Summary of the Dutch Practice Guideline on Pregnancy Wish and Pregnancy in CKD

Margriet F.C. de Jong, Henk W. van Hamersvelt, Inge W.H. van Empel, Ellen J.W. Nijkamp, A. Titia Lely and on behalf of the Dutch Guideline Working Group on Pregnancy in CKD Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, Groningen, the Netherlands; Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Obstetrics and Gynecology, Radboud University Medical Center, Nijmegen, the Netherlands; and Department of Obstetrics and Gynecology, Utrecht University Medical Center, Utrecht, the Netherlands


INTRODUCTION Background
The number of women with chronic kidney disease (CKD) desiring a pregnancy is increasing. First, it is because of the increasing maternal age with the inherent higher incidence of CKD. Second, it is because of improved treatment options and higher numbers of kidney transplantations leading to increased number of fertile women with CKD for whom pregnancy can be a safe option. Furthermore, due to improved preconception care and multidisciplinary care before, during, and after pregnancy, maternal and fetal outcomes have improved. Nevertheless, preexisting CKD has negative effects on maternal and fetal outcomes (Figures 1 and 2). Patients with CKD or a kidney transplant and their offspring have an increased risk for pregnancy complications such as temporary or permanent kidney function decline, hypertension, preeclampsia, preterm birth, and intrauterine growth restriction. [1][2][3][4][5][6][7][8][9] Aims The aim of this guideline is to provide structured and where possible, evidence-based standard of care for patients with CKD throughout the process of planning a pregnancy to delivery and the early postpartum period including lactation ( Figure 3).

Scope
The clinical issues covered in this guideline include the following ( Figure 3): Part 1: Preconception risk stratification of pregnant women with CKD

EXECUTIVE SUMMARY
The Dutch practice guideline on "Pregnancy Wish and Pregnancy in Patients with CKD" was developed by a multidisciplinary working group composed of all relevant specialisms and representatives of patients, and published in the Dutch medical guideline database in 2021. Guideline recommendations are based on available relevant studies and appraisal of the quality of the evidence. The strength of recommendations is based on the "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) approach. Scope of the guideline was determined by clinical issues, such as preconception (genetic) counseling, diet restrictions, treatment of hypertension and anemia, immunosuppressive medication, and the obstetric treatment. The goal of the guideline is to provide clinicians and patients a useful resource with actionable patient-centered, structured, and where possible evidence-based care recommendations for the process of planning a pregnancy to delivery and the early postpartum period including lactation. Finally, knowledge gaps for each clinical issue are described.

LAY SUMMARY
The Dutch practice guideline on "Pregnancy Wish and Pregnancy in Patients with CKD" was developed by a multidisciplinary working group composed of all relevant specialisms (nephrologists, gynecologists, and clinical geneticist) and representatives of patients. It was published in the Dutch medical guideline database in 2021. Guideline recommendations are based on available relevant studies and appraisal of the quality of the evidence. The strength of recommendations is based on the GRADE approach. The scope of the guideline was determined by clinical issues. Examples of the issues include the following: -discussing the pregnancy wish before an actual pregnancy, review of risk factors for pregnancy complications and worse kidney outcomes, need for referral to a clinical geneticist, and a medication review, -diet restrictions, -treatment of high blood pressure and anemia, -immunosuppressive medication, and -the obstetric treatment. The goal of the guideline is to provide clinicians and patients a useful resource with actionable patientcentered, structured and where possible, evidencebased care recommendations. This includes the whole process of planning a pregnancy to delivery and the early postpartum period including lactation. Finally, knowledge gaps for each clinical issue are described.

METHODS
For development of this guideline a multidisciplinary working group was composed of all relevant specialisms and representatives of patients. The scope of the guideline was determined by clinical issues that were framed by a research question and background. Literature searches were conducted by literature specialists using specific search terms related to each of the issues covered. The research question, background, search and select method, results, conclusion, rationale, and recommendations were described for each clinical issue. Strength of evidence was determined by the GRADE method. 10,11 When GRADE was not possible because studies found by the literature search did not meet the inclusion criteria, studies were described in the analysis of the literature if relevant for the direction of the recommendations. For this publication, recommendations were officially translated from Dutch by a forward and backward method. Other parts of the Dutch guideline were (somewhat shortened) translated by the authors. The full guideline is reported in the Supplementary Materials.

