Abstract
Aim As diagnostic and therapeutic options have improved in recent years, women with limited renal function of varying etiologies are now able to become pregnant. Depending on the extent of disease and the patientsʼ comorbidities, the care of these women can be especially challenging. This guideline aims to improve the interdisciplinary care offered to pregnant women with kidney disease.
Methods A selective literature search was carried out. This S2k guideline was then compiled using a structured consensus-based process which included representatives from different medical specialties and professional societies.
Recommendations Recommendations for the care of pregnant women with renal disease were developed to cover preconception counseling, the recording of risks, special aspects of prenatal care and prenatal screening, as well as the specific treatment options for the underlying disease in women wanting to have children and pregnant women.
Key words: chronic kidney disease, pregnancy, complications, renal function, preconception counseling, guideline
I Guideline Information
Guidelines program of the DGGG, OEGGG and SGGG
For information on the guidelines program, please refer to the end of this guideline.
Citation format
Chronic Kidney Disease and Pregnancy. Guideline of the DGGG, OEGGG, DGfN (S2k Level, AWMF Registry No. 015 – 090). Geburtsh Frauenheilk 2022; 82: 795–830
Guideline documents
The complete long version of this guideline together with a list of the conflicts of interest of all of the authors are available on the homepage of the AWMF.
Guideline authors ( Tables 1 and 2 )
Tab. 1 Lead author and/or coordinating guideline author.
| Author | AWMF professional society |
|---|---|
| Prof. Dr. Ute Schäfer-Graf | DGGG – AG G |
| Prof. Dr. Markus Schmidt | DGGG – AG G |
| Prof. Dr. Sylvia Stracke | German Society for Nephrology (Deutsche Gesellschaft für Nephrologie, [DGfN]) |
Tab. 2 Contributing guideline authors (in alphabetical order).
| Author Mandate holder |
DGGG working group/AWMF/ non-AWMF professional society/ organization/associations |
|---|---|
| Prof. Uwe Schneider Prof. Dr. Bettina Kuschel |
German Society for Prenatal and Obstetric Medicine (Deutsche Gesellschaft für Pränatal- und Geburtsmedizin [DGPGM]) |
| Prof. Dr. Thorsten Feldkamp | German Society for Internal Medicine (Deutsche Gesellschaft für Innere Medizin [DGIM]) |
| PD Dr. Sandra Habbig | Society for Neonatology and Pediatric Intensive Care Medicine (Gesellschaft für Neonatologie und Pädiatrische Intensivmedizin [GNPI]) |
| PD Dr. Karoline Mayer-Pickel | Austrian Society for Gynecology and Obstetrics (Österreichische Gesellschaft für Gynäkologie und Geburtshilfe [ÖGGG]) |
| Dr. Andreas Hartung | Professional Association of Gynecologists (Berufsverband der Frauenärzte [BVF]) |
| Prof. Dr. Sylvia Stracke Dr. Birgit Bader Prof. Dr. Julia Weinmann-Menke |
German Society for Nephrology (Deutsche Gesellschaft für Nephrologie [DGfN]) |
| Uwe Korst | Federal Kidney Association (Bundesverband Niere e. V.), patient representative |
| Prof. Dr. Ute Schäfer-Graf | German Society for Gynecology and Obstetrics (Deutsche Gesellschaft für Gynäkologie und Geburtshilfe [DGGG]) |
| Prof. Dr. Markus Schmidt | German Society for Perinatal Medicine (Deutsche Gesellschaft für Perinatale Medizin [DGPM]) |
| Prof. Dr. Frank vom Dorp | German Society for Urology (Deutsche Gesellschaft für Urologie [DGU]) |
II Guideline Application
Justification for the choice of guideline topic
With increasing numbers of women becoming pregnant at an older age, the number of pre-existing diseases which can have a significant impact on the course of pregnancy for mother and infant has increased. Improvements in diagnostic and therapeutic options have allowed even women with limited renal function of varying etiologies to become pregnant. Depending on the extent of disease and the patientsʼ comorbidities, providing these women with appropriate care is a particular challenge.
Purpose and objectives
The guideline aims to provide clinicians with a range of instruments which will improve and standardize the care given to this risk population. To do this, all relevant areas of prenatal care including preconception counseling and postpartum consequences for mother and infant have been reviewed and discussed.
Targeted areas of patient care
Inpatient care
Outpatient care
Target patient groups
The guideline is aimed at women with chronic kidney disease and includes non-pregnant women who wish to have children and pregnant women.
Target user group/target audience
This guideline is aimed at the following groups of people:
Practice-based gynecologists
Hospital-based gynecologists
Internists and general practitioners specializing in nephrology
Neonatologists
Other target groups (to provide them with information):
Nursing staff
Midwives
Adoption and period of validity
The validity of this guideline was confirmed by the executive boards/heads of the participating professional societies/working groups/organizations/associations as well as by the board of the DGGG and the DGGG guidelines commission in September 2021 and was thus approved in its entirety. This guideline is valid from 1st October 2021 through to 30th September 2024. Because of the contents of this guideline, this period of validity is only an estimate.
III Methodology
Basic principles
The method used to prepare this guideline was determined by the class to which this guideline was assigned. The AWMF Guidance Manual (version 1.0) has set out the respective rules and requirements for different classes of guidelines. Guidelines are differentiated into lowest (S1), intermediate (S2), and highest (S3) class. The lowest class is defined as consisting of a set of recommendations for action compiled by a non-representative group of experts. In 2004, the S2 class was divided into two subclasses: a systematic evidence-based subclass (S2e) and a structural consensus-based subclass (S2k). The highest S3 class combines both approaches.
This guideline has been classified as: S2k
Grading of recommendations
The quality of the presented evidence (strength of evidence) is an indication of the dataʼs reliability and therefore indicates the extent of certainty/uncertainty regarding the information. The level of recommendation indicates the strength of the recommendation after desirable and undesirable consequences of alternative procedures have been weighed up.
The binding nature of the respective recommendation indicates the level of medical obligation to comply with the substance of the guideline recommendation as long as the recommendation complies with the current state of scientific knowledge. In cases where this does not apply, the recommendation does not have to or should not be complied with. The editors of the guideline have not defined any legal obligations because the guideline does not have the capacity to enact laws, issue directives or enact statutes (as defined in the German law on statutes). This approach has been confirmed by the Federal Supreme Court of Germany (judgement of the Federal Supreme Court VI ZR 382/12).
The use of SIGN and GRADE to grade evidence in a S2e/S3-level guideline is used to indicate the level of recommendation typical for this type of guideline. There are three levels of recommendation, and the different strengths of recommendation are indicated not by symbols but by the respective choice of words. This commonly used method to grade recommendations is not just used by the AWMF but also by the German Medical Association in its National Guidelines on Care ( Nationale Versorgungsleitlinien , NVL). The wording chosen for each level of recommendation is explained in the background text ( Table 3 ).
Tab. 3 Grading of recommendations.
| Binding nature of the recommendation | Expression |
|---|---|
| Strong recommendation, highly binding | must/must not |
| Simple recommendation, moderately binding | should/should not |
| Open recommendation, not binding | may/may not |
Statements
Expositions or explanations of specific facts, circumstances or problems without any direct recommendations for action included in this guideline are referred to as “statements” . It is not possible to provide any information about the level of evidence for these statements.
Achieving consensus and level of consensus
As part of the structured process to achieve (S2k/S3 level) consensus, authorized participants attending the sessions vote on draft recommendations and statements. This can lead to significant amendments and changes to wordings, etc. Finally, the level of consensus is determined based on the number of participants ( Table 4 ).
