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?
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?
Most patients on dialysis suffer from amenorrhea and sexual dysfunction:
Early menopause is common in women treated with standard three-times per week dialysis regimens.
Patients have lower estradiol levels, diminished desire, and fewer sexual encounters than age-matched controls.
Pregnancy can occur in women on dialysis, especially those on home or nocturnal therapies with the dialysis dose is often greater. Ovulation may be restored in women who begin intensified hemodialysis regiments
When pregnancy occurs in a patient on dialysis, diagnosis often occurs late. Irregular menses and abdominal complaints are common in dialysis patients, and these symptoms may not be considered as related to pregnancy.
A pregnancy diagnosis should be confirmed with ultrasound as beta-HCG levels can be elevated in non-pregnant dialysis patients.
Once pregnancy is confirmed, dialysis should be intensified to a minimum of 36 hours per week.
What should we know and counsel about the effects of pregnancy on chronic kidney disease?
Chronic kidney disease increases both maternal and fetal risk.
The higher the serum creatinine, the greater the chance for renal functional decline during pregnancy. Etiology of kidney disease is less important than the degree of kidney dysfunction in estimating decline of kidney function during pregnancy:
Two observational cohorts showed that fewer than 10% of women with known kidney disease experience a decline in kidney function with a serum creatinine <1.5 mg/dL. In the same studies, women with "moderate" kidney dysfunction (serum creatinine either 1.5 – 2.9 mg/dL or 1.4 – 2.0 mg/dL), experienced a 40-60% decline in function.
In women with advanced CKD (serum creatinine 3.0 mg/dL and above) permanent loss of glomerular filtration rate (GFR) is more frequently seen. Many women will progress to ESRD during pregnancy.
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.
An understanding of normal renal physiology is helpful to understand clinical findings in pregnant patients with CKD.
Systemic vascular resistance and blood pressure go down in pregnancy despite blood volume expansion and an increase in cardiac output.
GFR increases. Mild hyponatremia can occur due to ‘resetting of thermostat’.
Kidney size increases by up to 30%, due to increases in the vascular and interstitial compartments. Renal pelvises can be dilated due to hormonal (progesterone) and mechanical 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. Some women resume normal ovulation within 1 month post-transplantation.
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
What tests to perform?
An ultrasound should be performed to confirm a viable pregnancy and assess for dates of the pregnancy. Human chorionic gonadotropin hormone is excreted by the kidney. Thus, women on dialysis may have elevated levels, making it less useful to diagnose pregnancy in women on dialysis due to the risk of a false positive result.
Chronic kidney disease
Frequent monitoring of kidney function (e.g., 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.
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. Dialysis is recommended for a minimum of 36 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.
Patients should avoid both metabolic acidosis and metabolic alkalosis, thus the bicarbonate concentration in the dialysate must be tailored carefully. A 4K+ bath is recommended to avoid hypokalemia. Given extended dialysis, phosphorus levels should be monitored closely and supplemented as necessary. Ultrafiltration should be tailored to minimize the risk of hypotension.
Patients on peritoneal dialysis may continue on that modality if it provides adequate clearance. Many authorities advocate for women to be switched to hemodialysis during pregnancy to optimize clearance.
Hypertension and volume status management are crucial. Dry weights need to be slowly adjusted upward as pregnancy progresses. Maternal hypotension or volume depletion may have negative consequences for the fetus.
Nutritional management is 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, 1500 mg/day, and is usually maintained with a 2.5 mEq/L calcium bath. Phosphorus can be given orally to maintain > 2.5 mM.
Anemia 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 > 30% is recommended.
Obstetric and fetal monitoring via nonstress testing, ultrasounds, visits to high-risk obstetrics groups, and meetings with a neonatalogists are recommended.
If severe preeclampsia develops, use of magnesium needs to be monitored cautiously in dialysis patients who are at high risk for toxicity.
There are higher rates of cervical incompetence in women in dialysis. This should be monitored and cerclage performed if necessary.
Hypertension management is crucial, at a minimum to a goal of < 160/105 or lower. Many providers most would advocate <140/90.
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, 1500 mg / 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 > 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.
The physiological changes of pregnancy resolve in approximately 3 months. During the first 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 done 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.
The National Transplant Registry recommends the following prenatal care:
Delay conception for at least 1 year with adequate contraception
Assess and monitor graft function
Maintain immunosuppressive regimen
Manage comorbid conditions
Discuss the effect of pregnancy on transplant organ function
Discuss risks of maternal complications: hypertension, preeclampsia, diabetes, rejection, and graft loss
Obtain good control of prepregnancy hypertension and diabetes
Discuss risks of neonatal complications: prematurity and low birth weight
Modification of immunosuppressive regimen if necessary
Test for cytomegalovirus and other potential infections
Accurate and early diagnosis and dating of pregnancy
Close monitoring of graft function and immunosuppressive drug levels
Surveillance for bacterial infection [urine culture and viral infection (cytomegalovirus and herpes simplex virus)]
Fetal surveillance for malformation, fetal growth, and well-being
Maternal surveillance for hypertension, gestational diabetes, and preeclampsia
Labor and Delivery
Aim to deliver at term
Perform cesarean delivery only for appropriate obstetric reasons
Monitor immunosuppressive drug levels and alter doses and regimen as necessary
Begin contraception when appropriate
The documented benefits of breastfeeding may outweigh the potential risks of infant immunosuppressive exposure
Mental health counseling if needed for postpartum depression
What happens to patients with chronic kidney disease, ESRD, or transplant who are pregnant?
Maternal mortality is extremely rare. Fetal outcomes have improved over time, with live birth rates >80% in centers where intensified dialysis regimens are performed.
Preterm labor occurs in about 80% of patients from many causes, such as maternal hypertension, intrauterine growth retardation, polyhydramnios, infections, and fetal distress.
Polyhydramnios can occur due to fetal diuresis with high maternal BUN levels. This often indicates that more weekly dialysis is necessary.
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. 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 rates are lower.
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).
Postpartum, women with CKD should be encouraged to breastfeed their infants. The National Library of Medicine LactMed database has comprehensive information regarding safety of prescription medications during lactation (https://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm).
Metoprolol and Labetalol have not been associated with adverse events in infants, and have the lowest transfer into milk. Atenolol should be avoided. 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. These medications should be encouraged in women with proteinuric CKD who have clear benefit from their use. 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.
The American Society of Transplantation recommends the timing of pregnancy be based on:
No rejection in the past year
Adequate and stable graft function (e.g., creatinine less than 1.5 mg/dl) or no or minimal proteinuria
No acute infections that may impact the fetus (i.e. CMV)
Maintenance immunosuppression at stable dosing. MMF and Sirolimus should be stopped 6 weeks before conception is attempted.
Cyclosporine, Tacrolimus, Azathioprine and Prednisone are considered relatively safe during pregnancy
All immunosuppressants cross the placental barrier
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
ACEI are contraindicated in pregnancy
In terms of obstetrical management: management of all pregnant patients should be by a high risk obstetrician in cooperation with a transplant nephrologist
Graft dysfunction during pregnancy warrants appropriate work up including graft biopsy
Hyperemesis gravidum may lead to decreased absorption or inadequate immunosuppression.
How to utilize team care?
Multidisciplinary teams are necessary to care for pregnant women on dialysis, CKD or transplants including nephrologist, high risk OB, neonatologist, nutritionist.
Are there clinical practice guidelines to inform decision making?
The National transplant registry guidelines (2013)
The American Society of Transplantation Consensus summary on Reproductive issues and transplantation published in 2005.
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