicine unit (1D).We recommend pregnant women with CKD have scans to assess fetal growth and wellbeing in the third trimester (1C).We recommend pregnant women taking prednisolone and/or calcineurin inhibitors are screened for gestational diabetes (1C).We recommend women with CKD are offered low-dose aspirin (75-150 mg) in pregnancy to reduce the risk of pre-eclampsia (1B).We suggest kidney donors are offered low dose aspirin (75 mg–150 mg) to reduce the risk of pre-eclampsia (2D).We recommend that the target blood pressure during pregnancy for women with CKD is 135/85 mmHg or less, which should be documented in the woman’s healthcare record (1D).We suggest antihypertensive treatment in women with CKD is continued in pregnancy unless systolic blood pressure is consistently < 110 mmHg systolic, or diastolic blood is pressure consistently < 70 mmHg diastolic BP, or there is symptomatic hypotension (2D).We recommend labetalol, nifedipine and methyldopa can be used to treat hypertension in pregnancy (1B).We recommend angiotensin converting enzyme inhibitors, angiotensin receptor antagonists and diuretics are not used to treat hypertension in pregnancy (1B).in a woman with non-proteinuric CKD, if she develops new hypertension (systolic BP > 140 mmHg and/or diastolic BP > 90 mmHg) and proteinuria (uPCR > 30 mg/mmol or uACR > 8 mg/mmol) or maternal organ dysfunction after 20 weeks’ gestation (1B).in a women with proteinuric CKD if she develops new hypertension (systolic BP > 140 mmHg and/or diastolic BP > 90 mmHg) or maternal organ dysfunction after 20 weeks’ gestation (1B)in a women with chronic hypertension and proteinuria, if she develops maternal organ dysfunction after 20 weeks’ gestation (1B).We recommend a diagnosis of superimposed pre-eclampsia is considered:We suggest in women with chronic hypertension and proteinuria that the development of sustained severe hypertension (systolic BP > 160 mmHg and/or diastolic BP > 110 mmHg or doubling of antihypertensive agents) and/or a substantial rise in proteinuria (doubling of uPCR or uACR compared to early pregnancy) should prompt clinical assessment for superimposed pre-eclampsia (2D).We suggest a role for angiogenic markers (PlGF±sFlt-1) is considered as an adjunct to diagnose superimposed pre-eclampsia, dependent upon on-going research in women with CKD (2C).We recommend that women with nephrotic-range proteinuria (uPCR> 300 mg/mmol or ACR > 250 mg/mmol) be offered thromboprophylaxis with low molecular weight heparin in pregnancy and the post-partum period unless there is a specific contraindication including risk of labour or active bleeding (1D).We suggest that non-nephrotic range proteinuria in pregnancy is a risk factor for thrombosis and thromboprophylaxis with low molecular weight heparin should be considered in the presence of additional risk factors (2D).We recommend pregnant women with CKD are given parenteral iron if indicated (1C).We recommend erythropoietin stimulating agents are given if indicated in pregnancy (1C).We recommend women with CKD who are vitamin D deficient be given vitamin D supplementation in pregnancy (1B).We recommend calcimimetics are discontinued in pregnancy (1D).We recommend non-calcium based phosphate binders are discontinued in pregnancy (1D).We recommend if a histological diagnosis will change management in pregnancy then renal biopsy can be performed in the first and early second trimester of pregnancy (1C).We recommend women with CKD receive routine peripartum care, with additional specialist input (1D).We recommend women with CKD have observations taken and documented during any hospital admission. This includes temperature, heart rate, blood pressure, respiratory rate, and oxygen saturation. An early warning score should be calculated and actioned appropriately (1D).We recommend additional assessment for women with an elevated early warning score, for women considered to be high-risk, and for any women in whom there is any clinical concern. This includes examination of jugular venous pressure, lung auscultation and urine output monitoring  in addition to routine parameters (1D).We recommend women with CKD at risk of volume depletion or volume overload are highlighted by the MDT in advance of delivery (1D).We recommend that fluid balance is managed with the aim of maintaining normal fluid volume, avoiding dehydration and pulmonary oedema, with input from clinicians with expertise in fluid balance and renal disease (1D).We recommend all clinicians are aware of the increased risk of pulmonary oedema in women with CKD and pre-eclampsia (1D).We recommend the timing of birth for women with CKD is determined by obstetric indications, with consideration of renal factors including deteriorating renal function, symptomatic hypoalbuminaemia, pulmonary oedema, and refractory hypertension (1D).We recommend that non-steroidal anti-inflammatories should not be given (1C).We recommend women with CKD have a planned early postpartum renal review (1D).We recommend that women with CKD are prescribed medications that are compatible with breastfeeding whenever possible (1D).We recommend that women with CKD are offered safe and effective contraception post-partum and receive updated pre-pregnancy counselling before future pregnancies (1D).We recommend women with renal transplants wait until their kidney function is stable on medications that are safe in pregnancy before conceiving, which is usually more than one year after transplantation (1D).We recommend that plans for delivery in a woman with a renal transplant are discussed with the local surgical transplant team (1D).We recommend that mode of delivery in women with renal transplants is based on obstetric indications and maternal preference (1D).We recommend that caesarean delivery in a woman with a renal transplant patient is performed by the most senior obstetrician available, ideally a consultant (1D).We recommend that women with kidney-pancreas transplants, kidney-liver transplants, and dual kidney transplants are managed during pregnancy and delivery by a multidisciplinary team including transplant physicians and surgeons, at a transplant centre (1D).Guideline 5.2.1We recommend women established on dialysis prior to pregnancy receive pre-pregnancy counselling including the options of postponing pregnancy until transplantation (when feasible) and the need for long frequent dialysis prior to and during pregnancy (1C).Guideline 5.2.2We recommend women established on haemodialysis prior to pregnancy receive long, frequent haemodialysis either in-centre or at home to improve pregnancy outcomes (1C).Guideline 5.2.3We suggest women receiving haemodialysis during pregnancy have dialysis dose prescribed accounting for residual renal function, aiming for a pre-dialysis urea < 12.5 mmol/l (2C).Guideline 5.2.4We recommend women established on peritoneal dialysis prior to pregnancy should convert to haemodialysis during pregnancy (1D).Guideline 5.2.5We suggest haemodialysis should be initiated in pregnancy when the maternal urea concentration is 17-20 mmol/L and the risks of preterm delivery outweigh those of dialysis initiation. Gestation, renal function trajectory, fluid balance, biochemical parameters, blood pressure and uraemic symptoms should be considered in addition to maternal urea concentration (2D).We recommend that women with lupus or vasculitis should be advised to wait until their disease is quiescent for at least 6 months before conceiving (1B).We recommend that all women with lupus should be advised to take hydroxychloroquine in pregnancy unless it is contraindicated (1C).We recommend that women with lupus be monitored for disease activity during pregnancy (1D).We recommend that women who are positive for anti-Ro (SSA) or anti-La (SSB) antibodies be referred for fetal echocardiography in the second trimester (1C).We recommend women with antiphospholipid syndrome and a history of a confirmed thromboembolic event or previous adverse obstetric outcome  receive low molecular weight heparin in pregnancy and for six weeks postpartum (1B).We recommend that steroids, azathioprine, calcineurin inhibitors, intravenous immunoglobulin and plasma exchange can be used to treat lupus in pregnancy (1C).We recommend that women with diabetic nephropathy have optimisation of blood glucose, blood pressure and proteinuria prior to conception (1C).We recommend that women with diabetic nephropathy continue angiotensin converting enzyme inhibitors until conception, with regular pregnancy testing during attempts to conceive (1C).We recommend that the schedule of care, surveillance and management of women with diabetic nephropathy should be untaken according to national guidelines for diabetes in pregnancy, in addition to specialist monitoring of renal disease in pregnancy (1D).We suggest women with reflux nephropathy, congenital anomalies of the kidneys and urinary tract (CAKUT), women with CKD taking immunosuppression, and women with a history of recurrent UTI should be offered antibiotic prophylaxis during pregnancy after a single UTI in pregnancy, including asymptomatic bacteriuria (2D).We recommend pre-pregnancy UTI prophylaxis be continued in pregnancy using agents known to be safe (1D).We recommend women with previous bladder surgery  should be discussed during pregnancy with a urologist with expertise in bladder reconstruction to evaluate options for delivery (1D).We recommend that antenatally detected abnormalities in the fetal kidneys and/or urinary tract should be discussed with fetal medicine and paediatric nephrology specialists to determine appropriate neonatal management (1D).We recommend that children with antenatally detected abnormalities in the fetal kidneys and/or urinary tract should have specialist follow up if features of urinary tract infection are identified (1C).Audit Measure 1: Proportion of UK renal units and obstetric centres with access to a multidisciplinary