Tab. 4 Level of consensus based on extent of agreement.
| Symbol | Level of consensus | Extent of agreement in percent |
|---|---|---|
| +++ | Strong consensus | > 95% of participants agree |
| ++ | Consensus | > 75 – 95% of participants agree |
| + | Majority agreement | > 50 – 75% of participants agree |
| – | No consensus | < 51% of participants agree |
Expert consensus
As the term already indicates, this refers to consensus decisions taken specifically with regard to recommendations/statements issued without a prior systematic search of the literature (S2k) or where evidence is lacking (S2e/S3). The term “expert consensus” (EC) used here is synonymous with terms used in other guidelines such as “good clinical practice” (GCP) or “clinical consensus point” (CCP). The strength of the recommendation is graded as previously described in the chapter Grading of Recommendations but without the use of symbols; it is only expressed semantically (“must”/“must not” or “should”/“should not” or “may”/“may not”).
IV Guideline
1 Renal function in pregnancy
1.1 Definition of chronic kidney disease (CKD)
KDIGO (Kidney Disease: Improving Global Outcomes) defines chronic kidney disease (CKD) as abnormalities of normal kidney structure or function which are present for more than 3 months with negative implications for health. There are many causes and types of renal damage which can be measuring using different parameters; they include albuminuria, urine sediment abnormalities, renal tubular problems, histological changes, and structural anatomical abnormalities.
Underlying disease, glomerular filtration rate and rate of albumin excretion are used to categorize chronic kidney disease.
The CGA classification of chronic kidney disease is based on the underlying disease (cause), the glomerular filtration rate category and the albuminuria category. The glomerular filtration rate has five categories (G1–5), and albuminuria has three (A1–3).
GFR is categorized as follows:
stage 1: GFR ≥ 90 ml/min
stage 2: GFR 60 – 89 ml/min
stage 3: GFR 30 – 59 ml/min
stage 4: GFR 15 – 29 ml/min
stage 5: GFR < 15 ml/min
1.2 Determining renal function
Glomerular filtration rate
The glomerular filtration rate (GFR) is the most important measure of the kidneysʼ excretory function. It is calculated using approximation formulas based on creatinine serum concentrations. In young healthy adults, the glomerular filtration rate is approximately 125 ml/min/1.73 m 2 . Chronic kidney disease is present when the glomerular filtration rate has decreased to less than 60 ml/min/1.73 m 2 .
Albumin excretion
If the blood–urine barrier in the glomeruli is damaged, protein may pass from the blood into urine. The urinary albumin concentrations are measured and correlated with the creatinine concentrations in urine measured at the same time (normal values: albumin-to-creatinine ratio < 30 mg/g).
Measuring the glomerular filtration rate (GFR)
The glomerular filtration rate (GFR) cannot be measured directly; instead, the clearance rate of the best marker of filtration is calculated to indicate the glomerular filtration rate. Inulin clearance, which has been used since 1935, is still considered the gold standard (most precise method).
Creatinine
The creatinine levels in the patientʼs blood (serum) are measured. This is one of the most important laboratory tests. Reduced kidney function means that glomeruli are no longer able to filter sufficient amounts of creatinine, leading to elevated creatinine serum levels.
Serum creatinine levels only become pathological when kidney function has already decreased by more than 50%. This means that creatinine is not suitable as an isolated marker to estimate kidney function (GFR) and not useful for the early detection of kidney disease because creatinine levels only rise in the later stages of decreased kidney function and also depend on age, gender, ethnicity, muscle mass and diet.
Cystatin C
Cystatin C (also: CysC) is a low molecular protein produced in the body; it is used in diagnostic kidney tests to determine the glomerular filtration rate (GFR). Normal CysC serum levels in humans are between 0.53 and 0.95 mg/l for both genders. In contrast to creatinine, cystatin C levels already begin to rise when there is a mild decrease in GFR; this makes it easier to detect any decrease in the GFR despite an apparently normal kidney function rather than measuring serum creatinine levels or using GFR formulas.
Kidney function in pregnancy
The kidneys adapt to the changing conditions of pregnancy. Because of the increased vascularization of the placenta, the total volume of the vascular area being supplied with blood increases, leading to a decrease in blood pressure. As the mother needs to ensure a sufficient blood supply both for herself and for the fetus, the volume of blood, maternal heart rate and therefore maternal cardiac output per minute increase to compensate for this drop. This increase is accompanied by an increase in renal plasma flow (RPF) of 60 – 80% and an increase in the glomerular filtration rate (GFR) of around 50% while the intraglomerular pressure remains approximately the same.
As a result, concentrations of metabolites in maternal serum eliminated via the kidneys decrease; this also applies to the retention parameters creatinine, uric acid, and urea. Normal serum creatinine values measured in non-pregnant women would be considered elevated if measured during pregnancy and as a possible indication of kidney damage.
Physiological changes:
creatinine level decreases to 0.4 to 0.5 mg/dl (36 – 45 µmol/l)
urea decreases to 18 mg/dl (3.0 mmol/l)
uric acid decreases to 3.2 – 4.3 mg/dl (190 – 256 µmol/l)
The permeability of the glomerular filter also changes: proteinuria up to a maximum of 300 mg per day (measured by 24-hour urine collection) is considered physiologically normal in pregnancy.
The decreased vascular resistance caused by vasoactive substances leads to activation of the renin-angiotensin-aldosterone system (RAAS). The kidney increases in volume and length (1 – 2 cm), resulting in physiological hydronephrosis in up to 80% of pregnancies. The resulting dilation of the renal pelvis and urinary tract (or ureters) can mimic urinary retention and lead to a more frequent occurrence of vesicoureteral reflux and stasis in the ureters due to compression of the urethral ostium which, in turn, encourages bacteriuria, ascending urinary tract infections and even pyelonephritis.
1.3 Epidemiology
Chronic kidney disease is a rare entity in pregnancy, although the precise incidence is unknown.
In general, pregnancies in women with chronic kidney disease are differentiated into three risk constellations:
patients with almost normal or only slightly impaired kidney function (serum creatinine < 1.5 mg/dl or GFR > 70 ml/min),
patients with moderately impaired kidney function (in most studies, serum creatinine is 1.5 – 3.0 mg/dl),
patients with higher-level kidney function impairment (serum creatinine > 3.0 mg/dl).
Because of the high rate of complications, pregnancy is generally not recommended for women with moderate to high-level kidney function impairment. Women who wish to have children should receive counseling which takes account of the patientʼs individual health conditions and life situation.
Even pregnant women with kidney disease not (yet) associated with reduced kidney function have a significantly higher risk of poor pregnancy outcomes.
2 Preconception counseling
2.1 Complications of pregnancy in women with chronic kidney disease
| Consensus-based recommendation 2.E1 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Safe and effective contraceptive methods must be recommended to the following groups of women: women currently taking teratogenic medication, women with active glomerulonephritis, women who have had a kidney transplant one year ago or less or who have suffered transplant rejection. The underlying disease should be taken into consideration when advising women about the choice of contraceptive. | |
| Consensus-based recommendation 2.E2 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Women with chronic kidney disease must be informed about the increased risk of complications of pregnancy such as miscarriage, preterm birth, preeclampsia, fetal growth restriction, preterm placental abruption and intrauterine fetal death as well as the deterioration of renal function. | |
Women with chronic kidney disease have a higher risk of developing complications of pregnancy.
The incidence of complications and the times when complications of pregnancy occur depend on the severity of chronic kidney disease as well as the underlying disease and its treatment.
There are no threshold values for kidney parameters beyond which women would be advised not to become pregnant. The decision for or against pregnancy is an individual choice and must be made together with the patient after considering her individual risk factors. Successful pregnancies have been reported for both dialysis patients and patients who have had a kidney transplant.
Kidney and diabetes
| Consensus-based recommendation 2.E3 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Prior to conception, the aim should be to achieve metabolic management and an HbA 1c of less than 7.0%. | |
| Consensus-based recommendation 2.E4 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Blood pressure should be optimized prior to conception. | |
Diabetes is the most common cause of CKD in women of reproductive age. Even without prior CKD, diabetic women have a higher risk of hypertension, proteinuria and preeclampsia.
