Pregnancy in CKD, ESRD, and transplant recipients
- Does this pregnant patient have chronic kidney disease. end-stage renal disease, or has she received a transplant?
- What tests to perform?
- How should patients with chronic kidney disease, ESRD, or who have received a transplant who are pregnant be managed?
- What happens to patients with chronic kidney disease, ESRD, or transplant who are pregnant?
- How to utilize team care?
Are there clinical practice guidelines to inform decision making?
What is the evidence?
Does this pregnant patient have chronic kidney disease. end-stage renal disease, or has she received a transplant?
What should we know about the care of a pregnant patient on chronic dialysis?
Pregnancy rates for dialysis patients are exceedingly low. In one study from Belgium, the pregnancy rate was 0.3 for 100 patient-years in women of childbearing age, which was one-fortieth the rate of the general population. One United States registry found a pregnancy rate of 2.2% over 4 years, relatively similar to the Belgian study. Many have said that dialysis is one form, albeit imperfect, of contraception.
Most patients on chronic dialysis suffer from sexual dysfunction, both due to physiological and psychosocial causes.
Patients have lower estradiol levels, diminished desire, and fewer sexual encounters than age-matched controls
Diagnosis often occurs later in dialysis patients, with an average fetal gestational age of 16 weeks. Irregular menses and abdominal complaints are common in dialysis patients, and these symptoms may not be considered as related to pregnancy. Pregnancy is more common in patients with residual renal function.
Spontaneous abortions occur in 1 of 5 of the pregnancies reaching the second trimester in this population. Premature delivery occurs in approximately four of five live births.
What should we know and counsel about the effects of pregnancy on chronic kidney disease?
Kidney function can decline more frequently in patients with pre-existing chronic kidney disease (CKD) than in patients without kidney disease.
The higher the serum creatinine, the greater the chance for renal functional decline. Two observational cohorts showed that fewer than 10% of women with known kidney disease experience a decline in kidney function with a serum creatinine <1.5mg/dL. In the same studies, women with "moderate" kidney dysfunction (serum creatinine either 1.5 – 2.9 mg/dL or 1.4 – 2.0mg/dL), experienced a 40-60% decline in function. Many of these women had a return to baseline kidney function after delivery.
At a serum creatinine of 3.0 mg/dL and above, rates of functional decline are worse during pregnancy, and permanent loss of glomerular filtration rate (GFR) is more frequently seen. If women with such severe CKD are candidates for renal transplantation, they may want to wait 1-2 years post-renal transplantation for optimal fetal and maternal outcomes. (See chapter on pregnancy and kidney transplantation).
Etiology is less of a factor than the degree of kidney dysfunction in estimating decline of kidney function during pregnancy and permanent loss of GFR post-partum.
Half of pregnant women with CKD will experience worsening of pre-existing proteinuria, and about one quarter will experience worsening hypertension. The severity of hypertension is greater in patients with CKD, and can result in worse outcomes for the mother and the fetus. (See chapter on pregnancy and hypertension.) Many of these changes will improve or resolve post-partum in patients with mild to moderate CKD (serum creatinine < 3.0 mg/dL), although those with uncontrolled hypertension can experience permanent loss of kidney function in up to 50% of cases.
An understanding of normal renal physiology is helpful to understand clinical findings in pregnant patients with CKD.
Systemically,there is a fall in vascular resistance and blood pressure, with blood volume expansion and an increase in cardiac output.
The GFR increases. Mild hyponatremia can occur due to ‘resetting of thermostat’. Mild hypernatremia is seen less commonly in women, who have an increase in alcohol dehydrogenase (ADH) metabolism and polyuria .
Kidney volume increases by up to 30%, mainly in the vascular and interstitial volume. Renal pelvises can be dilated due to mechanical compression or progesterone effects. Up to three quarters of patients can have mild to moderate hydronephrosis (right more often than left sided), which may not resolve until 2-3 months post-partum.