team  to advise and/or manage renal disease in pregnancy.Audit Measure 2: Incidence of pregnancies (including spontaneous miscarriage and elective terminations of pregnancy) exposed to mycophenolate mofetil and cyclophosphamide within 6 weeks prior to date of conception.Audit Measure 3: Proportion of women of reproductive age with CKD within the first year of transplantation offered safe and effective contraception.Audit Measure 4: Proportion of women of reproductive age with CKD within 6 months of a lupus flare offered safe and effective contraception.Audit Measure 5: Proportion of women of reproductive age with CKD taking teratogenic medication  offered safe and effective contraception.Audit Measure 6: Proportion of pregnant women with CKD with quantification of proteinuria before 20 weeks’ gestation.Audit Measure 7: Proportion of women with CKD taking prednisolone or calcineurin inhibitors who are screened for gestational diabetes.Audit Measure 8: Proportion of pregnant women with CKD offered low dose aspirin (75-150 mg) before 16 weeks’ gestation.Audit Measure 9: Proportion of pregnant women with CKD that have a target blood pressure for pregnancy documented in their antenatal record.Audit Measure 10: Proportion of women with CKD given non-steroidal anti-inflammatory drugs in the post-partum period.Audit Measure 11: Proportion on women with CKD who are breastfeeding their infants (exclusively or mixed feeding) at 6 weeks post-partum.The UK Kidney Research Consortium has highlighted the need for better evidence in order to define care pathways, assess acceptability to patients and ensure optimum outcomes. These recommendations for research are very relevant to pregnancy in women with CKD. The guideline committee therefore suggest the following research recommendations:Research recommendation 1: Qualitative evaluation of methods used to communicate risk in pregnancy in order to achieve understanding of risk and facilitate shared decision-making regarding reproductive health.Research recommendation 2: Establishment of multicentre registries with standardisation of data collection from pregnant women with CKD to allow prospective, large cohort studies to evaluate:renal disease aetiology and mechanisms of disease progressionfactors influencing outcomes in women with dialysis, transplantationoptimal schedule of care in pregnancyoptimal management of hypertension, proteinuria, medications, anaemia, vitamin D concentrationsimpact of kidney donation on pregnancy and renal outcomesResearch recommendation 3: Assessment of the impact of CKD on aneuploidy screening methods including cell-free fetal DNA.Research recommendation 4: Validation of angiogenic (PlGF) and antiangiogenic (sFlt-1) biomarkers in the diagnosis of superimposed pre-eclampsia and prediction of adverse pregnancy outcomes in women with CKD.Research recommendation 5: Evaluation of short- and long-term outcomes in the children of women with CKD, including the excretion into breast milk of medications used in women with CKD.We recommend multidisciplinary teams  are established to offer advice and care for women with CKD who are pregnant or planning a pregnancy. All healthcare professionals caring for women with CKD should be able to access this MDT (1D).Women with CKD have an increased risk of adverse pregnancy outcomes including pre-eclampsia, fetal growth restriction, preterm delivery and deterioration in maternal renal function. A recommendation for expert multidisciplinary care in pregnancy exists for women with other medical comorbidities associated with increased risk in pregnancy including cardiac disease , diabeteWe recommend that low dose aspirin, low molecular weight heparin, labetalol, nifedipine, methyldopa, prednisolone, azathioprine, ciclosporin, tacrolimus and hydroxychloroquine are safe for use in pregnancy (1B).We recommend concentrations of calcineurin inhibitors  are checked throughout pregnancy and immediately postpartum, as blood concentrations may change (1C).We recommend that medications which interfere with calcineurin inhibitor metabolism  are avoided in pregnant and post-partum women taking tacrolimus or ciclosporin whenever possible (1D).We recommend mycophenolate mofetil, methotrexate and cyclophosphamide are not taken in pregnancy as they are teratogenic (1B).We recommend mycophenolate mofetil is stopped before pregnancy, as use in pregnancy is associated with an increased risk of spontaneous miscarriage and fetal abnormality. A 3-month interval is advised before conception to allow conversion to a pregnancy-safe alternative and ensure stable disease/kidney function (1C).We recommend that, when other treatment options exist, rituximab is avoided in pregnancy due to the risk of neonatal B cell depletion and unknown long-term outcomes (1D).We recommend sirolimus and everolimus are avoided in pregnancy due to insufficient safety data (1D).We suggest the benefits of eculizumab in pregnancy for organ threatening disease are likely to outweigh risk (2D).2 and stable renal function during pregnancy (1D).We recommend metformin can be used in pregnancy for women with a pre-pregnancy eGFR>30mls/min/1.73mWe recommend immunosuppressive treatment is not increased routinely in the peripartum period and that dose changes are based on clinical indications and blood concentrations (1D).We recommend women can breastfeed whilst taking prednisolone, hydroxychloroquine, azathioprine, ciclosporin, tacrolimus, enalapril, captopril, amlodipine, nifedipine, labetalol, atenolol and low molecular weight heparin (1C).Prescribing any medication in pregnancy should involve balancing the risks to the women of uncontrolled disease, with any real or theoretical perceived harm to the fetus. Inappropriate cessation or failure to initiate therapy when clearly indicated can be more harmful than judicious use to maintain maternal health. Medication should be prescribed in pregnancy if the benefit to the woman (and therefore the fetus) outweighs the potential or theoretical risk to the fetus. The woman should be involved in discussions about medication in pregnancy, which should ideally take place before the pregnancy as part of pre–pregnancy counseling .Very few drugs are licensed for use in pregnancy. Surveillance of pregnancy outcomes in women exposed to drugs is therefore used to assess safety in pregnancy. Such outcomes may be confounded by the underlying medical conditions for which treatment is required, and clinical interpretation of data must be balanced and pragmatic. There are no randomised controlled trials of medication in pregnancy in women with CKD. Where randomised controlled trial data are available, they are generalised from unselected or control obstetric cohorts , 9.Table We recommend advice on safe and effective contraception is offered to all women of reproductive age with CKD (1D).RationaleAlthough CKD impacts on mechanistic and psychological aspects of fertility, reducing the likelihood of spontaneous conceptions (see section 3.2), unintended pregnancies occur. Although there are no recent data, a historical questionnaire study of 76 women with CKD revealed that despite 50% being sexually active, only 36% used contraception, and only 13% had discussed reproductive health issues with their nephrologist . A surveWe recommend safe and effective contraception is offered to women of reproductive age who are taking teratogenic medication, have active glomerulonephritis, are within one year of renal transplantation or acute graft rejection, and for any woman who does not wish to conceive (1D).RationaleExposure to teratogenic medications such as mycophenolate mofetil and cyclophosphamide in the first trimester of pregnancy can lead to abnormalities in the developing fetus (see Section 2). Meta-analyses of observational studies show that active lupus nephritis is a significant risk factor for the development of maternal hypertension and preterm delivery (see Section 5.3) , 69. TheWe recommend that the progesterone only-pill, a progesterone subdermal implant, and the progesterone intra-uterine system are safe and effective for women with CKD (1C).We recommend that progesterone-only emergency contraception is safe for women with CKD (1C).RationaleThe risks and acceptability of different contraceptive methods should be balanced against the risks of an unplanned pregnancy. All oestrogen-containing contraceptives confer risk of hypertension, venous thromboembolism (VTE), arterial thrombosis and cervical cancer . These rProgesterone-only methods including the progesterone-only pill (‘mini-pill), the progesterone-containing intrauterine system (Mirena®) and the progesterone subdermal implant (Nexplanon®), do not confer these risks and are therefore considered safe . The abi+ T cell count [There is theoretical concern that the efficacy of intrauterine devices is reduced in women taking immunosuppression due to inhibition of uterine inflammation, which is believed to contribute to the underlying contraceptive mechanism. However, the uterine milieu is predominantly populated by macrophages, and immunosuppression used in the management of immune-mediated renal disease and transplantation acts predominantly via lymphocyte inhibition. There is no evidence of an excess of intrauterine device failures following transplantation , 77. Conll count . A retroll count .Data on the risk of breast cancer with progesterone methods of contraception are conflicting with a large population study suggesting  and a laAssessment of contraceptive efficacy should be based on ‘typical use’ rather than presuming ‘perfect use’, as discrepancies exist in the failure rate of some contraceptive methods . TypicalIn the UK, emergency contraceptive pills  do not contain oestrogen and can be safely prescribed in women with CKD within 72 h of unprotected sexual intercourse to prevent pregnancy.We suggest fertility preservation is considered for women of reproductive