2.2 Medication in pregnancy
| Consensus-based recommendation 2.E5 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Women with stage G3 – 5 (eGFR < 60 ml/min) or A3 (albumin excretion > 300 mg/g) chronic kidney disease should receive thrombosis prophylaxis with low-molecular-weight heparin during pregnancy and postpartum (6 – 8 weeks postpartum). | |
Low-molecular-weight heparin should be preferred to unfractionated heparin because of its higher bioavailability, longer half-life and more predictable therapeutic response.
| Consensus-based recommendation 2.E6 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Supplementation with vitamin D in women with chronic kidney disease which was initiated before the start of pregnancy must be continued throughout the pregnancy or must be initiated if vitamin D deficiency is diagnosed in pregnancy. | |
| Consensus-based recommendation 2.E7 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Women with chronic kidney disease must not be given calcium-mimetic agents or non-calcium-containing phosphate binders during pregnancy and breastfeeding. | |
Antihypertensives
| Consensus-based recommendation 2.E8 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Pregnant patients with kidney disease and pre-existing hypertension must be given calcium antagonists such as nifedipine or amlodipine as the 1st choice medication. Alpha methyldopa, urapidil, β1-selective betablockers or labetalol (A/CH) may be used alternatively or in addition. | |
| Consensus-based recommendation 2.E9 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Treatment with ACE inhibitors, AT1 receptor antagonists or renin inhibitors (RAS blockade) is contraindicated in pregnancy; diuretics should only be prescribed if treatment with diuretics is strongly indicated. | |
| Consensus-based recommendation 2.E10 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Patients receiving treatment with RAS blockers prior to pregnancy must be informed that this therapy must be discontinued once the patient is pregnant and patients must be switched to suitable alternative medications. Treatment with RAS blockers is not a medical indication for terminating a pregnancy. | |
Table 5 lists 1st and 2nd choice hypertensives as well as medications which are not suitable to treat hypertension in pregnancy.
Tab. 5 Antihypertensives in pregnancy.
| Medication | Conception | Pregnancy | Lactation | Dosage | Comments |
|---|---|---|---|---|---|
| Suitable medication | |||||
| Alpha methyldopa (Aldomet/Presinol) | safe | safe | safe | 200 – 250 mg (2 – 4 ×/day). Max. 2 g/day | 1st choice medication |
| Nifedipine retard (Adalat ret.) | safe | safe | safe | 20 – 60 mg. Max. 120 mg/day | |
| Amlodipine (Norvasc) | safe | data is limited | data is limited | 5 mg. Max. 10 mg/day | |
| Urapidil (Ebrantil) | not teratogenic, but data is limited | not teratogenic, but data is limited | not teratogenic, but data is limited | 30 – 60 mg. Max. 180 mg/day | |
| Limited suitability | |||||
| Selective β1-blockers (metoprolol) | not teratogenic | not teratogenic | safe | 25 – 100 mg/day (2 × daily) | Beware IUGR! Rare cases of neonatal bradycardia and hypoglycemia |
| Unsuitable | |||||
| Diuretics | not recommended | not recommended | not recommended | Potential negative impact on uteroplacental perfusion | |
| ACE inhibitors | not recommended | not recommended | not recommended | Especially in 2nd and 3rd trimester: AKF, pulmonary hypoplasia, bone and aortic arch malformations in neonates, oligohydramnios | |
| Angiotensin AT1 antagonists | not recommended | not recommended | not recommended | Oligohydramnios, skull hypoplasia, nephrotoxic | |
Cyclophosphamide
| Consensus-based recommendation 2.E11 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Women with chronic kidney disease who are given cyclophosphamide must be informed about the options of fertility protection in specialized centers. | |
Immunosuppressants
Immunosuppressants which can be taken during pregnancy are listed in Table 6 .
Tab. 6 Immunosuppressants in pregnancy.
| Medication | Conception | Pregnancy | Lactation | Dosage | Comments |
|---|---|---|---|---|---|
| Suitable medication | |||||
| Azathioprine | safe | safe | safe | maximum daily dose: 2 mg/kgKG | |
| Cyclosporine A | safe | safe | safe | target level (maintenance) 80 – 100 ng/ml | Beware medications affecting calcineurin inhibitor metabolism (e.g., erythromycin, clarithromycin). Possibly increased risk of gestational diabetes |
| (Hydroxy-) chloroquine | safe | safe | safe | 200 – 400 mg/d | |
| Tacrolimus | safe | safe | safe | target level (maintenance) 5 – 8 ng/ml | Beware medications affecting calcineurin inhibitor metabolism (e.g., erythromycin, clarithromycin). Possibly increased risk of preterm birth, gestational diabetes and neonatal hypokalemia |
| Limited suitability | |||||
| Eculizumab | not teratogenic | not teratogenic | possible | Almost no data and almost only case reports | |
| Rituximab | not teratogenic | not teratogenic | not recommended | Careful in 2nd and 3rd trimester because of (transient) immunosuppression or B-cell depletion in the neonate | |
| Unsuitable | |||||
| Mycophenolate mofetil | teratogenic | teratogenic | very little data, better not | Increased risk of miscarriage, contraception should be used during and for 6 months after treatment | |
| Cyclophosphamide | teratogenic | teratogenic | not recommended | Increased risk of miscarriage, increased risk of IUGR and pancytopenia in 2nd and 3rd trimester. Contraception should be used during and at least 3 months after treatment | |
| Leflunomide | teratogenic | teratogenic | not recommended | Increased rate of malformations; wash out leflunomide with cholestyramine 6 months prior to planned conception | |
2.3 Genetics
| Consensus-based recommendation 2.E12 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Women with known or suspected hereditary kidney disease must be offered genetic counseling about the risk of passing on their condition, genotype-phenotype variability, prognosis and options (preimplantation genetic diagnosis, prenatal diagnostic testing, options during the pregnancy and postpartum) before they start planning their pregnancy/if they wish to have children. | |
Genetic counseling is indicated for families with known or suspected hereditary kidney disease.
| Consensus-based recommendation 2.E13 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| If one or more unilateral or bilateral renal cysts and/or renal hyperechogenicity in one or both kidney(s) with/without oligohydramnios are detected in the fetus, the mother must be offered detailed screening for malformations which must be carried out by qualified professionals (DEGUM 2). | |
| Consensus-based recommendation 2.E14 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| If one or more unilateral or bilateral renal cysts and/or renal hyperechogenicity in one or both kidney(s) with/without oligohydramnios are detected in the fetus, genetic counseling and an assessment with regard to hereditary kidney disorders/intermarriage must be carried out. | |
Cystic nephropathy and dysplasia have a very wide range of phenotypes and are genetically very heterogeneous.
| Consensus-based recommendation 2.E15 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Interdisciplinary counseling involving specialists in prenatal medicine, pediatric nephrology, neonatology and even human genetics must be offered to patients with pronounced, prenatally visible findings (particularly if there is a suspicion of kidney function disorder/oligohydramnios). | |
3 Pregnancy
3.1 Monitoring kidney functions
Excretory kidney function
Given that there are considerable differences in the kidney function of pregnant women compared to that of non-pregnant women, it is difficult to estimate GFR during pregnancy using standard formulas and procedures (Cockroft–Gault, MDRD, CKD-EPI).