What are the key issues on the medical management of a pregnant patient with a kidney transplant?
Fertility rates increase after transplantation
Careful contraceptive counseling is required before transplantation, as within 6 months post-transplantation gonadal dysfunction usually reverses in women on dialysis or with CKD stage V
Should be introduced at pre-transplant evaluation
Should be followed up throughout the post transplant period and should be offered to both the patient and her partner
Patients should be vaccinated before transplantation, if not, they should be vaccinated before pregnancy (influenza, pneumococcus, hepatitis B and tetanus)
The patient should undergo perinatal preconception counseling to review obstetric complications including preterm labor as well as fetal growth restriction
There are multiple types of contraception available for transplant recipients including:
1. Intra-uterine devices (1-2% FR)
2. Combined pill (0.1% FR)
3. Condom (0.4-1.6% FR)
4. Vasectomy (0.1 % FR)
5. Diaphragm (2 % FR)
6. Spermicidal form (3% FR)
7. Other less successful methods with less success include lactation for12 months (25 % failure rate (FR)) and coitus interruptus (9% FR)
What tests to perform?
Human chorionic gonadotropin levels should be assessed. This hormone is excreted by the kidney. Thus, women on dialysis may have slightly elevated levels, making it more difficult to find a true positive value.
An ultrasound should be performed to confirm a viable pregnancy and assess for dates of the pregnancy.
Chronic kidney disease
Frequent monitoring of kidney function (eg, monthly) should be considered during the first and second trimesters with a panel that measures serum creatinine, potassium, total CO2, and sodium concentrations. Exact frequency can be determined by the care team, depending on the clinical scenario. Liver function tests and hemoglobin values should be monitored, the latter of which can decrease, both as a result of normal physiological changes in pregnancy and worsening of kidney function.
Urine measurements for bacteriuria and protein excretion are essential.
Renal biopsy can be considered if it changes management in patients with new or worsening manifestations of kidney disease, such as worsening proteinuria or unexpected findings in the urine sediment, such as signs of glomerulonephritis. Typically, biopsies are avoided after the second trimester, but some literature suggests they can be performed safely up to 32 weeks of gestation.
The National transplant registry guidelines (2007) recommends the following prenatal care for transplant pregnant patients:
Accurate early diagnosis and dating of pregnancy
Clinical and laboratory monitoring of functional status of transplant organ and immunosuppressive drug levels every 4 weeks until 32 weeks, then every 2 weeks until 36 weeks, and then weekly until delivery.
Monthly urine cultures
Surveillance for rejection with biopsy
Surveillance for bacterial or viral infections;, ie; cytomegalovirus (CMV), toxoplasmosis, hepatitis
Monitor for hypertension and nephropathy
Surveillance for pre-eclampsia
Screening for gestational diabetes
How should patients with chronic kidney disease, ESRD, or who have received a transplant who are pregnant be managed?
The hemodialysis prescription needs to be tailored carefully, at least 20 hours per week, for 5-6 times per week, with the possibility of longer treatments (nocturnal). Studies show improved fetal survival at 24 hours per week. Predialysis blood urea nitrogen (BUN) should be < 50 mg/dl. No Kt/V value has been associated with improved outcomes, as data are insufficient to identify a goal. Most authorities recommend non-reuse biocompatible dialyzers with low surface area to potentially decrease ultrafiltration per treatment.
Patients should avoid both metabolic acidosis and metabolic alkalosis, thus the bicarbonate concentration in the dialysate must be tailored carefully. A 3 to 4K+ bath is recommended, and avoids hypokalemia. Predialysis phosphate should be 4-5 mM. Ultrafiltration of 1.5kg or less per treatment is recommended due to the possibility of hypotension and fetal distress. Intradialytic hypotension should be avoided, and some authorities advise uterine and fetal monitoring during dialysis, if possible.