age who require treatment with cyclophosphamide (2C).We recommend women who have had previous treatment with cyclophosphamide have early investigation of infertility (1D).RationaleCohort studies show that cyclophosphamide causes age and dose-dependent gonadotoxicity in women with systemic lupus erythematosus , 84 and Fertility preservation techniques will depend upon the urgency of treatment of the underlying condition and availability. Cryopreservation of oocytes and gametes can be undertaken, but this usually requires ovarian stimulation, which will typically delay cyclophosphamide administration and, given the immunomodulatory role of oestrogen believed to underlie the female predominance of lupus, carries a theoretical risk of lupus flare. Published data on the risks of ovarian stimulation are limited, conflicting, and there is an absence of prospective trials , 88. Nat2) being better predictors of premature ovarian failure than GnRHa use [Luteinising hormone releasing hormone analogues (LHRHa)/gonadotrophin releasing hormone agonists (GnRHa) can be used to inhibit the hypothalamic-pituitary-ovarian axis, leading to a protective reduction in ovarian blood flow for the duration of cyclophosphamide treatment. Data on the use of LHRH/GnRHa in women with CKD are limited. A retrospective cohort of 20 women receiving cyclophosphamide (cumulative mean dose 12.5 g) for lupus nephritis showed a reduction in the incidence of premature ovarian failure (amenorrhoea > 12 months and follicle-stimulating hormone level > 40mIU/ml) with use of an LHRH analogue compared to that of age and dose-matched controls  . Most danRHa use . Use of nRHa use ), and innRHa use .Age, anticipated cyclophosphamide dose and patient preference should inform fertility preservation in women with CKD. Whether the assessment of ovarian reserve by serum anti-Mullerian hormone concentrations has clinical utility in predicting benefit from fertility preservation remains unknown.As cyclophosphamide exposure is a recognized predisposing factor for infertility, a referral for fertility assessment can be made before one year of regular unprotected intercourse, particularly in women with CKD who are aged 36 and over, according to national guidance .We suggest women with CKD are referred for pre-pregnancy counselling before receiving assisted reproduction (2D).RationaleWomen with CKD considering pregnancy should be offered pre-pregnancy counselling by an expert multidisciplinary team (see Section 3.3). Healthcare providers should recognise that discussions of fertility and referrals for fertility assessment provide an opportunity for expert pre-pregnancy counselling in women with CKD.We recommend single-embryo transfer is performed to reduce risk of complications associated with multifetal pregnancies in women with CKD (1C).RationaleA small case-control study of 15 twin pregnancies in women with CKD shows a higher risk of preterm delivery, growth restriction, neonatal unit admission, weight discordance, perinatal mortality and neonatal mortality compared to both low-risk twin pregnancies and twin pregnancies complicated by either chronic hypertension or collagen disease . This geWe suggest women with CKD considering pregnancy are offered pre-pregnancy counselling by a multidisciplinary team including a consultant obstetrician and nephrologist or expert physician (2D).We recommend women with CKD are advised there is an increased risk of complications in pregnancy including pre-eclampsia, preterm birth, fetal growth restriction, and neonatal unit (NNU) admission, and that they are more likely to require caesarean delivery (1C).RationaleCohort studies –100 and 2, women with CKD progression, women with uncontrolled hypertension (> 140/90 mmHg), women with nephrotic-range proteinuria, women with active renal disease, women with lupus nephritis, women with renal transplants and all women with previous adverse obstetric outcomes.The provision of pre-pregnancy counselling is likely to depend upon local availability of expertise. However the guideline committee recommend expert, multidisciplinary pre-pregnancy counselling for women with an eGFR < 60 ml/min/1.73mWe recommend women with known or suspected inheritable renal diseases are offered genetic counselling including inheritance risk, prognosis, and intervention options including pre-implantation genetic diagnosis (1C).RationaleGenetic counselling is indicated for families with a history of known or suspected inheritable renal disease to assist in decision-making regarding pursuing a pregnancy. Referral for specialist counselling with clinical genetics teams may be indicated to facilitate genetic diagnosis, the testing of family members or for discuss regarding the possibility of pre-implantation genetic diagnosis (PGD). PGD is approved by the Human Fertilisation and Embryology Authority for autosomal dominant and recessive forms of polycystic kidney disease, Alport syndromes, Fabry disease and Cystinosis  and thisstabilising disease activity in advance of pregnancy on minimised doses of pregnancy-appropriate medications (1B).optimising blood pressure control (< 140/90 mmHg) on pregnancy-appropriate medications (1B).optimising glycaemic control in women with diabetes mellitus (1A) (see section 5.4).minimising risk of exposure to teratogenic medications (1C) (see section 2).making a treatment plan in the event of hyperemesis or disease exacerbation/relapse during pregnancy (1D).We recommend pre-pregnancy counselling for the optimisation of maternal and neonatal outcomes in women with CKD, which may include:RationaleIn addition to specialist renal care, pre-pregnancy advice for women with CKD should follow advice available from the National Institute for Health and Care Excellence to promote optimal long and short-term health outcomes of all women and their children during and after pregnancy .There are observational data that associate active lupus nephritis, nephrotic syndrome and small vessel vasculitis are associated with increased risks of adverse pregnancy outcomes including fetal demise –110. TheHypertension is a recognised risk factor for progression of CKD. Non-pregnant women with CKD should therefore be treated according to up to date blood pressure targets. In addition, prospective cohort studies of preconception hypertension show an association with pregnancy loss , 113.We recommend women with CKD who are taking angiotensin converting enzyme inhibitors have a plan for discontinuation/conversion guided by the strength of indication for renin-angiotensin blockade and the likelihood of pregnancy confirmation in the first trimester (1B).We recommend angiotensin receptor antagonists are discontinued in advance of pregnancy (1D).RationaleAngiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor antagonists are fetotoxic in the second and third trimesters. Exposure to ACEi in the second and third trimester may lead to major birth defects including renal agenesis, and should be avoided. Although retrospective cohort studies show an apparent increased rate of congenital malformation associated with first trimester exposure to ACEi , such asTo avoid the risk of inadvertent second trimester exposure to ACEi, these agents can be stopped prior to pregnancy, or as soon as pregnancy is confirmed in women with a strong indication for continued renin-angiotensin blockade during the unknown period of time taken to conceive, such as proteinuric renal disease. Women who continue to take ACEi during attempts to conceive need to be counselled to perform regular pregnancy tests, at least monthly.There are limited data addressing the risks of exposure to angiotensinogen receptor antagonists in the first trimester. Limited reports of harm  and inadWe suggest women with CKD stages 4 and 5 contemplating pregnancy are offered pre-dialysis education (2D).RationaleObservational data from the 1970s identified that women commencing pregnancy with advanced CKD had a 1 in 3 risk of requiring dialysis within a year of the pregnancy. Cohort studies from the 1980s, 1990s and 2000s continue to describe a 1 in 3 risk of dialysis for patients whose serum creatinine approximates to pre-pregnancy CKD stage 4 and 5 , 117. EdWe recommend renal function in pregnancy is assessed using serum creatinine concentrations as estimated GFR (eGFR) is not valid for use in pregnancy (1C).RationaleDue to increased plasma flow and dynamic changes in filtration fraction during pregnancy , glomeruEstimated glomerular filtration rate (eGFR) derived by both Modified Diet in Renal Disease (MDRD) , 124 andWe recommend women with CKD have formal quantification of proteinuria in pregnancy (1D).RationaleThe amount of protein excreted into urine increases in normal pregnancy as a consequence of physiological changes in the kidney with gestation. These changes include an increase in renal blood flow with a corresponding increase in glomerular filtration, a more porous glomerular basement membrane, and altered tubular reabsorption. The amount of protein excreted by the kidney in pregnancy is greater than that in the non-pregnant population. The 95% confidence interval for 24 h urinary protein excretion in 270 healthy pregnant women was found to be 259.4 mg , hence aProteinuria in early pregnancy also predicts adverse fetal and maternal outcomes in women with CKD. The Torino-Cagliari Observational Study compared obstetric and renal outcomes in 504 women with CKD with 836 women without CKD. Proteinuria (> 1 g/24 h) was an independent risk factor for preterm birth before 37 weeks’ gestation (odds Ratio (OR) 3.65; 95% confidence interval (CI): 1.61–8.24) and 34 weeks’ gestation  . AdverseWe recommend quantification of proteinuria is undertaken by protein:creatinine ratio (uPCR) or albumin:creatinine ratio (uACR). Twenty-four hour urine collection for quantification of protein is not required (1B).RationaleDipstick testing of urine with