| Consensus-based recommendation 3.E 16 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Serum creatinine levels ≥ 0.87 mg/dl (77 µmol/l) in pregnant women should be investigated by a nephrologist. | |
| Consensus-based recommendation 3.E17 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Serum creatinine levels should be used to estimate kidney function during pregnancy. To investigate specific issues, creatinine clearance based on 24-hour urine collection should be used to determine GFR. | |
| Consensus-based recommendation 3.E18 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| All formulas used for eGFR determination were developed in healthy, non-pregnant test subjects, have not been validated for pregnancy, and should therefore not be used. | |
In normal pregnancies, the glomerular filtration rate (GFR) usually increases by 50% by the end of the first trimester of pregnancy. For women of reproductive age, a serum creatinine level between 0.51 and 1.02 mg/dl is considered “normal” or unremarkable. The following serum creatinine values are outside the ranges of a normal pregnancy:
1st trimester: > 0.86 mg/dl (> 76 µmol/l)
2nd trimester: > 0.81 mg/dl 1(> 72 µmol/l)
3rd trimester: > 0.87 mg/dl (> 77 µmol/l)
| Consensus-based statement 3.E19 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Proteinuria should be quantified in pregnant women with chronic kidney disease. | |
| Consensus-based recommendation 3.E20 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Pregnant women with a protein level of ≥ 1+ (0.3 g/l) or more on Stix test should undergo further testing to quantify proteinuria (spot urine test and protein-to-creatinine ratio or 24-hour urine collection). | |
| Consensus-based recommendation 3.E21 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| In pregnant women, proteinuria > 300 mg/24 hours or a protein-to-creatinine ratio > 30 mg/mmol (> 0.3 mg/mg) is pathological and should be investigated further in women with chronic kidney disease. | |
| Consensus-based recommendation 3.E22 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| During pregnancy, proteinuria should be quantified using 24-hour urine collection or spot urine tests and the urine protein-to-creatinine ratio. | |
In most (but not all) cases, urine dipstick tests can be used to exclude significant proteinuria.
The daily excretion of protein by non-pregnant women is usually less than 150 mg/d and the protein consists of up to 20 mg/d albumin and other proteins, mostly of tubular origin. In a normal pregnancy, albumin excretion remains unchanged while the total amount of excreted protein increases. The upper limit for normal protein excretion in urine during pregnancy is 300 mg/d. A protein-to-creatinine ratio of > 30 mg/mmol (0.3 mg/mg) in midstream urine (spot urine test) correlates with proteinuria of > 300 mg/d.
Proteinuria occurring before the 20th week of gestation is considered an indication of pre-existing kidney disease.
3.2 Prenatal care of women with chronic kidney disease
| Consensus-based recommendation 3.E23 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Pregnant women with chronic kidney disease should be given acetylsalicylic acid (ASS) 150 mg/day, starting from week 11 + 0 or at the latest by week 16 of gestation, to reduce the risk of preeclampsia; ASS administration should be continued until completing week 34 – 36 of gestation. Discontinuing ASS may be considered if the results of preeclampsia screening are negative. | |
| Consensus-based recommendation 3.E24 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Early organ screening (DEGUM level II) which includes screening for preeclampsia (MAD, PlGF, uterine artery resistance) may be offered between week 11 + 0 and week 13 + 6 of gestation. | |
| Consensus-based recommendation 3.E25 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Because of the higher risk of fetal malformations for pregnant women with chronic kidney disease, DEGUM level II screening for fetal malformations should be carried out in weeks 20 – 22 of gestation. | |
| Consensus-based recommendation 3.E26 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Doppler sonography of the uterine arteries can be carried out to predict the risk of preeclampsia and identify angiogenic factors in the second and third trimester of pregnancy. | |
| Consensus-based recommendation 3.E27 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Pregnant women with chronic kidney disease should be examined at least once every 4 weeks to check for the development of fetal growth restriction (fetal biometry, Doppler sonography, assessment of amniotic fluid volume). | |
| Consensus-based recommendation 3.E28 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| A full blood count should be carried out every 4 weeks in pregnant women with chronic kidney disease, and pregnant women with CKD should be tested for ferritin and transferrin saturation every 12 weeks; iron therapy should be started if necessary or the administration of erythropoietin should be considered. | |
| Consensus-based recommendation 3.E29 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Women with chronic kidney disease and iron deficiency should receive oral iron supplementation up to an Hb of 10.5 g/dl or IV supplementation with Fe (III) derivates up to 8.5 g/dl. | |
| Consensus-based recommendation 3.E30 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Erythropoiesis-stimulating agents (ESA) should be recommended when indicated. | |
Women with kidney disease have a higher risk of complications of pregnancy such as miscarriage, preeclampsia, preterm birth and fetal growth retardation. Provided women receive the appropriate intensive specialized interdisciplinary care, most women with kidney disease will nevertheless be able to give birth to a healthy infant.
Prenatal diagnostic workup
Maternal kidney disease is not associated with a higher risk of aneuploidy. When counseling patients, it is important to be aware that certain kidney diseases such as polycystic kidney dysplasia have an autosomal recessive or autosomal dominant mode of inheritance. DEGUM level II organ screening should be carried out in pregnant women with CKD, particularly if the disease has a genetic origin, but also because women with CKD typically have a history of previous medication and may be anxious about the impact of previous medication.
If first trimester screening is carried out at the patientʼs request it is important to consider the possibility that there may be a higher rate of false-positive results, as renal insufficiency may have resulted in elevated β-HCG MoM levels. The standards when carrying out non-invasive prenatal tests (NIPTs) are the same as those for patients without disease.
Diabetes screening
Steroids and calcineurin may contribute to a diabetogenic metabolism. In women who have been regularly taking such medication, screening for pre-existing diabetes should be carried out in the 1st trimester of pregnancy. It is additionally recommended that screening in week 24 – 28 of gestation should primarily be done by 75 g oral glucose tolerance test (oGTT).
Preeclampsia
Pregnant women with pre-existing kidney disease have a 3 times higher risk of developing preeclampsia in pregnancy. Preeclampsia affects the kidneys and typically manifests as proteinuria of ≥ 300 mg/d or a protein-to-creatinine ratio of ≥ 30 mg/mmol or, in cases with pre-existing proteinuria, as an increase in protein excretion.
The only currently effective prevention of preeclampsia for women at risk due to their prior medical history and/or with a higher risk of preeclampsia based on the results of their 1st trimester screening consists of the oral intake of low-dose acetylsalicylic acid (ASS: 150 mg/day), starting in early pregnancy (before week 16 + 0 of gestation, if possible).
During the further course of the pregnancy, screening for preeclampsia should consist of regular monitoring of maternal blood pressure and proteinuria in accordance with German maternity policy guidelines. An increase in the mean pulsatility index (PI) of the uterine arteries, either alone or in combination with late systolic notching, is considered the best predictive marker for preeclampsia in the second trimester of pregnancy, with a sensitivity of up to 93%.
If there is a suspicion of preeclampsia or preeclampsia cannot be excluded, the sFlt-1/PLGF ratio (angiogenic factors) can be used to exclude or confirm a diagnosis of preeclampsia.
Fetal monitoring
Regular ultrasound examinations to evaluate gestational age-appropriate growth should be performed, especially in third trimester because of the higher risk of intrauterine growth restriction (IUGR).
Anemia
Hemodilution caused by the increase in extracellular volume results in a physiologically lower Hb level in pregnancy; the lowest threshold for intervention is 10 mg/dl.
Planning the birth
| Consensus-based recommendation 3.E31 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| CKD is not an indication per se to induce labor at ≤ 40 weeks of gestation. The time of delivery should be determined by the presence of fetal or maternal complications. | |
3.3 Specific aspects associated with hypertension ( Table 7 )
Tab. 7 Recommendations for the management of hypertension in pregnancy – guideline adaptation from the 2018 ESC Guidelines.