RECOMMENDATIONS Preconception Risk Stratification and Counseling
Risk Stratification (no GRADE) 1. Preconception consultation of women with CKD stage 3 or higher, or with a kidney transplant, or with a systemic autoimmune disease (regardless of the use of immunosuppressants) should preferably be performed in a university hospital by a maternalfetal medicine specialist and a nephrologist. Both specialists should be experienced in supervising pregnant women with CKD. For women with CKD stage 1 or 2 without a kidney transplant or systemic autoimmune disease, the working group suggests that it is useful to receive counseling at a university hospital. 2. Pregnant women with CKD stage 1 or 2 without a kidney transplant and without systemic autoimmune disease needing immunosuppressants may receive specialist care in a general hospital. This care should be given by an obstetrician and a nephrologist with affinity for pregnancy in patients with CKD. If the patient's condition or renal function deteriorates or fetal complications (are likely to) develop, the attending physician should consult with the specialized team at a university hospital and refer the patient without hesitation.

Pregnant women with CKD stage 3 or higher should
preferably be treated in a university hospital by a maternal-fetal medicine specialist and a nephrologist who should both be experienced in the treatment of pregnant patients with CKD.
4. Referral to a university hospital is strongly recommended for patients with a kidney transplant, patients with CKD due to a systemic autoimmune disease needing immunosuppressants and dialysis patients.
Preconception Counseling (no GRADE) 1. Recommend patients with CKD who do not want to become pregnant (yet) to use safe and effective contraception. Actively inquire into the desire to conceive. 2. Consultation with a CKD patient who wants to conceive, to be conducted by a nephrologist and maternal-fetal medicine specialist, should at least address the following aspects: the possible effects of pregnancy on the underlying kidney disease and assessment of the risk of transient and/or permanent loss of renal function timing of pregnancy the effects of CKD on pregnancy, specifically the risks of pregnancy complications such as hypertension, preeclampsia, intrauterine growth restriction, and (iatrogenic) premature birth (Figures 1 and 2 symptomatic CKD at a young age (<20 years old), -CKD stage 4 or 5 in a patient younger than 40 years patients with a positive family history of primary kidney disease or hereditary disorders with renal involvement such as atypical hemolytic uremic syndrome adult patients with a confirmed hereditary disorder if they have not had preconception counseling or if the preconception counseling was more than 5 years ago patients who desire prenatal diagnostics: B who consulted with a clinical geneticist more than 2 years ago B whose prenatal diagnostics report or instructions are not explicit enough B who did not receive genetic counseling at the center where the prenatal diagnostics will be conducted. In the above cases, contact the clinical geneticist at the center where the prenatal diagnostics will be conducted to verify if a referral is indicated. Patients with a confirmed hereditary disorder who may wish to be eligible for preimplantation genetic diagnostics (In the Netherlands, patients will always have to be referred for such preimplantation genetic diagnostics via a clinical geneticist).