reagent strips to detect proteinuria preferentially detects albumin. False positives occur with dehydration, exercise, infection and alkaline urine. False negatives occur with dilute urine, and non-albumin proteinuria. A systematic review of seven prospective studies showed that the sensitivity and specificity of a dipstick result of ≥1+ protein for predicting abnormal proteinuria in pregnancy (> 300 mg/24 h) ranges from 47 to 86% and 39–95% respectively, leading to the conclusion that the accuracy of dipstick urinalysis with a 1+ threshold in the prediction of significant proteinuria is poor . However24-h urine collection is time-consuming and subject to inadequacies in collection . Outsidep = 0.004). However it remains unclear whether this small absolute difference translates into significant clinical benefit. Cost effectiveness for uACR over uPCR was also suggested, although 95% confidence intervals for the incremental cost-effectiveness ratio crossed zero due to significant uncertainty and the small difference in incremental cost and quality added life years [There is on-going debate as to whether uPCR or uACR should be preferentially used for the quantification of proteinuria in pregnancy. In non-pregnant patients with CKD, uACR is the investigation of choice as it provides greater sensitivity at lower levels of proteinuria, although uPCR can be used as an alternative, particularly where uACR is 70 mg/mmol or greater . In contfe years . There afe years .We suggest pregnant women with CKD who have not had pre-pregnancy counselling by the MDT are referred to the MDT and receive the same counselling and optimisation as for women attending pre-pregnancy (2D).We recommend pregnant women with CKD receive routine antenatal care, in addition to specialist input (1D).We recommend pregnant women with CKD be referred for assessment by a consultant obstetrician (1D).We recommend pregnant women with CKD have access to usual trisomy screening with specialist interpretation of high-risk results (1C).We recommend women with CKD exposed to teratogenic drugs in the first trimester are referred to a specialist fetal medicine unit (1D).We recommend pregnant women with CKD have scans to assess fetal growth and wellbeing in the third trimester (1C).We recommend pregnant women taking prednisolone and/or calcineurin inhibitors are screened for gestational diabetes (1C).RationaleWomen with CKD who present for the first time in pregnancy should have an opportunity for individualised risk counselling and optimisation of health for pregnancy. These women should therefore be referred to the MDT as early as possible in pregnancy to ensure that the same topics are covered as for women receiving pre-pregnancy counselling (see section 3.3). This reflects lessons learned from MBRRACE-UK , which has identified maternal medical comorbidities to be significantly associated with maternal morbidity and mortality , 140.There is no specific literature on the schedule of care for women with CKD. Women with CKD should be supported to access routine antenatal care, with increased surveillance in line with national guidance for antenatal care , and guiPathways for care for women with CKD in pregnancy should map to those agreed for the regional Maternal Medicine Network and Maternal Medicine Centre. If the Maternal Medicine Centre and the regional renal unit are not co-located (which was the case for 31% of responders to the consensus survey undertaken for this guideline) then the consultant obstetrician and consultant nephrologist should communicate regularly during the pregnancies of women with CKD, ensuring access to all notes and results.Women with CKD should be offered usual trisomy screening. If they have abnormal renal function, the pre-test counselling for combined screening using blood markers should include discussion of a potentially increased false positive rate as the multiple of the median may be increased for beta human chorionic gonadotrophin, though not for pregnancy associated plasma protein-A . Other sThe care pathway should include determination of frequency of third trimester ultrasound for evaluation of fetal growth based on a woman’s individualised risk assessment for fetal growth problems. In light of the known association between steroids and calcineurin inhibitors with impaired glucose metabolism , screeniAdvice regarding pregnancy care and delivery, with referral back to the local maternity unitShared maternity care between the Maternal Medicine Centre and the local unitMaternal Medicine Centre to lead and deliver maternity careOptions for maternity care, determined by the MDT, include:We recommend women with CKD are offered low-dose aspirin (75-150 mg) in pregnancy to reduce the risk of pre-eclampsia (1B).We suggest kidney donors are offered low dose aspirin (75 mg–150 mg) to reduce the risk of pre-eclampsia (2D).RationaleWomen with CKD have an increased risk of pre-eclampsia compared to women without CKD  and shouWomen who have donated a kidney are at increased risk of pre-eclampsia  . Pre-eclThe benefit of calcium supplementation in reducing the prevalence of pre-eclampsia remains unclear. A Cochrane systematic review of randomised controlled trials showed that supplementation of a least 1 g calcium per day was associated with a 55% reduction in pre-eclampsia, although the effect was mostly shown in smaller trials, with possible confounding by low dietary calcium intake . In contWe recommend that the target blood pressure during pregnancy for women with CKD is 135/85 mmHg or less, which should be documented in the woman’s healthcare record (1D).We suggest antihypertensive treatment in women with CKD is continued in pregnancy unless systolic blood pressure is consistently < 110 mmHg systolic, or diastolic blood is pressure consistently < 70 mmHg diastolic BP, or there is symptomatic hypotension (2D).We recommend labetalol, nifedipine and methyldopa can be used to treat hypertension in pregnancy (1B).We recommend angiotensin converting enzyme inhibitors, angiotensin receptor anatgonists and diuretics are not used to treat hypertension in pregnancy (1B).in a woman with non-proteinuric CKD, if she develops new hypertension (systolic BP > 140 mmHg and/or diastolic BP > 90 mmHg) and proteinuria (uPCR > 30 mg/mmol or uACR > 8 mg/mmol) or maternal organ dysfunction after 20 weeks’ gestation (1B).in a women with proteinuric CKD if she develops new hypertension (systolic BP > 140 mmHg and/or diastolic BP > 90 mmHg) or maternal organ dysfunction after 20 weeks’ gestation (1B)in a women with chronic hypertension and proteinuria, if she develops maternal organ dysfunction after 20 weeks’ gestation (1B).We recommend a diagnosis of superimposed pre-eclampsia is considered:We suggest in women with chronic hypertension and proteinuria that the development of sustained severe hypertension (systolic BP > 160 mmHg and/or diastolic BP > 110 mmHg or doubling of antihypertensive agents) and/or a substantial rise in proteinuria (doubling of uPCR or uACR compared to early pregnancy) should prompt clinical assessment for superimposed pre-eclampsia (2D).We suggest a role for angiogenic markers (PlGF±sFlt-1) is considered as an adjunct to diagnose superimposed pre-eclampsia, dependent upon on-going research in women with CKD (2C).Rationalen = 638) [There is no evidence on treatment initiation thresholds or blood pressure targets in pregnancy for women with CKD. Randomised controlled trial data from women with non-proteinuric hypertension demonstrate that tight blood pressure control (aiming for a diastolic BP of 85 mmHg) reduces severe maternal complications, with no evidence of perinatal harm . Evidencn = 638) . Antihypn = 638) .Making the diagnosis of superimposed pre-eclampsia is complex in women with chronic kidney disease, particularly in the presence of pre-existing proteinuria and/or hypertension as these two signs are part of the diagnostic criteria for pre-eclampsia. Appearance of a new feature and/or the development of maternal organ dysfunction Table  should lNational guidelines recommend the use of placental growth factor-based testing  test or the Elecsys immunoassay soluble fms-like tyrosine kinase 1 (sFlt-1)/PlGF ratio), alongside standard clinical assessment and subsequent clinical follow-up, to help rule-out pre-eclampsia in women presenting with suspected pre-eclampsia between 20 weeks and 34 weeks plus 6 days of gestation . These tWe recommend that women with nephrotic-range proteinuria (uPCR> 300 mg/mmol or ACR > 250 mg/mmol) be offered thromboboprophylaxis with low molecular weight heparin in pregnancy and the post-partum period unless there is a specific contraindication including risk of labour or active bleeding (1D).We suggest that non-nephrotic range proteinuria in pregnancy is a risk factor for thrombosis and thromboprophylaxis with low molecular weight heparin should be considered in the presence of additional risk factors (2D).RationaleThe guideline committee endorses the assessment and management of VTE risk in women with CKD according to guidance from the Royal College of Obstetricians and Gynaecologists (RCOG) which states that all pregnant women undergo a documented assessment of risk factors for venous thromboembolism . NephrotThere is also consensus, but insufficient evidence, that sub-nephrotic levels of proteinuria confer a risk of thrombosis although the threshold level of proteinuria at which the risk of VTE is clinically significant remains unknown. Consequently, thromboprophylaxis in women with CKD varies across the UK and internationally. There are anecdotal data that regions with a higher threshold for thromboprophylaxis do not report many/any thrombotic events attributable to proteinuria alone. In contrast, clinicians with a lower threshold for recommending thromboprophylaxis accept the compromise that maternal morbidity and mortality from thrombosis justifies the number needed