| Recommendation | Level of evidence |
|---|---|
| SBP – systolic blood pressure, DBP – diastolic blood pressure | |
| Low dose aspirin (150 mg in the evening) in weeks 12 – 36 of gestation as prophylaxis against preeclampsia | A |
| Pre-existing hypertension, pregnancy-induced hypertension with proteinuria and preeclampsia and hypertension with subclinical organ damage/symptoms should be treated with medication (at the latest) when SBP > 140 or DBP > 90 mmHg | C |
| Pregnant women with CKD should be hospitalized if SBP is > 160 or DBP is > 110 mmHg | C |
| Recommended drug therapy consists of calcium antagonists (nifedipine/amlodipine), alpha methyldopa or β-blockers (labetalol/metoprolol), which are considered safe |
B
(methyldopa)/
C (β-blockers and calcium antagonists) |
| Calcium antagonists and β-blockers are more effective than alpha methyldopa to treat severe hypertension | B |
| ACE inhibitors, angiotensin receptor blockers, renin inhibitors are not recommended | C |
| Consensus-based statement 3.S32 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| The target blood pressure range is between 110/70 mmHg and 135/85 mmHg. Blood pressure readings must be recorded. | |
| Consensus-based recommendation 3.E33 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Antihypertensive therapy must be continued during pregnancy, unless systolic blood pressure is constantly < 110 mmHg or diastolic blood pressure is constantly < 70 mmHg and/or symptomatic hypotension is present. | |
| Consensus-based recommendation 3.E34 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Preeclampsia should be diagnosed if hypertension (> 140/90 mmHg) occurs in a pregnant woman with CKD without pre-existing proteinuria/albuminuria together with at least one organ manifestation; this also includes an abnormal sflt-1/PLGF ratio. | |
| Consensus-based recommendation 3.E35 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| In pregnant women with CKD, pre-existing hypertension and proteinuria/albuminuria, clinical tests should be carried out to exclude preeclampsia if hypertension becomes severe (> 160/>110 mmHg or the dose of antihypertensive medication doubles) and/or there is a strong increase in proteinuria/albuminuria (doubling of the levels measured in the first trimester). | |
| Consensus-based recommendation 3.E36 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| PlGF and sflt-1 should be used as additional diagnostic parameters if preeclampsia is suspected in patients with CKD. | |
3.4 Dietary needs of pregnant women with CKD
| Consensus-based recommendation 3.E37 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| In pregnancy, women with CKD should be offered nutritional counseling to adjust the calorific value and the vitamin, folic acid, iron, phosphate, protein, potassium and salt content of their diet in accordance with their state of health and comorbidities. | |
| Consensus-based recommendation 3.E38 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| The dietary energy intake of pregnant women with stage G3 – 5 CKD should be 30 – 35 kcal/kg/d. An additional 250 kcal/d should be added to this baseline value in the 2nd trimester of pregnancy and an additional 500 kcal/d should be added to the baseline value in the 3rd trimester of pregnancy. | |
| Consensus-based recommendation 3.E39 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| The aim for pregnant women with stage G3 – 5 CKD must be to achieve normal serum calcium and phosphate levels. | |
| Consensus-based recommendation 3.E40 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| The protein intake of pregnant women with CKD who do not require dialysis must be 0.8 – 1.0 g/kg/d plus 10 g protein/d. | |
| Consensus-based recommendation 3.E41 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| The protein intake of pregnant women who require hemodialysis must be about 1.2 g/kg/d plus 10 g protein/d because of the loss of amino acids in the dialysate. | |
| Consensus-based recommendation 3.E42 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| The dietary salt intake of pregnant women with CKD G3 – 5 must not exceed 6 g (which corresponds to 2 – 3 g sodium) per day. | |
| Consensus-based recommendation 3.E43 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Micronutrient and mineral levels, particularly the levels of iron, folic acid, Vitamin B 6 and B 12 , Vitamin D, zinc, sodium, potassium, calcium and phosphate, of pregnant women with stage G3 – 5 CKD should be checked and supplemented; the need for supplementation is even higher for pregnant patients who require hemodialysis. | |
Large meta-analyses have shown that a healthy diet of fruit, vegetables, fish, cereals, wholegrain foods and dietary fiber together with small amounts of red meat, salt and refined sugar is associated with a lower incidence of CKD; in groups with CKD, a healthy diet was associated with lower mortality rates and fewer people requiring dialysis ( Table 8 ).
Tab. 8 Dietary recommendations for pregnant women with CKD stage G3 – 5.
| CKD G3 – 5 | Hemodialysis | CAPD | ||
|---|---|---|---|---|
| * refers to weight prior to pregnancy CAPD – continuous ambulatory peritoneal dialysis | ||||
| Macronutrients | ||||
| Energy | kcal/kg/d 1st trimester |
35 | 30 – 35 | 25 – 30 |
| kcal/kg/d 2nd – 3rd trimester |
30 – 35 (+ 300) | 30 – 35 (+ 300) | 25 – 30 (+ 300) | |
| Protein | g/kg/d* | 0.6 – 0.8 (+ 10 g) | 1.2 (+ 10 g) | 1.2 (+ 10 g) |
| Micronutrients | ||||
| Folic acid (mg/d) | 6 | 2 – 5 | ||
| 25-OH Vitamin D 3 (IU/d) | 1000 – 2000 | 1000 – 2000 | ||
| Zinc (mg/d) | 15 | 15 | ||
| Iron (mg/d) | 20 – 30 | 20 – 30 | ||
| Electrolytes | ||||
| Calcium (mg/d) | < 2000 | 1500 – 2000 | ||
| Phosphate (mg/d) | CKD4 – 5: 800 – 1000 | |||
| Potassium (mEq/l/d) [g] | depends on serum potassium | < 75 [3 g] | ||
Dietary needs of pregnant women requiring dialysis
The dietary energy intake of pregnant women with CKD who require dialysis is initially the same as that of pregnant women with CKD who do not need dialysis ( Table 9 ).
Tab. 9 Useful strategies to support the nutritional status of pregnant women requiring dialysis.
| Settings | Recommendations | Comments | |
|---|---|---|---|
| Counseling prior to pregnancy | Clinical condition, comorbidities, teratogenic medication, social context taken into account | ||
| Dietary modifications | Eating habits are recorded | Early stages: habits and economic situation must be taken into account; Individual needs must be defined | Take account of medical nutritional therapy |
| Supplements | Depends on general and disease-specific recommendations | ||
| Dialysis management | Dialysis dose | Increase dialysis dose: hemodialysis (HD) at least > 20 h/week; intensify peritoneal dialysis exchanges (not defined; poss. consider changing to HD) | Pre-dialysis urea level must be < 50 mg/dl; increased removal of micronutrients with dialysis |
| Fluid management | Must be adapted to expected weight gain | ||
| Composition of dialysate | Individual adjustment of potassium, calcium and phosphate levels | Higher calcium concentrations often required | |
| Adjust dialysis-related medication | Phosphate binders | Often paused, depending on serum levels | If necessary, also switch to calcium-containing phosphate binders |
| Vitamin D and iron supplementation | Both oral and IV administration are considered safe | Frequent monitoring of mineral balance and anemia necessary |
Dietary recommendations for pregnant women who have had a kidney transplant
The dietary recommendations for pregnant women who have had a kidney transplant are initially the same as those for pregnant women with CKD.
Pregnant women who have had a kidney transplant must receive individual nutritional counseling which is adapted to their measured laboratory parameters (especially levels of electrolytes, uric acid, lipids, blood glucose) and their individual immunosuppressive therapy ( Table 10 ).
Tab. 10 Reference values for laboratory parameters of pregnant women with and without CKD.
| Women with CKD | Pregnancy without CKD | |||
|---|---|---|---|---|
| 1st trimester | 2nd trimester | 3rd trimester | ||
| Bone metabolism | ||||
| Calcium (mg/dl) | 9 – 10.5 | 8.8 – 10.6 | 8.2 – 9.0 | 8.2 – 9.7 |
| Phosphate (mg/dl) | 3 – 4.5 | 3.1 – 4.6 | 2.5 – 4.6 | 2.8 – 4.6 |
| 25-OH Vitamin D 3 (pg/ml) | 30 – 65 | 20 – 65 | 72 – 160 | 60 – 119 |
| Parathyroid hormone (pg/ml) | CKD3: 35 – 70 | 10 – 15 | 18 – 25 | 9 – 26 |
| CKD4: 70 – 110 | ||||
| CKD5: 150 – 300 | ||||
| Alkaline phosphatase (IU/l) | 30 – 85 | 17 – 88 | 25 – 126 | 38 – 229 |
| Iron status | ||||
| Hemoglobin (g/dl) | 11 – 12 | > 11 | > 10,5 | > 11 |
| Hematocrit (%) | 37 – 47 | > 33 | > 33 | > 33 |
| Serum iron (µg/dl) | 50 – 170 | 72 – 143 | 44 – 178 | 30 – 193 |
| Ferritin (ng/ml) | without dialysis: > 30; HD: > 20, PD: > 100 | 6 – 130 | 2 – 230 | 0 – 116 |
| Total iron binding capacity (µg/dl) | 250 – 420 | 278 – 403 | – | 359 – 609 |
| Transferrin saturation (%) | > 20 | not specified | 18 – 92 | 9 – 98 |
4 Specific aspects
4.1 Diabetes
| Consensus-based recommendation 4.E44 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Prenatal care and prenatal monitoring should be carried out in accordance with the guideline on the care of pregnant women with diabetes, with appropriate adjustments based on obstetric indications. | |
In the majority of pregnant women with nephropathy, pregnancy leads to a temporary increase in proteinuria which can transition to nephrotic syndrome. According to existing studies, 10% of women with advanced nephropathy during pregnancy go on to develop severe proteinuria; after preterm delivery of their infant, these women require regular dialysis.