Nephrological Treatment During Pregnancy
Diet Restrictions (no GRADE-Very Low GRADE) 1. Check sodium excretion in the 24-hour urine of pregnant patients with CKD (nondialysis (ND)) and limit their daily salt intake to a maximum of 6 grams (¼ 100 mmol of sodium chloride equivalent to 2400 mg of sodium) as recommended for all patients with CKD. (very low GRADE) 2. For pregnant women with CKD and (expected) high degree of sodium retention during pregnancy (manifesting as excessive weight gain combined with edema and/or hypertension), consider further limiting the daily salt intake to 3 grams (1200 mg sodium) during pregnancy. Refer patients to a dietician for this purpose. (very low GRADE) 3. Regularly check the salt excretion of pregnant women with CKD and a good indication for salt restriction using 24-hour urine or the sodium-tocreatinine ratio (mmol sodium/10 mmol creatinine) in a spot urine sample. (no GRADE) 4. Continue or start pregnant patients with CKD and a good nephrological indication for protein restriction on a diet of 0.8 g/kg ideal weight per day throughout pregnancy and, therefore, be reluctant to increase protein intake in the second and third trimesters as recommended for healthy pregnant women. This recommendation does not apply to dialysis patients. (no GRADE) 5. For kidney patients with a (highly) advanced CKD stage (G3b-G5ND), consider prescribing a (stricter) protein-restricted diet of less than 0.8 g/kg ideal weight per day during pregnancy to maintain their serum urea level at <17 mmol/l in order to prevent polyhydramnios, and thereby attain a longer gestational age and a higher birth weight. (no GRADE) 6. Consider supplementing this strictly proteinrestricted diet with amino acid supplements to ensure an equivalent daily protein intake of at least 0.8 grams/kg ideal weight/day by referring patients to a dietician with expertise in this area. (no GRADE) 7. Consider regularly checking the urea level in 24hour urine or a spot urine sample to estimate protein intake and thereby assess dietary compliance, and avoid excessively low protein intake. (no GRADE) 1. When treating hypertension in patients with CKD and a desire to conceive, aim preconceptionally for blood pressure <130/80 mm Hg, regardless of the proteinuria level. (no GRADE) 2. During pregnancy, only initiate antihypertensive treatment in patients with CKD (with or without albuminuria) who have not used antihypertensives before or during pregnancy if their blood pressure is higher than 140/90 mm Hg on repeated measurements. (no GRADE) 3. In patients with CKD who already used antihypertensives before conception, only intensify the ACR $30 mg/mmol, corresponding to proteinuria $0.5 g protein/24 hours or protein/creatinine ratio $0.5 g/10 mmol creatinine). 13. In patients with CKD with proteinuria who develop nephrotic range proteinuria (>3 grams/day) during pregnancy, consider one or more of the following measures: further restricting the dietary sodium intake to approximately 1200 mg/day limiting the daily protein intake to 0.6 to 0.7 grams/kg ideal weight, supplemented with amino and keto acids equivalent to 0.2 to 0.3 grams of protein/kg ideal weight adding the potassium-sparing diuretic amiloride in patients who already use a diuretic and develop (severe) sodium retention from the twentieth week onwards, because of its beneficial effect on sodium retention caused by proteinuria starting with a dihydropyridine calcium antagonist only if the patient's systolic blood pressure is above 140 mm Hg or diastolic blood pressure is above 90 mm Hg on repeated measurements despite the maximum dose of the thiazide diuretic and beta-blocker. (no GRADE) 14. For women who need an antihypertensive during lactation, the potential advantages and disadvantages of the various agents must be considered. When there is proteinuria >0.5g/24h or diabetic nephropathy, start with enalapril if antihypertensive treatment is indicated, as soon as possible after birth. For women with CKD who need a beta-blocker during lactation, choose a beta-blocker with favorable pharmacokinetic properties (high protein binding, low kidney excretion: labetalol, metoprolol, pindolol, or propranolol) because these can be safely used during lactation. Avoid prescribing alpha-blockers during lactation because it is largely unknown whether these drugs find their way into breast milk and the neonatal risks are still unknown. (no GRADE)