Patients on peritoneal dialysis may continue on that modality, and do not seem to experience different outcomes than patients on hemodialysis. Patients should be vigilant regarding sterile technique and avoidance of contamination, as peritonitis should be avoided at all costs.
Hypertension and volume status management are crucial. Patient dry weights need to be slowly adjusted upward depending on rate of weight gain. Some recommend increasing patient ‘dry’ weight by 0.5kg per week after the first trimester. Maternal hypotension or volume depletion may have negative consequences for the fetus. Blood pressure goals are discussed elsewhere (refer to pregnancy and hypertension section) and should aim for nothing > 160/110.
Typically first-line oral agents would include labetolol, methyldopa, hydralazine, or a calcium channel blocker. Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) should be avoided, and patients who are considering pregnancy should discontinue these agents prior to attempts. These agents should be discontinued as soon as women find out that they are pregnant, due to associated birth defects.
Nutritional management is very important. Protein intake should be at least 1.5 g/kg/d in hemodialysis patients and 1.8 mg/kg/d in peritoneal dialysis patients. Caloric intake should be 30-35 ml/kg/day, with fluid intake of 1-1.5 L / day. Vitamin supplementation should include thiamine, riboflavin, vitamin B6, folate, and niacin. Calcium intake must be adequate, 1500mg / day, and is usually maintained with a 2.5mEq/L calcium bath. Phosphorus can be given orally to maintain > 2.5mM.
Anemia control can worsen as the plasma volume expands 3-4L without a concomitant increase of red cell mass in dialysis patients. Erythropoietin stimulating agents may need to be increased 25-100% to achieve hemoglobin levels of 10-11g/dL. Use of iron to maintain an iron saturation of > 20-30% is recommended.
Obstetric and fetal monitoring via nonstress testing , ultrasounds, visits to high-risk obstetrics groups, and meetings with a neonatalogists are recommended.
Preterm labor, although common, should be avoided. Use of magnesium needs to be monitored cautiously in dialysis patients, at levels no greater than 5 mg/dL. Progesterone use seems to be beneficial in small trials in the general populations, and indomethacin has been used in the short term.
Chronic kidney disease
Aggressive hypertension management is crucial, at a minimum to a goal of < 160/105. (refer to section on hypertension and pregnancy).
Laboratory assessment should be performed as outlined above.
Nutritional assessments should include recommendations about sodium, potassium, and fluid intake, depending on the severity of kidney disease.
Calcium intake must be adequate, 1500mg / day, and phosphorus levels can be should be maintained in a normal range, either by supplementation if low, or by careful phosphorus restriction or binders if too high.
Anemia control can worsen as the plasma volume expands 3-4L without a concomitant increase of red cell mass in dialysis patients. Erythropoietin stimulating agents may need to be increased 25-100% to achieve hemoglobin levels of 10-11 g/dL. Use of iron to maintain an iron saturation of > 20-30% is recommended.
Diabetics with kidney disease should maintain tight glucose control.
Frequent fetal surveillance via ultrasound should monitor heart rate, growth rate, and overall well-being. Obstetric and fetal monitoring via nonstress testing, visits to high-risk obstetrics groups, and meetings with a neonatologist are recommended.
Preterm labor, although more common in this population, should be avoided if possible. Use of magnesium needs to be monitored cautiously in patients with CKD, with goals of levels no greater than 5 mg/dL. Progesterone use seems to be beneficial in small trials in the general populations, and indomethacin has been used in the short term, although non-steroidal anti-inflammatory agents should be avoided if possible in patients with kidney disease.
The physiological changes of pregnancy resolve in approximately 3 months. During pregnancy the kidney increases production of vitamin D, rennin and erythropoietin. Also, increased renal blood flow leads to an increase glomerular filtration of more than 50%. Radio logic changes seen in pregnancy include an increase in size of kidneys as well as renal pelvis and ureteric dilatation. These changes are demonstrated on ultrasonography, sometimes mimicking true hydronephrosis obstructing urinary outflow.