to treat. In the light of this uncertainty, the guideline committee suggest that non-nephrotic range proteinuria (uPCR> 100 mg/mmol or uACR> 30 mg/mmol) be considered a risk factor for thrombosis and thromboprophylaxis with low molecular weight heparin be offered in the presence of additional risk factors. Recognised risk factors include gestation, other medical comorbidity (including active lupus), age, BMI, parity, smoking, gross varicose veins, pre-eclampsia, assisted reproduction, operative delivery, post-partum haemorrhage, still-birth, hyperemesis, infection, and immobility [We recommend pregnant women with CKD are given parenteral iron if indicated (1C).We recommend erythropoietin stimulating agents are given if indicated in pregnancy (1C).RationaleGestational increases in plasma volume are higher than the corresponding increase in red blood cell mass, leading to haemodilution and lower haemoglobin levels in pregnancy. The lower reference limit for haemoglobin concentrations in pregnancy is 105 g/L-110 g/L depending on gestation , 159, wiThe most common cause of anaemia in pregnancy is iron deficiency, which is estimated to affect greater than 40% of pregnancies . MarkersErythropoietin concentrations increase approximately two-fold during pregnancy . As womeHypoxia-inducible factor (HIF) activators are an emerging class of drugs with a therapeutic role in the management of renal anaemia. However, the small size of these molecules potentially enables placental transfer, and HIF has multiple direct and indirect effects on developmental and physiological processes . No formWe recommend women with CKD who are vitamin D deficient be given vitamin D supplementation in pregnancy (1B).We recommend calcimimetics are discontinued in pregnancy (1D).We recommend non-calcium based phosphate binders are discontinued in pregnancy (1D).Rationale2-vitamin D). Serum calcitriol levels are approximately threefold higher in the first trimester and 5–6 times higher in the third trimester compared with those in non-pregnant women [, as the enzyme is also found in colon, skin, macrophages and the placenta. In the absence of better evidence, the guideline committee suggests that, once serum calcifediol levels are replete, activated vitamin D analogues  can be continued in pregnancy at a dose that would be considered appropriate for maintenance treatment outside of pregnancy. For women with CKD who do not require activated analogues, a maintenance daily dose of vitamin D 400-1000iu can be given in pregnancy, depending on ethnicity and body mass index.Vitamin D deficiency is estimated to affect 13–64% of pregnant women  and is ant women . To whatCalcimemtics  and non-calcium phosphate binders  have insufficient safety data in pregnancy and should therefore be discontinued in advance of pregnancy and during lactation.We recommend if a histological diagnosis will change management in pregnancy then renal biopsy can be performed in the first and early second trimester of pregnancy (1C).Rationalep = 0.001). Complications, including macroscopic haematuria, perirenal haematomata, and the need for blood transfusion were described between 23 and 28 weeks’ gestation. No serious complications occurred prior to 22 weeks’ gestation.Published data on antenatal renal biopsy are limited by heterogeneity and cohort size. The most commonly described risk is bleeding. Contributory factors are thought to include the increased renal blood flow in pregnancy and the technical difficulty in performing a renal biopsy in the standard prone position at later gestations. A systematic review on renal biopsy in pregnancy including 39 studies published between 1980 and 2012, examined 243 antenatal biopsies compared with 1236 postpartum biopsies . This shWomen who undergo renal biopsy in pregnancy have histological diagnoses spanning the spectrum of glomerular disease , althougThe decision to undertake renal biopsy in pregnancy must balance the increased risk of bleeding, the likelihood of a change in management based on the biopsy result, and the risks of either iatrogenic preterm delivery or a delay in management until a biopsy can be performed post-partum. It is the consensus of the guideline group that renal biopsy in pregnancy should be performed by the most experienced clinician available, under ultrasound guidance.We recommend women with CKD receive routine peripartum care, with additional specialist input (1D).We recommend women with CKD have observations taken and documented during any hospital admission. This includes temperature, heart rate, blood pressure, respiratory rate, and oxygen saturation. An early warning score should be calculated and actioned appropriately (1D).We recommend additional assessment for women with an elevated early warning score, for women considered to be high-risk, and for any women in whom there is any clinical concern. This includes examination of jugular venous pressure, lung auscultation and urine output monitoring  in addition to routine parameters (1D).RationaleThe guideline committee endorses existing guidelines on Intrapartum Care for Healthy Women and Babies , IntrapaFailure to recognise the signs of illness in obstetric patients is a recurrent feature of cases of maternal morbidity and mortality , 175. ThWe recommend women with CKD at risk of volume depletion or volume overload are highlighted by the MDT in advance of delivery (1D).We recommend that fluid balance is managed with the aim of maintaining normal fluid volume, avoiding dehydration and pulmonary oedema, with input from clinicians with expertise in fluid balance and renal disease (1D).We recommend all clinicians are aware of the increased risk of pulmonary oedema in women with CKD and pre-eclampsia (1D).RationaleIt is the experience of the guideline committee that fluid management for women with CKD is often complex and needs to be tailored to the individual. Women at risk of either volume depletion or fluid overload should be highlighted in advance of delivery to ensure that clinical review of fluid state is undertaken prior to being prescribed intravenous fluids, or the institution of a fluid restriction. On-going fluid balance review should then be performed during labour and in the immediate post-partum period with the aim of euvolaemia and the avoidance of both pulmonary oedema and superimposed kidney injury. Fluid balance assessment should be undertaken by a competent clinician with an understanding of the haemodynamic changes in pregnancy and the puerperium. This may include nephrologists, anaesthetists, obstetric physicians, and maternal medicine specialists.The guideline committee endorses the NICE guideline on hypertension in pregnancy for the management of pre-eclampsia in pregnancy . The risWe recommend the timing of birth for women with CKD is determined by obstetric indications, with consideration of renal factors including deteriorating renal function, symptomatic hypoalbuminaemia, pulmonary oedema, and refractory hypertension (1D).RationaleIn women with CKD mode and timing of birth is usually determined by obstetric factors. Where maternal complications arise, clinicians must balance the competing risks of preterm delivery and maternal wellbeing. Potential maternal complications, which may inform the decision for iatrogenic preterm delivery in women with CKD, include loss of maternal renal function, symptomatic nephrotic syndrome including pulmonary oedema, and refractory hypertension. If maternal complications develop before 34 weeks’ gestation, attempts should be made to continue the pregnancy if possible, due to the reduction in adverse neonatal and developmental outcomes at gestations of 34 weeks’ gestation and more , althougThere is no evidence that mode of delivery affects maternal renal function. Mode of delivery should therefore be based on obstetric indications and maternal preference according to guidance in women without CKD .We recommend that non-steroidal anti-inflammatories should not be given (1C).Rationale2 [2  [Given that the risk of renal side effects from short-term use of non-steroidal anti-inflammatory drugs in patients without pre-existing risk factors is considered to be rare, NSAIDs are currently recommended in the postpartum period for perineal pain when paracetamol provides insufficient relief of symptoms . Althoug2 . There aegnancy) , 190, anegnancy) .We recommend women with CKD have a planned early postpartum renal review (1D).RationaleThere are no published data to guide post-partum surveillance on women with CKD. Whilst guidelines for the management of CKD do not require follow up secondary care for all patients, every woman with suspected kidney disease (acute or chronic) newly identified in pregnancy and all those with known CKD should have a clear plan in place for appropriate postpartum follow up , 191. TiWe recommend that women with CKD are prescribed medications that are compatible with breastfeeding whenever possible (1D).RationaleWomen with CKD should be supported in their wish to breastfeed and be prescribed medications which are considered safe in lactation (see section 2). Currently, breastfeeding is not advised for infants of mothers taking mycophenolate mofetil as there are no data to confirm safety. If mycophenolate mofetil is deemed to be the only therapeutic option, then breastfeeding should be avoided.We recommend that women with CKD are offered safe and effective contraception post-partum and receive updated pre-pregnancy counselling before future pregnancies (1D).RationaleThe provision of information and a choice regarding contraceptive method within seven days of delivery has been set as a quality standard in the UK, addressing a priority area for quality improvement in health and social care . Safe anEvents during pregnancy including obstetric complications, the development of superimposed pre-eclampsia, and a decline in maternal renal function will inform