Anemia (No GRADE)
1. Aim at a ferritin level >80 mcg/l to 500 mcg/l in pregnant patients with CKD with intact renal function (estimated glomerular filtration rate [eGFR] >60; stage G1-2) and anemia. 2. Aim at a ferritin level >200 mcg/l to 500 mcg/l in pregnant patients with CKD with impaired renal function (eGFR <60; stage G3-5ND) and anemia. 3. In principle, do not prescribe iron in pregnant patients with CKD with ferritin level >500 mcg/l and/or transferrin saturation >30%. 4. Aim at a transferrin saturation between 30% and 50% and a ferritin level >300 mcg/l to 800 mcg/l in pregnant dialysis patients with anemia. 5. Start pregnant patients with CKD with irondeficiency anemia on oral iron supplements; aim at a ferritin level >80 mcg/l. 6. Consider starting pregnant patients with CKD with even mild iron deficiency on such supplements even if their hemoglobin (Hb) is normal. 7. In the second and third trimesters, switch to parenteral iron supplements if the target levels cannot be achieved with oral agents and regularly check Hb and iron levels. 8. If pregnant patients with CKD must be given parenteral iron supplements, prescribe one of the modern, stable iron supplements such as iron carboxymaltose (Ferinject) with a maximum dose of 1000 mg (up to 15 mg/kg/dose) or iron isomaltoside (Monofer/Diafer) in doses of up to 1000 to 2000 mg (maximum 20 mg/kg/dose). 9. If one of the older, less stable iron supplements such as iron sucrose (Venofer) is selected for pregnant hemodialysis patients, give a low dose of GUIDELINES up to 62.5 to 100 mg during dialysis because of the possibility of fetal iron accumulation. 10. Aim for an Hb of 6.2 to 6.8 mmol/l (corresponding with an Ht of 30% to 35%) in pregnant patients with CKD (with or without dialysis), because the obstetrical outcomes are better if Hb >6.2 mmol/l. 11. Exclude iron, folic acid, and vitamin B12 deficiencies and adequately treat any deficiencies before considering prescribing rhEPO. 12. Consider starting pregnant patients with CKD with (renal) anemia (Hb <6.2 mmol/l) on rhEPO. When doing so, always weigh the potential benefits for the well-being of the mother and the obstetrical outcome against the potential risks of vasoconstriction with aggravation of hypertension, particularly if Hb rises quickly. 13. If a rapid increase in Hb is desired, for example because labor is approaching, consider leukocytedepleted, Parvovirus B19-free, and cEKcompatible erythrocyte transfusions as a good alternative to rhEPO. Because of the leukocyte depletion, these transfusions are CMV-free too. 14. Because of erythropoietin resistance during pregnancy, consider increasing the rhEPO dose for pregnant patients who already used rhEPO before pregnancy by 50% to 100% to achieve and/or maintain the Hb target value. Regularly review the rhEPO dose in the light of the patient's Hb. For most patients, a maximum dose of twice the normal starting dose can be used as a safe dose. 15. For pregnant patients with CKD, perioperative transfusions should be given if Hb <4.5 mmol/l and considered if Hb <5.0 mmol/l in a stable situation. However, consider transfusions if Hb <6.0 mmol/l and major blood loss is expected (e.g., around birth) because the obstetrical outcomes are better if Hb >6.2 mmol/l. 16. Consider blood transfusions for pregnant dialysis patients who are classified as ASA 3 due to the dialysis if their Hb <6.0 mmol/l and it cannot be expected that Hb can be corrected within a few weeks with parenteral iron supplements and/or rhEPO. Always give blood transfusions if Hb < 6.0 mmol/l and major blood loss is expected (e.g., around birth). 17. When considering the need for transfusions, consider the risk of allosensitization in view of organ transplantation in the near or far future. Discuss the potential consequences of blood transfusions.

New Onset of Nephrological Problems During Pregnancy
Proteinuria/nephrotic syndrome/thrombotic microangiopathy (no GRADE) 1. In pregnant women showing a decline in eGFR and/ or proteinuria >300 mg/day during the first half of their pregnancy, analyze the cause of the renal insufficiency using diagnostic tools that would also be used outside pregnancy (ultrasonography, urine tests, and, if indicated, specific immunological tests or a selectivity index).

Pregnant women with symptomatic urolithiasis
should primarily receive conservative treatment. Be reluctant to apply retrograde urological interventions in the urinary tract due to the risks of inducing preterm labor and urosepsis. 3. Consider thrombotic microangiopathy that is not part of hemolysis, elevated liver enzymes and low platelets for women with acute kidney injury and hemolysis during pregnancy and after birth. Differentiation between preeclampsia and kidney disease (no GRADE) 1. Do not use the soluble fms-like tyrosine kinase-1/ placental growth factor ratio in daily practice to distinguish between preeclampsia and (underlying) primary kidney disease because the available data is not yet sufficiently reliable.
Indication for kidney biopsy (no GRADE)

Do not refrain from a kidney biopsy in pregnancy if
there is a strict indication to do so because the risks of a kidney biopsy under ultrasonographic guidance with an automatic biopsy device are the same for pregnant and nonpregnant women. The main indications are: severe nephrotic syndrome in the first or second trimester, nephrotic syndrome with progressive renal failure in all trimesters, suspicion of acute glomerulonephritis in patients with progressive renal failure with glomerular erythrocyturia with or without proteinuria, suspicion of acute rejection of a kidney transplant. 2. In patients with postpartum persistent nonnephrotic range proteinuria without (progressive) renal failure, only perform a renal biopsy at least 6 months after the birth due to the high likelihood of spontaneous recovery of pregnancy-related glomerular abnormalities in this postpartum period.