During the 12 weeks post-partum, careful attention to fluid balance, kidney function, blood pressure, and edema with adjustment of the medication regimen is often necessary.
Women who developed proteinuria during pregnancy should be monitored carefully post-partum. Quantification of proteinuria should be pursued between 6-12 weeks post partum. Further work up for proteinuric kidney diseases should be attempted if significant proteinuria persists after 12 weeks post partum. A kidney biopsy should be considered in some patients. Pre-eclampsia related hypertension usually disappears within a few weeks, usually within 3 weeks or so. In very rare cases will take as long as 6 months
What happens to patients with chronic kidney disease, ESRD, or transplant who are pregnant?
Maternal mortality is extremely rare. Fetal outcomes, however, are not as optimistic. Survival ranges from 40-85% in most large studies, and has improved over time.
Preterm labor occurs in about 80% of patients from many causes, such as maternal hypertension, intrauterine growth retardation, polyhydramnios, infections, and fetal distress.
Polyhydramnios is common, at rates usually over 30%. This could be due to fetal diuresis with high maternal BUN levels or shifting of fluids into the amniotic fluid when solutes are rapidly removed during clearance on dialysis.
Patients with chronic kidney disease should be counseled about maternal and fetal outcomes in advance of pregnancy, given the differences from the general population.
Chronic kidney disease
Contraception options should be discussed prior to pregnancy, particularly for those with SCr > 2.0 mg/dL, given concerns about fetal survival and maternal progression of CKD.
Maternal mortality is rare, reported as < 1% in one US registry (3 of 382 patients died).
Fetal survival is excellent in CKD patients not on dialysis, even if SCr is modestly elevated ( > 1.4mg/dL). For those that progress to ESRD, however, fetal survival ranges from 40-50%. Dialysis patients can be counseled to consider waiting for kidney transplantation, as fetal survival improves to 80-90%.
Risk of ESRD quoted from one prospective observational trial is essentially nil for a SCr < 1.4mg/dL, 2% at SCr 1.4-2.0 mg/dL, and 35% with a SCr > 2.0 mg/dL.
Preterm labor occurs in about 80% of ESRD patients (See chapter on pregnancy and dialysis).
Polyhydramnios is common in advanced CKD, at rates usually over 30% in dialysis patients.
Patients with diabetic nephropathy have survival rates that parallel the general population, but suffer from increased fetal and maternal morbidity in comparison to non-diabetics and diabetics without kidney disease. Other special populations that experience slightly worse outcomes include those with scleroderma and those with systemic lupus erythematosus (SLE).
Women with CKD should be encouraged to breastfeed their infants.
The National Library of Medicine has produced a database, The LactMed database; this has become a very comprehensive information resource regarding safety of prescription medications during lactation (http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen? LACT)
Metoprolol and Labetalol have not been associated with adverse events in infants, and have the lowest transfer into milk. Atenolol should be avoided as well as Acebutolol given risk of neonatal bradycardia.
Calcium channel blockers (Diltiazem, Nifedipine, Nicardipine, Verapamil) are compatible with breastfeeding
Captopril and Enalapril have deemed to be safe on lactation by the American Academy of Pediatricians. We tend to avoid prescribing these medications to mothers especially with premature newborns or newborns small for gestational age, who appear to be more susceptible to due to side-effects related to the these medications.
Diuretics are deemed to be safe by the American Academy of Pediatricians. Women should be aware of the risk of reducing milk volume while on diuretics.
Non-steroidal anti-inflammatory medications should be avoided in pregnant women with CKD or hypertension in the post-partum period. These may cause or aggravate further kidney dysfunction, also may contribute to blood pressure elevation post-partum.
Pregnancy after transplantation does not increase risk of loss of allograft function. It appears this applies to patients with stable creatinines values below 1.5 mg/dl and when the patient is on stable immunosuppressive regimen.