The presence of diabetic nephropathy also increases the risk of complications of pregnancy, especially preeclampsia, preterm birth (21% before week 32 of gestation and 70% before the 37th week of gestation), and cesarean section.
Antiphospholipid syndrome and systemic lupus erythematosus with lupus nephritis
| Consensus-based recommendation 4.E45 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| ASS 100 – 150 mg/day and low-molecular-weight heparin should be administered during pregnancy and up to 6 weeks postpartum to women with antiphospholipid syndrome. | |
| Consensus-based recommendation 4.E46 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Women with lupus erythematosus should aim for 6 months without clinical symptoms before attempting to become pregnant. | |
| Consensus-based recommendation 4.E47 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| If hydroxychloroquine is administered to women with lupus erythematosus or antiphospholipid syndrome, this treatment must be continued during pregnancy. | |
| Consensus-based recommendation 4.E48 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Disease activity and lupus nephritis activity should be monitored regularly during pregnancy in women with lupus erythematosus. | |
| Consensus-based recommendation 4.E49 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| If anti-Ro/SSA or anti-La/SSB antibodies are present, fetal echocardiography must be carried out from week 16 of gestation to exclude fetal atrioventricular (AV) block. | |
| Consensus-based recommendation 4.E50 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Steroids, azathioprine, calcineurin inhibitors, hydroxychloroquine, intravenous immunoglobulin treatment and plasma exchange can be used during pregnancy to treat women with lupus nephritis. | |
Lupus nephritis is a severe organ manifestation of SLE. Data from systematic reviews and meta-analyses consistently show that active lupus nephritis is associated with undesirable pregnancy outcomes. As a lupus nephritis flare has a negative impact on pregnancy, SLE should be in remission before planning a pregnancy to allow medication to be optimized before the start of pregnancy.
Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by arterial or venous occlusions accompanied by complications of pregnancy and the simultaneous presence of antiphospholipid antibodies (aPL).
Antiphospholipid syndrome is characterized by the following criteria:
-
The occurrence of venous or arterial thromboses and/or complications of pregnancy such as
the unexplained death of morphologically normal fetuses after week 10 of gestation
delivery before week 34 of gestation because of eclampsia, severe preeclampsia or placental insufficiency
3 spontaneous miscarriages before week 10 of gestation with no chromosomal, anatomical or hormonal causes.
The detection of lupus anticoagulant (LA), often accompanied by anticardiolipin antibodies (aCL > 40 U/ml) and/or anti-β2-glycoprotein-I antibodies (anti-β(2)GPl > 99th percentile). For a diagnosis and risk assessment of APS, aPL titer must be detected at least 2 times at an interval of ≥ 12 weeks and ≤ 5 years.
When treating pregnant women with APS, the therapeutic goal must be the primary or secondary prevention of thromboembolic complications and the prevention of complications of pregnancy.
Combined treatment consisting of 100 mg aspirin and prophylactic doses of heparin is recommended for pregnant women with APS without a previous history of thrombosis. Patients with a prior history of arterial or venous thrombosis should receive therapeutic doses of heparin.
Acute kidney failure in pregnancy
| Consensus-based recommendation 4.E51 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| If thrombocytopenia, anemia and/or kidney failure occur in late pregnancy or peripartum, the differential diagnosis must also consider other possible causes such as thrombotic thrombocytopenic purpura (TTP), atypical hemolytic uremic syndrome (aHUS) or acute fatty liver of pregnancy (AFLP). | |
| Consensus-based recommendation 4.E52 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| If unexplained kidney failure occurs during pregnancy or peripartum, a nephrologist and, if necessary, a hematologist must be called in. | |
Acute kidney failure (AKF), defined clinically as a rapid fall in the rate of glomerular filtration (GFR), is the most common kidney disease in hospital; it is associated with an increased mortality irrespective of other comorbidities. The clinical syndrome of AKF includes a wide and heterogeneous range of causes. They are categorized into 3 groups:
prerenal AKF: when blood supply to the kidneys is compromised and renal perfusion is insufficient to maintain GFR
renal AKF: when the GFR drops due to direct injury to the kidneys
postrenal AKF: when the GFR is decreased due to blockage or obstruction of urine flow
Common causes of prerenal failure in pregnant women include acute hypoperfusion due to hemorrhage, e.g., in cases with placenta previa or in the context of fulminant uterine atony. Severe hyperemesis gravidarum can also lead to kidney failure. In rare cases, postrenal acute kidney failure may be caused by functional hydronephrosis. In most cases, this does not impair kidney function.
Renal causes such as glomerulonephritis, inflammatory kidney disease and toxic kidney damage can occur incidentally during pregnancy.
Acute kidney failure can also occur in the context of preeclampsia, HELLP syndrome, fatty liver of pregnancy or, more rarely, may be caused by microangiopathic hemolytic anemias such as thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Obtaining the correct differential diagnosis is important for the choice of therapeutic approach but is often difficult due to similarities in clinical symptoms.
Table 11 lists some of the differences between the various diseases that can be used to obtain a differential diagnosis.
Tab. 11 Differential diagnostic parameters used to differentiate between preeclampsia, HELLP, TTP, aHUS, AFLP and SLE.
| Pre-/eclampsia | HELLP | TTP | aHUS | AFLP | SLE | |
|---|---|---|---|---|---|---|
| HELLP – hemolysis, elevated liver enzyme, low platelets; TTP – thrombotic thrombocytopenic purpura; aHUS – atypical hemolytic uremic syndrome; AFLP – acute fatty liver of pregnancy; SLE – systemic lupus erythematosus; MAHA – microangiopathic hemolytic anemia; DIC – disseminated intravascular coagulopathy; AKF – acute kidney failure; CNS – central nervous system | ||||||
| Time of occurrence | 2nd–3rd trimester | 3rd trimester | 1st–3rd trimester | 3rd trimester postpartum | 3rd trimester | 1st–3rd trimester |
| MAHA | + | ++ | +++ | +++ | (+) | + |
| Thrombopenia | + | ++ | +++ | ++ | + | + |
| DIC | (+) | ++ | 0 | 0 | +++ | (+) |
| Hypertension | +++ | ++ | + | ++ | 0 | + |
| Elevated transaminase levels | + | +++ | (+) | (+) | +++ | (+) |
| Proteinuria | ++ | ++ | (+) | ++ | 0 | ++ |
| AKF | (+) | + | + | +++ | + | ++ |
| CNS involvement | ++ | + | +++ | ++ | ++ | + |
| Leukocytosis | – | – | – | – | +++ | (+) |
Atypical hemolytic uremic syndrome (aHUS) is characterized by primary impairment of kidney function (oliguria, anuria) which takes the form of acute kidney failure, dialysis dependency, and the development of terminal renal insufficiency in 76% of cases; it can affect women from a few days after delivery to ten weeks postpartum.