future obstetric risk, necessitating the need for new pre-pregnancy counselling to ensure informed decision-making regarding future pregnancy.We recommend women with renal transplants wait until their kidney function is stable on medications that are safe in pregnancy before conceiving, which is usually more than one year after transplantation (1D).RationalePregnancy rates are lower in women of reproductive age with renal transplants compared to the general population , 194. ItThere are few data supporting timing of pregnancy in women with renal transplants. Older reports suggested that a shorter interval from transplant to pregnancy was associated with worse pregnancy outcomes , 195. HoEuropean Best Practice Guidelines (2001) recommended a delay of 24 months between transplantation and conception , but AmeOther factors to consider regarding timing of pregnancy include recent episodes of rejection, stability and level of graft function, presence of cytomegalovirus, maternal age, diabetes and blood pressure control, but direct evidence regarding impact of these factors on pregnancy and graft outcomes is limited.We recommend that plans for delivery in a woman with a renal transplant are discussed with the local surgical transplant team (1D).We recommend that mode of delivery in women with renal transplants is based on obstetric indications and maternal preference (1D).We recommend that caesarean delivery in a woman with a renal transplant patient is performed by the most senior obstetrician available, ideally a consultant (1D).We recommend that women with kidney-pancreas transplants, kidney-liver transplants, and dual kidney transplants are managed during pregnancy and delivery by a multidisciplinary team including transplant physicians and surgeons, at a transplant centre (1D).RationaleThe majority of women with renal transplants have caesarean deliveries . HoweverDual organ transplants are associated with higher rates of adverse pregnancy outcomes . A smallGuideline 5.2.1We recommend women established on dialysis prior to pregnancy receive pre-pregnancy counselling including the options of postponing pregnancy until transplantation (when feasible) and the need for long frequent dialysis prior to and during pregnancy (1C).Guideline 5.2.2We recommend women established on haemodialysis prior to pregnancy receive long, frequent haemodialysis either in-centre or at home to improve pregnancy outcomes (1C).Guideline 5.2.3We suggest women receiving haemodialysis during pregnancy have dialysis dose prescribed accounting for residual renal function, aiming for a pre-dialysis urea < 12.5 mmol/l (2C).Guideline 5.2.4We recommend women established on peritoneal dialysis prior to pregnancy should convert to haemodialysis during pregnancy (1D).RationaleReported pregnancy outcomes for renal transplant recipients remain better than for dialysis recipients, and advice to wait for a renal transplant prior to pregnancy is appropriate for most women with established end stage renal disease .Evidence for the management of pregnancy in women receiving dialysis is limited to observational cohort studies, and prone to publication bias. Nevertheless, cohort studies and meta-analysis show an association between increased dialysis provision and improved fertility and pregnancy outcomes , 204–207It is acknowledged that achieving 48 ± 5 h/week dialysis is not feasible for many women or dialysis centres in the UK. An alternative approach is an increase in haemodialysis provision guided by biochemical parameters. A retrospective observational study of 28 pregnancies in women on haemodialysis compared successful pregnancies in which the baby survived to one year with unsuccessful pregnancies. Despite no overall difference in weekly dialysis hours between groups (19.2 ± 3.3 versus 16.3 ± 4.3 h/week), maternal urea was measurably lower in the pregnancies with successful outcomes (16.2 mmol/L versus 23.9 mmol/L). In addition, maternal urea showed a negative correlation with both birth weight and gestation at delivery with a maternal serum urea < 17.5 mmol/L (48 mg/dL) correlating with delivery after 32 weeks’ gestation and birth weight greater than 1500 g . A gradeThe provision of long, frequent haemodialysis has implications for electrolyte and nutritional provision and pregnant women on dialysis should have access to nutritional assessment and dietary counselling. Nutritional support is considered in many publications on dialysis in pregnancy, although data are diverse with different nutrients reported across the various studies, and no consensus in the vitamins and microelements that should be routinely monitored . Expert There are inadequate data to confirm the efficacy, safety and equivalence of peritoneal dialysis in supporting pregnancy, compared to enhanced haemodialysis. A systematic review of 38 pregnancies in women receiving peritoneal dialysis prior to pregnancy reported fetal survival in 83% of pregnancies, with 39% delivering prior to 34 weeks and 65% of babies being small for gestational age . ContinuGuideline 5.2.5We suggest haemodialysis should be initiated in pregnancy when the maternal urea concentration is 17-20 mmol/L and the risks of preterm delivery outweigh those of dialysis initiation. Gestation, renal function trajectory, fluid balance, biochemical parameters, blood pressure and uraemic symptoms should be considered in addition to maternal urea concentration (2D).RationaleThe guideline committee acknowledges that there are inadequate data to produce evidence-based recommendations for the initiation of dialysis during pregnancy. However a specific request from the UK renal community was received, for expert, opinion-based practice.In pregnancy, concern regarding the fetotoxicity of urea is likely to precede maternal indications for dialysis, which are the same as outside of pregnancy: refractory hyperkalaemia, acidosis and/or fluid overload, and uraemic symptoms that impact upon daily living . A recomResidual renal function is hypothesised to contribute to improved pregnancy outcomes in women commencing dialysis during pregnancy, compared to women established on dialysis prior to pregnancy  and inteWe recommend that women with lupus or vasculitis should be advised to wait until their disease is quiescent for at least 6 months before conceiving (1B).RationaleData from systematic reviews and a meta-analysis consistently report that having active lupus nephritis is associated with adverse pregnancy outcomes , 219. InWe recommend that all women with lupus should be advised to take hydroxychloroquine in pregnancy unless it is contraindicated (1C).RationaleThe guideline committee recommends that all patients with lupus should take hydroxychloroquine in pregnancy, endorsing EULAR , 223 andWe recommend that women with lupus be monitored for disease activity during pregnancy (1D).RationaleThe guideline committee endorses EULAR and BSR guidance , 221 thaWe recommend that women who are positive for anti-Ro (SSA) or anti-La (SSB) antibodies be referred for fetal echocardiography in the second trimester (1C).RationaleThe guideline committee endorses the EULAR and British Society of Rheumatology (BSR) guidance recommending fetal echocardiography from week 16 for women who are positive for anti-Ro (SSA) or anti-La (SSB) antibodies , 221. HoWe recommend women with antiphospholipid syndrome and a history of a confirmed thromboembolic event or previous adverse obstetric outcome  receive low molecular weight heparin in pregnancy and for six weeks postpartum (1B).RationaleThe guideline committee endorses recent expert guidance advising aspirin for all women with antiphospholipid syndrome, including those with recurrent early miscarriage; aspirin and low molecular weight heparin prophylaxis for those with of a history mid/late trimester pregnancy morbidity or loss; and high prophylactic or treatment dose low molecular weight heparin for those with prior thrombotic episodes , 230. A We recommend that steroids, azathioprine, calcineurin inhibitors, intravenous immunoglobulin and plasma exchange can be used to treat lupus in pregnancy (1C).RationaleThe safety of anti rheumatic drugs in pregnancy is comprehensively reviewed in the 2016 EULAR guideline . StandarWe recommend that women with diabetic nephropathy have optimisation of blood glucose, blood pressure and proteinuria prior to conception (1C).We recommend that women with diabetic nephropathy continue angiotensin converting enzyme inhibitors until conception, with regular pregnancy testing during attempts to conceive (1C).We recommend that the schedule of care, surveillance and management of women with diabetic nephropathy should be untaken according to national guidelines for diabetes in pregnancy, in addition to specialist monitoring of renal disease in pregnancy (1D).RationaleMost women with diabetic nephropathy have successful pregnancy outcomes –238. Hown = 8–24) show that reduction of pre-pregnancy proteinuria with angiotensin converting enzyme inhibitors (ACEi) is associated with a reduction in proteinuria in pregnancy [n = 7) treated with ACEi prior to pregnancy to achieve blood pressure < 135/85 mmHg and albuminuria < 300 mg/day have been shown to have pregnancy outcomes comparable to women with diabetes in the absence of nephropathy [Pre-pregnancy counselling of women with diabetes is associated with improved glycaemic control prior to pregnancy and a reduction in rates of spontaneous pregnancy loss and congenital malformations . Data frregnancy , 245. Wohropathy . The perProteinuria increases in pregnancy in the majority of women with diabetic nephropathy, including progression to the nephrotic range . Low molThe guideline committee endorses national guidance for the management of diabetes in pregnancy .We suggest women with reflux nephropathy, congenital anomalies of the kidneys and urinary tract (CAKUT), women with CKD taking immunosuppression, and