The American Society of Transplantation Consensus summary on reproductive issues and transplantation published in 2005 recommends the timing of pregnancy be based on:
1. No rejection in the past year
2. Adequate and stable graft function (e.g. creatinine less than 1.5 mg/dl) or no or minimal proteinuria (level to be defined, some authors consider < 0.5 g/24 hr)
3. No acute infections that may impact the fetus
4. Maintenance immunosuppresion at stable dosing. MMF and Sirolimus should be stopped 6 weeks before conception is attempted.
5. Special circumstances that impact above recommendations:
Rejection within the last year
Establish medical non-compliance
Cyclosporine, Tacrolimus, Azathioprine and Prednisone are considered relatively safe during pregnancy
All immunosuppressants cross the placental barrier, prednisolone has been associated with neonatal adrenal insufficiency, and Azathioprine has been associated with small gestational age (SGA) babies and in rare cases with myelosuppresion in the fetus.
Cyclosporin has been associated with prematurity and growth retardation. Tacrolimus has been associated with hyperkalemia and renal insufficiency in the fetus
Mycophenolate mofetil and Sirolimus are contraindicated in pregnancy on the basis of multiple reports of suggesting teratogenicity.
ACEI are contraindicated in pregnancy. A large epidemiologic study of first trimester exposure to ACEI reported a 7% rate of major congenital abnormalities compared to 2 % on the unexposed group.
Steroids, Azathioprine, Cyclosporine and Tacrolimus are excreted in breast milk in small percentages. Breastfeeding is not recommended.
In terms of obstetrical management: management of all pregnant patients should be by a high risk obstetrician in cooperation with a transplant nephrologist
Cesarean indications are for obstetric reasons however overall cesarean section rate is increased in transplant patients
Graft dysfunction during pregnancy warrants appropriate work up including graft biopsy
Hyperemesis gravidum may lead to decreased absorption or inadequate immunosuppresion.
How to utilize team care?
It does take a village to adequately provide the complex care needed during pregnancy.
Team members would include:
the nephrologist, to provide intensive dialytic therapy with reassessment for dose, blood pressure control, and anemia management on a very frequent basis.
A high risk obstetrics provider will monitor the patient and watch for sings of negative outcomes, listed above.
The dialysis unit staff needs to be incorporated in this plan to provide care in a real-time basis.
A nutritionist is essential to modify the patient diet.
A neonatalogist should provide supportive care and counseling as well.
Chronic kidney disease
Pregnant women with kidney disease should be managed jointly by a nephrologist and obstetrician who are familiar with the effects of pregnancy and CKD. This team approach can result in earlier detection and treatment of problems encountered in this patient population, such as worsening of hypertension, a decline in kidney function, and preeclampsia.
Prenatal visits are more frequent, such as twice monthly until 24 weeks, then weekly. This facilitates more aggressive treatment for hypertension.
Monthly laboratory evaluation can monitor for worsening of kidney function, presence or worsening of proteinuria, and abnormalities in liver function tests, which can be a sign of preeclampsia, and . Early asymptomatic bacteriuria.
Team care should consist of the obstetrician, who may have expertise in 'high-risk' patients, a nephrologist, and the neonatologist if any newborn concerns.
In addition, other support team members can include nursing specialists, social workers, and other support persons such as friends, family, and others with post-partum expertise.
Are there clinical practice guidelines to inform decision making?
The National transplant registry guidelines (2007)
The American Society of Transplantation Consensus summary on Reproductive issues and transplantation published in 2005.
What is the evidence?
Okundaye, I, Aprinko, P, Hou, S. "Registry of pregnancy in dialysis patients". Am J Kindey Dis. vol. 31. 1998. pp. 766.
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Hou, S. "Pregnancy in dialysis patients: where do we go from here?". Semin Dial. vol. 16. 2003. pp. 376.