Although it is necessary to differentiate hemolytic uremic syndrome from thrombotic thrombocytopenic purpura, obtaining a differential diagnosis in an acute setting is often difficult. Because of new therapeutic options, a differential diagnosis of HUS has practical implications, making it important to differentiate HUS from TTP. Just like HUS, TTP leads to generalized thrombotic microangiopathy (TMA) and it can manifest in the same way as HUS does. TTP has very high rates of acute mortality if left untreated, meaning that waiting for the definitive diagnostic diagnosis before starting specific treatment for TTP is not possible. Plasmapheresis with membrane separation and fresh plasma exchange must be initiated very quickly and without delay. Determination of ADAMTS13 activity (A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13) is essential for the differential diagnosis. In TTP, the TMA is triggered by a severe drop in the activity of ADAMTS13, a plasma enzyme which is responsible for the cleavage of ultra-large multimers of von Willebrand Factor (vWF). As a general rule, plasma separation should be continued until ADAMTS13 activity can be measured as this is the only way to obtain the correct differential diagnosis.
For this reason, it is important to always also call in the services of a nephrologist and hematologist.
4.2 Pregnancy after kidney transplant
| Consensus-based recommendation 4.E53 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Conception should occur 1 year after transplantation at the earliest when the renal functions of the transplant have stabilized. | |
| Consensus-based recommendation 4.E54 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Immunosuppression in kidney-transplanted women who wish to have children should consist of a combination of calcineurin inhibitors, azathioprine and steroids. Mycophenolate mofetil, mTOR inhibitors and belatacept should not be used by women wanting to have children or pregnant women. | |
| Consensus-based recommendation 4.E55 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Pregnant kidney-transplanted patients must be cared for by an interdisciplinary team in which gynecologists work together with nephrologists. | |
| Consensus-based recommendation 4.E56 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Immunosuppressive and antihypertensive therapy must not be discontinued at the start of pregnancy but the medication may need to be adjusted. Any changes to therapy must be done by a nephrologist who has specialized in caring for kidney-transplanted patients in consultation with a specialist for perinatal medicine. | |
| Consensus-based recommendation 4.E57 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Kidney-transplanted patients should give birth in a perinatal center after consultation with the transplant surgeon, especially when patients have had a combined transplant (e.g., kidney–pancreas, kidney–liver). | |
| Consensus-based recommendation 4.E58 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| The decision about the method of delivery must be made by an experienced obstetrician when the patient visits the maternity hospital prepartum and must be primarily based on obstetric criteria. When carrying out a cesarean section, the obstetrician must take account of the location of the transplanted kidney. | |
Kidney-transplanted patients have the functional renal capacity of a single kidney and require lifelong immunosuppression. Fertility which has been reduced by terminal kidney insufficiency and during hemodialysis recovers within a few weeks of a successful kidney transplant (NTx).
As with other patients with chronic disease, pregnancies after NTx are also associated with higher rates of preterm birth (43 – 50%), fetal growth restriction (LBW 42%, VLBW 10%) and hypertension (50%)/preeclampsia (20 – 30%, RR around 6 times higher compared to a group of healthy controls) but also gestational diabetes (6 – 8%).
Kidney-transplanted women often deliver by cesarean section. The rates of caesarean section are around 60%. In general, a kidney transplant is not an indication for cesarean section; the decision to have a cesarean section is usually taken based on secondary factors. The decision to deliver by cesarean section should be made on the basis of an obstetric assessment and the decision should have the approval and consent of the patient; the intervention should be supported by an interdisciplinary team.
Dialysis patients
| Consensus-based recommendation 4.E59 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Women who require dialysis must be given counseling prior to becoming pregnant. Counseling must include advising the patient about the option of postponing the planned pregnancy until they have received a kidney transplant; the patient must be informed about the necessity of longer and more frequent hemodialysis sessions before and during pregnancy. | |
| Consensus-based recommendation 4.E60 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Women who require dialysis must receive high-frequency daily dialysis as this offers them the best chance of a successful pregnancy. | |
| Consensus-based recommendation 4.E61 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| During pregnancy, women who require dialysis should receive a dialysis dose which takes account of their residual renal function and aims for a pre-dialysis urea level of < 12.5 mmol/l (< 75 mg/dl). | |
| Consensus-based recommendation 4.E62 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Pregnant women who receive peritoneal dialysis must be switched to hemodialysis for the duration of the pregnancy. Continuing with peritoneal dialysis may be considered in individual cases. | |
| Consensus-based recommendation 4.E63 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Dry weight should be assessed clinically at least 1 ×/week based on ultrasound measurement of the inferior vena cava diameter; the typical weight gain during pregnancy of about 300 g/week from the 2nd trimester should be factored in. Blood pressure after dialysis should be < 140/90 mmHg and a drop in blood pressure during dialysis should be avoided. | |
| Consensus-based recommendation 4.E64 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| In pregnant women, hemodialysis should be initiated if maternal serum urea is 17 – 20 mmol/l (102 – 120 mg/dl) and the risks of preterm birth outweigh the risks of starting dialysis. Residual renal function, fluid balance, additional biochemical parameters, blood pressure and possible uremic symptoms should also be taken into account. | |
Women of reproductive age who require dialysis because of terminal renal failure often have anovulatory cycles and their prospects of spontaneous conception are therefore very low.
Pregnancy outcomes of kidney-transplanted women are better than those of women requiring dialysis; if possible, pregnancy should be postponed until the patient has had a successful kidney transplant.
4.3 Glomerulonephritis and pregnancy
To evaluate the effect of pregnancy on the renal function of a patient with glomerulonephritis, it is important to differentiate between acute pregnancy-associated changes and long-term effects on renal function. In general, proteinuria increases over the course of pregnancy in around 50% of patients and 20 – 30% of patients present with elevated blood pressure readings (with a potentially unfavorable impact on mother and fetus). Higher proteinuria may increase edema development.
Almost 50% of patients with serum creatinine levels of ≥ 1.5 mg/dl go on to have a preterm birth, mainly due to preeclampsia and intrauterine growth restriction.
The care of pregnant women with glomerulonephritis requires a close cooperation between gynecologists and nephrologists as well as regular prenatal screening and monitoring by both gynecologists and nephrologists. Serum creatinine of > 1.5 mg/dl is associated with a significantly higher risk for mother and child. Pregnancy is not advisable if serum creatinine levels are 3.0 mg/dl.
IgA nephropathy
The risk of complications during pregnancy for IgA patients with a GFR of more than 70 ml/min appears to be low. The rate of complications is significantly higher for women with higher grade renal insufficiency, uncontrolled arterial hypertension or pronounced tubulointerstitial injury.
| Consensus-based recommendation 4.E65 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| During pregnancy, the focus of IgA nephropathy treatment should be on antihypertensive/antiproteinuric therapy. | |
Immunosuppressive therapy of glomerulonephritis in pregnancy
Depending on the severity of disease and the underlying type of glomerulonephritis, patients who experience a flare-up during pregnancy or are newly diagnosed with glomerulonephritis requiring immunosuppressive therapy (in the majority of cases due to lupus nephritis) should be treated with steroids including pulse therapy, if necessary, in combination with azathioprine.