women with a history of recurrent UTI should be offered antibiotic prophylaxis during pregnancy after a single UTI in pregnancy, including asymptomatic bacteriuria (2D).We recommend pre-pregnancy UTI prophylaxis be continued in pregnancy using agents known to be safe (1D).RationaleAsymptomatic bacteriuria is estimated to occur in 2 to 7% of pregnancies with a risk of progression to acute pyelonephritis if untreated. A meta-analysis of studies to 2015 showed that treatment of asymptomatic bacteriuria reduced the incidence of pyelonephritis in pregnancy from 21 to 5% , with some poor quality evidence that antibiotic use also reduced the incidence of low birth weight babies and preterm delivery . ScreeniThe prevalence of UTI following renal transplantation varies from 23 to 75% according to diagnostic criteria, length of follow-up and antibiotic prophylaxis . RegistrIn the absence of evidence specifically examining women with CKD, the guideline committee endorses generic guidelines for UTI in pregnancy , 259–261Women who have been commenced on UTI prophylaxis prior to pregnancy should continue prophylaxis in pregnancy with an antimicrobial that is considered safe as their risk of infection is likely increased in pregnancy due to gestational changes to the urinary tract including dilatation of the renal pelvis and ureter, decreased ureteral peristalsis, and reduced bladder tone.2) can be used.Not all antimicrobials are considered safe in pregnancy. Penicillins, cephalosporins, fosfomycin, trimethoprim (not in first trimester) and nitrofurantoin  should be discussed during pregnancy with a urologist with expertise in bladder reconstruction to evaluate options for delivery (1D).RationaleThe majority of women with previous urinary tract surgery can have healthy, successful pregnancies without compromise to previous urinary tract reconstruction. No long-term adverse outcomes were identified in a case series of 29 pregnancies in the UK, although urinary tract infections (55%) and upper renal tract obstruction (10%) were common . The anaWe recommend that antenatally detected abnormalities in the fetal kidneys and/or urinary tract should be discussed with fetal medicine and paediatric nephrology specialists to determine appropriate neonatal management (1D).We recommend that children with antenatally detected abnormalities in the fetal kidneys and/or urinary tract should have specialist follow up if features of urinary tract infection are identified (1C).RationaleThere are inadequate data to define an evidence-based management strategy for antenatally detected abnormalities of the urinary tract. Expert consensus, based on observational data, is that infants of mothers with urinary tract abnormalities, who had normal urinary tracts on antenatal ultrasound scans do not need further follow up unless features of urinary tract infection are identified in childhood . NeonataThe inheritance pattern and penetrance of forms of CAKUT from parent to child is poorly defined. Heterogeneous multifactorial genetic traits are likely but monogenic forms of inheritance have also been described. Cohort studies report between 36 and 67% of children of patients with vesicoureteric reflux demonstrate reflux on a voiding cystourethrogram , 266. HoMost women with chronic kidney disease (CKD) have successful pregnancies, but kidney disease can affect the health of both pregnant women and their babies. For that reason, experts in renal disease and pregnancy should be available to all women with kidney disease in the UK to offer advice before pregnancy and to help support, monitor and treat women with kidney disease when they are pregnant and after delivery.® coil are safe and effective. Women should let their nephrologist know that they would like to consider pregnancy before they stop using contraception. Women of reproductive age with CKD should have an opportunity to discuss the likely risks of a pregnancy for both herself and her baby, with a specialist. Risks include delivering her baby before the due date, her baby being small and needing admission to intensive care, and a worsening of her kidney function in or after pregnancy. A woman’s kidney disease and blood pressure should be treated before she conceives. Medications may need to be adjusted so that they are safe for a developing baby. Many drugs are safe in pregnancy including ciclosporin, tacrolimus, hydroxychloroquine and azathioprine. However mycophenolate is harmful to a developing baby and it is important that mycophenolate is swapped for an alternative medication  and a woman’s kidney function to be monitored following this change before she tries to conceive. Blood pressure medications that end in ‘pril’ or ‘sartan’ also need to be stopped, either before pregnancy or as soon as possible in early pregnancy (before 12 weeks).Planning pregnancy is important for women with CKD. Women with kidney disease should have access to contraception until they are ready to become pregnant and the progesterone-only pill (‘mini pill’), contraceptive implant and MirenaWomen with CKD should have specialist care of kidney disease in pregnancy, in addition to routine antenatal care. This means that they will be seen by doctors (obstetricians) as well as midwives during their pregnancy, and they will have extra scans to check the growth and wellbeing of their baby. Many women with CKD will need treatment for their blood pressure in pregnancy and a number of different blood pressure medications are safe including labetalol, nifedipine, methyldopa. Pregnant women with CKD may need iron (which can be given by injection), and vitamin D. If women were taking erythropoietin (‘Epo’) before conceiving then the dose will need to be increased in pregnancy. Women with CKD, including women with renal transplants, can have a vaginal delivery. They can also breastfeed if they wish and can be given medications that are safe in breastfeeding if they need them.Compared with women without CKD, women with CKD have a higher risk of a condition called pre-eclampsia. This condition only occurs in pregnancy and goes away after delivery. It causes high blood pressure, protein leak into the urine, headaches and abnormal blood tests. It can also affect the growth of the baby. It can be difficult to know if a woman with CKD has pre-eclampsia if she had high blood pressure and protein in her urine before pregnancy, and specialists should be available to help with diagnosis and treatment. If a woman develops pre-eclampsia, she will need close monitoring and she may need to deliver her baby early. All women with CKD should take low-dose aspirin in pregnancy. This is safe and reduces the risk of pre-eclampsia.Women with kidney transplants, lupus and diabetes can have successful pregnancies. Timing of pregnancy in these conditions is particularly important in order to make sure kidney function is stable, and that lupus and diabetes are well controlled before pregnancy, in order to have the best chance of a healthy baby. Women who have congenital kidney disease and women who have had bladder surgery should have specialist advice on the best way to deliver their baby. Pregnancy while on dialysis has a very high risk of complications. Although the number of hours of dialysis can be increased in pregnancy, pregnancy outcomes are better for most women on dialysis if they can delay pregnancy until after successful kidney transplantation.


Altered mitochondrial function and large-scale changes to DNA methylation patterns in the nuclear genome are both hallmarks of colorectal cancer (CRC). Mitochondria have multiple copies of a 16 kb circular genome that contains genes that are vital for their function. While DNA methylation is known to alter the nuclear genome in CRC, it is not clear whether it could have a similar influence in mtDNA; indeed, currently, the issue of whether mitochondrial genome (mtDNA) methylation occurs is controversial. Thus our goal here was to determine whether the methylation state of mtDNA is linked to mitochondrial gene transcription in colorectal adenomas, and to assess its suitability as a biomarker in CRC.To investigate the relationship between DNA methylation and mitochondrial transcripts in adenomas, we performed RNA-sequencing and Whole Genome Bisulphite Sequencing (WGBS) of mtDNA-enriched DNA from normal mucosa and paired adenoma patient samples.P < 0.01). Methylation in mtDNA was low (1%) in both normal and adenoma tissue but we observed clusters of higher methylation at the ribosomal RNA genes. Levels of methylation within these regions did not differ between normal and adenoma tissue.Transcriptional profiling indicated that adenomas had reduced mitochondrial proton transport versus normal mucosa, consistent with altered mitochondrial function. The expression of 3 tRNAs that are transcribed from mtDNA were also decreased in adenoma. Overall methylation of CG dinucleotides in the nuclear genome was reduced in adenomas (68%) compared to normal mucosa  contains supplementary material, which is available to authorized users. The molecular development of colorectal cancer (CRC) is complex with multiple genetic mutations and epigenetic changes driving the transition from normal mucosal tissue to adenoma and ultimately invasive cancer . The chaDNA methylation of cytosine nucleotides is the most studied and best understood epigenetic modification. It is now recognised as an important regulator of gene transcription in plants and animals . In mammHowever, establishing the function, or even the presence of DNA methylation in mitochondria remains controversial even after over 4 decades of research –9. The dSome studies have reported the absence of mtDNA methylation , 15, howAnalysis of CRC has shown reduced mtDNA methylation in advanced tumour stage, increased mtDNA copy number and increased expression of mtDNA genes , 17. SevAdenomas, as an early detectable tissue-type in the progression