Dialysis (No GRADE)
1. In hemodialysis patients who want to become pregnant, consider whether a kidney transplant is possible and whether pregnancy can be postponed until 1 year after transplantation because the pregnancy outcomes after kidney transplantation are significantly better than during hemodialysis. 1. For any prospective parent (male/female) with CKD, consider whether there is an indication for advanced ultrasonography of the fetus. 2. All prospective parents with CKD due to a structural defect not based on a known genome abnormality and women with CKD who must use teratogenic medication during pregnancy have an indication for advanced ultrasonography of the fetus.
Decreasing Preeclampsia Risk (no GRADE) 1. Prescribe acetylsalicylic acid to any pregnant woman with CKD because they have a (substantially) higher preeclampsia risk.
2. Start prophylactic acetylsalicylic acid in doses of 80 to 150 mg/day from 12 weeks (after last menstruation) and preferably before the end of the sixteenth week. Stop the treatment at least 1 week before the expected natural birth or planned cesarean section, that is, usually at 36 weeks pregnancy, unless the birth is expected earlier.
Recommend that the woman takes the acetylsalicylic acid in the evening.
3. Recommend that any pregnant woman with CKD use at least 1000 mg/day of elemental calcium (preferably in their food) because this may lower the preeclampsia risk. 4. If insufficient calcium is ingested with food, start elemental calcium supplementation of 500-1000 mg (preferably a combination of calcium and 400 to 800 IU of colecalciferol), to be taken in 1 dose on an empty stomach, with the dose depending on the dietary calcium intake. Patients should not take calcium supplements at the same time as iron supplements, which should also be taken on an empty stomach. Be cautious when prescribing calcium supplements to patients with advanced CKD stages (G4 and higher) and hyperphosphatemia despite adequate dietary measures.
5. Do not recommend sodium or protein restriction to prevent preeclampsia in pregnant women with CKD.
If necessary, recommend this as part of their CKD treatment.
Delivery Plan (no GRADE) 1. In principle, aim at a vaginal delivery in women with CKD and/or a functioning kidney transplant. Time the delivery based on the clinical parameters. Discuss the advantages and disadvantages of inducing labor in patients with CKD after the thirty-eighth week due to the increased risks of preeclampsia, loss of renal function, and stillbirth. 2. In the event of obstetrical complications such as fetal growth restriction, preeclampsia, or deterioration of the mother's condition and/or kidney function, consider inducing labor early, preferably in consultation with the nephrologist. 3. In patients with CKD stages G4 and above (eGFR < 30 ml/min per 1.73 m 2 ), consider 1 or more of the following measures before or during labor: try to avoid neuroaxial techniques in patients who have stopped taking acetylsalicylic acid less than 5 days before GUIDELINES if potentially severe bleeding is expected or occurs due to uremic thrombocytopathy, especially if the patient stopped taking acetylsalicylic acid less than 5 days before: B blood transfusions if their Hb drops below 6.2 mmol/l B 0.3 to 0.4 mcg/kg of desmopressin intravenous. When desmopressin is given, limit the patient's fluid intake to a maximum of 1500 ml all-in over the first 24 hours after the desmopressin administration to prevent overfilling and hyponatremia with the associated risk of epileptic seizures. Regularly check the patient's blood pressure and serum sodium levels for the first 24 hours after administration preferably prime the cervix with a Foley balloon catheter if labor must be induced, do so with oxytocin because this does not require dose adjustments in patients with CKD lower the maintenance dose of magnesium sulfate: normal 4 g loading dose in 10 to 30 minutes and 0.5 g/hour maintenance dose. Frequently check the patient for signs of intoxication and regularly monitor their blood magnesium levels any drug given during labor should be checked to verify that it is allowed and whether the dose should be adjusted; do not hesitate to consult with a nephrologist and/or pharmacist. 4. Test a sample of umbilical cord blood for hematologic parameters if the mother has used immunosuppressants such as azathioprine or biopharmaceuticals during pregnancy. These agents may cause maternal leukopenia and/or thrombocytopenia and are known to cause neonatal bone marrow suppression.

CONCLUSION
The Dutch practice guideline on "Pregnancy Wish and Pregnancy in Patients with CKD" provides patientcentered, thorough, structured, and where possible evidence-based standard of care recommendations for patients with CKD throughout the process of planning a pregnancy to delivery and the first postpartum period including lactation.

DISCLOSURE
MFCdJ, IWHvE and ATL report receiving speaker fees from Alexion. All the other authors declared no competing interests.

SUPPLEMENTARY MATERIAL
Supplementary File (PDF) Dutch Practice Guideline: Pregnancy wish and Pregnancy in patients with chronic kidney disease. Figure S1. Birth weight and NICU admittance according to prepregnancy CKD stage. Figure S2. Maternal complications and admittance during pregnancy according to CKD stage. Figure S3. Kidney outcome 6 months postpartum according to prepregnancy CKD stage. Table S1. Considerations for use of antihypertensive agents during lactation.