| Consensus-based recommendation 4.E66 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| If glomerulonephritis is rapidly progressive despite immunosuppressive therapy with steroids and possibly azathioprine, termination of the pregnancy should be considered, particularly in the 1st trimester of pregnancy, and immunosuppressive therapy with mycophenolate mofetil or cyclophosphamide should be initiated. | |
| Consensus-based recommendation 4.E67 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Renal biopsy during pregnancy is only indicated in cases where the reason for the acute deterioration of renal function is unclear or in cases with pronounced nephrotic syndrome. | |
4.4 Status post living-donor transplant
| Consensus-based recommendation 4.E68 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Women who wish to have children should not be excluded from receiving a living-donor kidney transplant but should be informed about the consequences of a living-donor kidney transplant on subsequent pregnancies (increased risk of hypertension in pregnancy and preeclampsia). | |
4.5 Reconstructive surgery
| Consensus-based recommendation 4.E69 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Pregnant patients with previous reconstructive surgery of the urinary tract (ureter reimplant surgery, bladder reconstruction, complex pediatric-urological surgery) should be cared for by an interdisciplinary team. | |
| Consensus-based recommendation 4.E70 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| The method of delivery and any associated issues should be discussed and agreed upon by obstetricians and urologists specializing in reconstructive surgery. | |
| Consensus-based recommendation 4.E71 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| After an initial episode of urinary tract infection episode with evidence of asymptomatic bacteriuria, long-term antibiotic prophylaxis may be considered for pregnant patients with reflux nephropathy, patients who have had reconstructive surgery of the urinary tract, patients with congenital anomalies of the kidneys and the urinary tract (CAKUT), and patients with kidney disease and immunosuppression. | |
| Consensus-based recommendation 4.E72 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Any long-term therapy must be maintained using agents which are considered safe during pregnancy. | |
| Consensus-based recommendation 4.E73 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Mild proximal ureteral dilation is a physiological phenomenon; no therapy, especially no interventional therapy, should be carried out. | |
| Consensus-based recommendation 4.E74 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Urinary diversion using a ureteral stent is only indicated in individual cases with symptomatic hydronephrosis after conservative treatment methods have been exhausted, and the indication for urinary diversion should be weighed up very carefully. | |
| Consensus-based recommendation 4.E75 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| During pregnancy, uncomplicated urolithiasis should be treated conservatively. | |
| Consensus-based recommendation 4.E76 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| The imaging method of choice during pregnancy should be ultrasonography, possibly using the renal resistive index to evaluate kidney perfusion as evidence of ureteral obstruction. | |
| Consensus-based recommendation 4.E77 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| When treating patients proven to have urolithiasis requiring intervention, defined as a failure of conservative methods, progressive renal pelvis dilation of more than 2 cm, or preterm labor with cervical opening, ureteral stents must be used for primary urinary diversion. The definitive treatment to remove renal calculi should be carried out after the pregnancy has ended. Ureterorenoscopy to remove calculi may be considered in individual cases. | |
| Consensus-based recommendation 4.E78 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Extracorporeal shockwave lithotripsy (ESWL) and percutaneous nephrolithotomy (PCNL) are contraindicated in pregnancy. | |
5 Peripartum period
| Consensus-based recommendation 5.E79 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| In additional to peripartum obstetric care, women with mild CKD should be monitored by specialists for internal medicine and nephrology; women with moderate and severe CKD must also be managed by a nephrologist. | |
| Consensus-based recommendation 5.E80 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Care must be taken to maintain an adequate fluid balance in the peripartum period. | |
| Consensus-based recommendation 5.E81 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| The increased risk of lung edema in women with CKD and preeclampsia should be incorporated in therapeutic decision-making. | |
| Consensus-based recommendation 5.E82 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| The timing of the birth for women with CKD should be based on obstetric indications and be determined by renal factors such as deterioration of renal function, symptomatic hypoalbuminemia, pulmonary edema and refractory hypertension. | |
There are no data indicating that the method of delivery affects maternal renal function. The method of delivery should therefore be based on obstetric indications and maternal preferences in accordance with the guidelines for women without CKD.
| Consensus-based recommendation 5.E83 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| The decision to potentially suspend anticoagulation in the peripartum period should already be made when planning the birth. | |
The required level of anticoagulation for women with CKD should be determined based on the complications which occurred during pregnancy and the underlying disease, and the decision to possibly suspend anticoagulation should be made when planning the birth.
6 Postpartum period
6.1 Postpartum maternal care
| Consensus-based recommendation 6.E84 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| In accordance with the recommendations of the National Breastfeeding Commission, women with CKD should be encouraged to breastfeed for at least 4 months and should receive appropriate support. | |
| Consensus-based recommendation 6.E85 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| If it is medically justifiable from a nephrological point of view, the medication given in the postpartum period should be safe for the infant as this will allow the mother to breastfeed. | |
| Consensus-based recommendation 6.E86 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Non-steroidal anti-inflammatory drugs (NSAIDs) must not be prescribed for pain management in the postpartum period; paracetamol may be given as an alternative. | |
| Consensus-based recommendation 6.E87 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Women with (acute or chronic) kidney disease must be present to a nephrologist at an individually agreed time, at the latest 6 weeks after giving birth. | |
| Consensus-based recommendation 6.E88 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| If possible, the medication prescribed in the postpartum period for women with CKD should allow them to breastfeed. | |
Women with the following conditions would benefit from nephrological care starting 6 weeks after giving birth at the latest:
women newly diagnosed with kidney disease which developed in pregnancy
women with pre-existing kidney disease
women with risk factors for CKD
Women with CKD wishing to breastfeed should be supported as much as possible. They should receive medication which is compatible with breastfeeding for as long as they continue to breastfeed. The use of mycophenolate mofetil during the lactation period is contraindicated. Captopril, enalapril and quinapril as well as dihydralazine are all compatible with breastfeeding. Ramipril and losartan are not recommended during breastfeeding and some specialist information even states that their use during breastfeeding is contraindicated.
6.2 Neonatal care
| Consensus-based recommendation 6.E89 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Pregnant women must be transferred to a suitable center in accordance with the guidelines of the Federal Joint Committee ( Gemeinsamer Bundesausschuss , G-BA) early on. | |
| Consensus-based recommendation 6.E90 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Patients who require dialysis should give birth in a primary care hospital with a dialysis unit (level 1 perinatal center). | |
| Consensus-based recommendation 6.E91 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Critically ill patients with CKD and/or patients who are status post renal transplant where the infant is also at risk should give birth in a primary care hospital. | |
| Consensus-based recommendation 6.E92 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| Patients known to have comorbidities prepartum which require intensive monitoring during pregnancy but are not at acute risk for mother and fetus should give birth in center which offers at least secondary care. | |
a) Patients with additional diabetes mellitus (maternal risk factors)
| Consensus-based recommendation 6.E93 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| The maternity center should already be involved in the motherʼs care before the birth if the mother has diabetes requiring insulin treatment and the fetus or neonate are at risk. Prompt access to postnatal hypoglycemia treatment without separating mother and infant must be available even to patients whose diabetic metabolic state is under control. The birth must take place in a level 1 or 2 perinatal center. | |
| Consensus-based recommendation 6.E94 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| In cases with intrauterine growth restriction, care must be provided in accordance with the AWMF guideline “Intrauterine Growth Restriction”. | |
b) Treatment of prenatally diagnosed renal oligohydramnios (ROH) of the fetus and fetal renal disease (fetal risk factors)
A prenatal diagnosis of fetal renal disease presents an enormous challenge for both the parents and the physicians providing care, especially as it is difficult to make a definitive postnatal prognosis. An interdisciplinary consultation involving colleagues from the fields of obstetrics/prenatal medicine, neonatology and pediatric nephrology as well as other relevant medical specialties (pediatric surgery, gastroenterology) should be held prenatally.
| Consensus-based recommendation 6.E95 | |
|---|---|
| Expert consensus | Level of consensus +++ |
| If renal oligohydramnios is diagnosed prenatally, an interdisciplinary case conference should be held and the parents should be advised appropriately. If the parents request that the neonate receive maximum care, the birth should take place in a center with the relevant expertise (ventilation for pulmonary hypoplasia, neonatal dialysis). If the parents request palliative care, a center with the appropriate expertise and care facilities should be chosen. | |
Footnotes
Conflict of Interest/Interessenkonflikt The conflicts of interest of all of the authors are listed in the long (German-language) version of the guideline./Die Interessenkonflikte der Autor*innen sind in der Langfassung der Leitlinie aufgelistet.
References/Literatur
- The references are included in the long (German-language) version of the guideline./Das Literaturverzeichnis ist in der Langfassung der Leitlinie aufgeführt.