from normal mucosa to CRC are an attractive target lesion for prevention and intervention. Few studies have examined mitochondrial changes at the early stages of CRC. Wallace et al. (2016) reported an intriguing switch during tumour progression whereby, compared to normal tissue, mitochondrial gene expression was reduced in adenomas but increased in later stage adenocarcinomas . There aNo previous studies have examined mtDNA methylation in adenomas and it is unclear whether abnormal mtDNA methylation is associated with gene expression changes, as seen in the nuclear genome. Furthermore, the relationship between mtDNA methylation and mtDNA copy number in adenomas, and the relative timing of mtDNA methylation changes in the transition from normal mucosa to carcinoma are also yet to be explored.In this study we examined paired normal and adenoma tissues to determine whether mtDNA methylation changes occur in concert with mitochondrial gene expression and/or copy number changes in adenomas compared with normal tissues. We identified widespread gene expression changes indicating altered mitochondrial function but could not identify any DNA methylation changes in mtDNA in spite of a significant reduction in the nuclear genome methylation.DNA from CRC cell lines was obtained and extracted as previously described. For WGBS, adenomas and matched normal mucosa were obtained from 4 patients  using endoscopic mucosal resection . These adenomas were mixed flat and nodular lesions, and the flat and nodular components were analysed separately. Histologic assessment indicated lesions showed no evidence of submucosal invasion. Fresh colorectal cancer tissues were obtained from surgical resection specimens at St. Vincent’s Hospital, Sydney (ethics numbers H00/022 and 00113). Patient and pathology information on clinical samples is in Additional file p-value < 0.05 that also had an average increase or decrease of 20% compared to normal mucosa were analysed with the Database for Annotation, Visualization and Integrated Discovery (DAVID). Normalised gene expression levels in the nuclear and mtDNA genome analyses for all samples are in Additional file Next generation RNA sequencing of patient samples was performed as previously described , 29. RNAFive micrograms of genomic DNA from tissue samples was run on a 1% agarose gel and the 10-20 kb region excised and isolated with a Qiaex II gel extraction kit (Qiagen) to enrich for mtDNA. 5 ng of unmethylated lambda DNA (Promega) was spiked into each sample prior to conversion with an EpiTect bisufite kit (Qiagen). Libraries for next-generation sequencing were generated with a TruSeq DNA Methylation kit (Illumina) and sequenced on an Illumina HiSeq 2500 with 125 bp paired-end reads. Low quality scoring reads and adaptor sequences were removed using Trimmomatic (version 0.36). Remaining reads, 1,885,212–2,927,332 from normal mucosa, 436,044–3,244,228 from adenoma were aligned to the human genome (hg19) and methylation levels analysed using Bismark (version 0.16.1) [For PCA of the WGBS data the percentage methylation for each sample was calculated at each nucleotide where there was at least one read recorded. Then, an average methylation value was obtained by averaging methylation at all nucleotides within 100 kb bins across the genome  using BEDTools . A PCA wSphI restriction endonuclease (New England Biolabs) for 10 mins at 37 °C then incubated at 65 °C for 20 mins to inactivate the enzyme. The samples were then bisulphite converted with an EpiTect bisufite kit (Qiagen) using the manufacturer’s Protocol for Low Concentration Solutions. The SphI digestion linearises the mtDNA which has recently been shown to be required for effective bisulphite conversion [This technique determines the relative proportions of cytosine (indicating a methylated cytosine) and thymine  nucleotides at individual cytosine sites in PCR product from regions of interest. The patient samples used overlapped with the WGBS and RNA-seq analyses and are indicated in Additional file nversion , 21. Thenversion ,  by qPCR on a LightCycler480 (Roche). Representative regions of the mtDNA  and the nuclear genome (Nestin gene) were amplified and relative levels compared with the delta delta Ct method. An aliquot was taken from all samples was used to calibrate the delta delta Ct calculation. Primers used were; 16S F: CGAAAGGACAAGAGAAATAAGG; 16S R: CTGTAAAGTTTTAAGTTTTATGCC; Nestin F: AAACCAGAGCCATGAGACAC; Nestin R: TGGCCTACAGCCTCTTTTTC. For analysis of patient samples, the mtDNA copy number from each normal sample was given the value 100% and the relative change in the paired adenoma sample was calculated. Data from normal mucosa and adenoma groups were compared by using Student’s t-test.P < 0.05 Multiple testing error was controlled with the Benjamini-Hochberg Procedure, the critical value was calculated with a false discovery rate of 25%.). Analysis of these genes with the Database for Annotation, Visualization and Integrated Discovery (DAVID) found 1 Biological Processes that was significantly downregulated in adenomas after Benjamini correction (P < 0.05). This was ATP hydrolysis coupled proton transport which consists of genes required for establishment of the proton gradient that drives ATP production in the mitochondria  was performed. It revealed that genes MT-CO1, MT-ND5 and three tRNAs  were reduced in adenomas . In contrast no large scale differences in methylation level were seen in mtDNA. In all samples the level of mtDNA CG methylation (~ 1%) was much lower than in the nuclear genome (~ 70%). Non-CG methylation was also consistently ~ 1% in all groups. As the spiked lambda DNA controls revealed that ~ 99% of cytosines were converted by bisulphite treatment it is not possible to determine if the WGBS data reflect significant group differences  in mtDNA, or are caused by slight differences in the effectiveness of bisulphite conversion between groups.To identify regions of mtDNA that contain methylation we performed whole genome bisulphite sequencing (WGBS) on DNA from 4 normal mucosa and adenoma paired samples, plus an additional normal mucosa from a patient with CRC. A summary of the percentage of cytosines in CG, CHG and CHH contexts that resisted sodium bisulphite conversion in the nuclear genome, mtDNA and lambda control DNA is presented in Table Methylated cytosines were mapped on the heavy and light strands of mtDNA Fig. . While tThere was a large difference in the number of sequence reads that originated from the different strands. There were ~10x more reads from the minus/light strand than from the plus/heavy strand. This has been reported before in bisulphite-treated DNA sequencing and is thought to be due to DNA degradation when the depurination step of the process causes random strand breaks . It is pp = 0.007).To validate the WGBS result we performed locus-specific pyrosequencing of cytosines located at the 16S rRNA (MT-RNR2 gene) and the MT-CO1 gene . Consistent with the WGBS the pyrosequencing detected low methylation levels in mtDNA in both normal mucosa and adenoma .By investigating mtDNA methylation in adenomas we aimed to increase the knowledge on the molecular events in this early-stage of carcinogenesis and to evaluate the likelihood that it could be used as a biomarker for CRC risk. Methylation of a nuclear gene that encodes a mitochondrial protein (UQCRB) has been identified as a potential biomarker in colorectal cancers . FurtherIn patient samples we observed transcription changes which suggest that mitochondrial function was impaired in adenomas compared to normal mucosa. This fits with the shift in cancer cells from oxidative metabolism, to glycolysis for energy production . A recenOur observation of reduced genome-wide CpG methylation in adenoma may fit with a previous study that identified reduced LINE-1 methylation in adenomas (particularly in patients with adenomas and concomitant CRC) . LINE-1 Similar to previous reports, our WGBS data showed that mtDNA has a much lower level of CpG methylation than the nuclear genome , 45. We Multiple studies have described regional differences in the level of methylation across the 16Kb of human mtDNA , 20, 44.Our observation of increased methylation at the rRNA gene regions could be influenced by them containing relatively high levels of 5-hydroxymethylcytosine (5hmC) as well as 5-methylcytosine . As sodiA final potential explanation for the regional differences in mtDNA methylation and coverage could be copy number changes within the mtDNA molecule. Rare cases have been reported of mtDNA deletions and rearrangements in patients with mitochondrial disease  and neurIn conclusion, our study suggests that while alteration to mitochondrial function is a feature of all adenomas, extensive alteration of mtDNA methylation is not. Therefore mtDNA methylation is unlikely to be suitable as an early biomarker for CRC.Additional file 1:Table S1. Clinical sample and patient information and experimental usage. (DOCX 15 kb)Additional file 2:Figure S2. Quality control of ‘omics’. A Volcano plot depicting fold changes associated with differentially expressed nuclear genes in paired normal mucosa vs adenoma samples (n = 6 v12 respectively). B Principal Component Analysis of RNA-sequencing  using expression values for each identifier. C Principal Component Analysis of Whole Genome Bisulphite Sequencing  using average methylation in 100 kb bins, for regions where all 9 samples had at least one read. (DOCX 4237 kb)Additional file 3:Supplementary data. Nuclear and mtDNA RNA-seq gene expression levels. WGBS read counts. (XLSX 10324 kb)Additional file 4:Figure S1. DNA methylation levels at 4 CpG sites in MT-RNR1 and 2 CpG sites in MT-CO1 detected with pyrosequencing in normal mucosa (n = 3) and adenoma (n = 4) patient samples. Mean ± SEM displayed. N, normal mucosa; A, adenoma. No error bars indicates identical measurement in samples. (DOCX 57 kb)