Luders, C, Castro, MC, Titan, SM. "Obstetric outcome in pregnant women on long-term dialysis: a case series". Am J Kidney Dis . vol. 56. 2010. pp. 77.
Hou, S. "Pregnancy in chronic renal insufficiency and end-stage renal disease". Am J Kidney Dis. vol. 33. 1999. pp. 235.
Imbasciati, E, Gregorini, G, Cabiddu, G. " Pregnancy in CKD stages 3 to 5: fetal and maternal outcomes". Am J Kidney Dis. vol. 49. 2007. pp. 753.
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Epstein, FH. "Pregnancy I renal disease". N Engl J Med. vol. 335. 1996. pp. 277.
Fischer, MJ, Lehnerz, SD, Hebert, JR, Parikh, CR. "Kidney disease is an independent risk factor for adverse fetal and maternal outcomes in pregnancy". Am J Kidney Dis. vol. 43. 2004. pp. 415.
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Jungers, P, Houillier, P, Forget, D. "Influence of pregnancy on the course of primary chronic glomerulonephritis". Lancet . vol. 346. 1995. pp. 1122.
Keller, F, Griesshammer, M, Haussler, U. "Pregnancy and renal failure". Drugs. vol. 61. 2001. pp. 1901-1920.
Jones, DC, Hayslett, JP. "Outcome of pregnancy in women with moderate or severe renal insufficiency". N Engl J Med. vol. 335. 1996. pp. 226-232.
Cunningham, FG, Cox, SM, Harstad, TW. " Chronic renal disease and pregnancy outcome". Am J Obstet Gynecol. vol. 163. 1990. pp. 453-459.
"American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk". Pediatrics. vol. 108. 2001. pp. 776-789.
Sibanda, N, Briggs, JD, Davison, JM. "Pregnancy after organ transplantation: a report from the UK Transplant pregnancy registry". Transplantation. vol. 83. 2007. pp. 1301-1307.
McClure, Z. "Failure rates of contraceptive methods". Family Plann Inf Serv. vol. 6. 1982. pp. 59-61.
Davison, JM. "The effect of pregnancy on kidney function in renal allograft recipients". Kidney Int. vol. 27. 1985. pp. 74-79.
Armenti, VT, Radomski, JS, Moritz, MJ. "Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation". Clin Transpl. 2002. pp. 121-130.
First, MR, Combs, CA, Weiskittel, P. "Lack of effect of pregnancy on renal allograft survival or function". Transplantation. vol. 59. 1995. pp. 472-476.
Davison, JM. "Pregnancy in renal allograft recipients: prognosis and management". Baillieres Clin Obstet Gynaecol. 1987. pp. 1027-1045.
Thompson, BC, Kingdon, EJ, Tuck, SM. "Pregnancy in renal transplant recipients: the Royal Free Hospital experience". QJM. vol. 96. 2003. pp. 837-844.
Fischer, T, Neumayer, HH, Fischer, R. "Effect of pregnancy on long-term kidney function in renal transplant recipients treated with cyclosporine and with azathioprine". Am J Transplant. vol. 5. 2005. pp. 2732-2739.
Gaughan, WJ, Coscia, LA, Dunn, SR. "National Transplantation Pregnancy Registry. Pregnancy outcomes in cyclosporine-treated female kidney recipients with a conventionally recommended vs. a long transplant-to-conception interval". Am J Transplant. vol. 2. 2002. pp. 402.
McKay, DB, Josephson, MA, Armenti, VT. "Reproduction and transplantation: report on the AST Consensus Conference on Reproductive Issues and Transplantation". Am J Transplant. vol. 5. 2005. pp. 1592-1599.
Coscia, LA, Constantinescu, S, Moritz, MJ. " Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation". Clin Transpl. 2007. pp. 29-42.
"American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals into human milk". Pediatrics. 2001.
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