Dialysis dependency and pregnancy - can they co-exist?

Written by: Husam Alzayer MD, Priyadarshini John DM

AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.

The pregnancy journey is filled with the hope of bringing new life into the world. It is a journey that women with chronic kidney disease (CKD) take amid significant challenges, including the risk of worsening kidney function and the prospect of requiring kidney replacement therapy (KRT). Although considered a high-risk pregnancy, pregnancy outcomes for women with CKD have improved across all stages, including those receiving KRT. This is thought to be due to significant advancements in care delivered to these complex medical cases. This blog post will focus on pregnancy with kidney failure from preconception until delivery and how to provide better care for these patients.

Fertility of a patient with kidney failure

A person's fertility can be affected by multiple factors, including critical illness and chronic disease. Most patients with kidney failure have several comorbidities and suffer from polypharmacy. These factors, in association or causation, along with the ongoing inflammatory milieu and hormonal dysregulation of patients with kidney failure, all lead to reduced fertility.

The normal reproductive hormonal state is regulated via pulsatile hypothalamic secretion of gonadotropin-releasing hormone (GnRH) that leads to pulsatile luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion by the anterior pituitary gland. In males, in the presence of high tissue testosterone levels, LH stimulates testosterone secretion, and FSH stimulates spermatogenesis. In females, LH surge promotes ovulation, and FSH stimulates the growth and recruitment of immature ovarian follicles (Figure. 1).

This pulsatile hormonal regulation is lost in advanced CKD. LH can be detected in high levels but not in a pulsatile manner. The absent surge translates to decreased testosterone levels and impaired spermatogenesis in males, and impaired ovulation in females. These changes are thought to be secondary to the uremic state, losing control of the hormonal feedback mechanism, and elevated prolactin levels in patients with kidney failure.

Figure 1. Mechanisms of infertility in CKD from Ahmed SB, Semin Nephrol (credit to #NephMadness 2018: Women’s Health Region post)

Female fertility in kidney failure

As kidney function declines, female patients begin to experience menstrual irregularity around an eGFR of 15ml/min/1.73m2 and eventually amenorrhea with an eGFR of 5ml/min/1.73m2. Coupled with high prolactin levels due to low kidney clearance, even if patients had a menstrual cycle, it often is anovulatory. Uterine atrophy has been increasingly recognized due to low estradiol and progesterone levels in female uremic patients. Studies have also shown that female patients with kidney failure reach menopause earlier (median age 47) than their non-CKD counterparts (median age 51 years). Sexual dysfunction, low libido, and negative body image are other factors that contribute to lower fertility rates in female patients with kidney failure. Being mindful of these physiological changes that happen in kidney failure, nephrologists should be aware of the hazards of some medications on fertility in these patients. Choosing optimal regimens for induction and maintenance of disease remission is vital to preserving fertility.

Figure 2. Effect of ESK on fertility & pregnancy

Outcomes of kidney failure pregnancies

Due to the diminished fertility associated with declining kidney function, the incidence of successful pregnancies in patients with kidney failure is, not surprisingly, low. It is estimated that patients receiving hemodialysis (HD) have a reported incidence of <1% to 7%, while those receiving peritoneal dialysis (PD) reported having half of that, although both have increased over time, it is rare. Still, it does happen, and patients need proper counseling on contraception and pregnancy outcomes. Outcomes of kidney failure pregnancies can be classified into maternal or fetal-related outcomes, and adverse events are closely linked to the stage of kidney disease. (Table. 1 from Oliverio et al.). Thus, it is generally recommended to delay pregnancy attempts until receiving a kidney transplant with stable function for at least one year; creatinine less than 1.4 mg/dl, proteinuria <500 mg/day, and no evidence of rejection. However, the waiting time for some patients to receive a kidney transplant could be years, and pregnancy while on dialysis may be the best option for some.

Maternal outcomes

Pre-kidney replacement therapy, disease progression with pregnancy is of significant concern. Those receiving KRT will have an increased risk of:

• worsening or developing hypertension,

• worsening proteinuria or development of preeclampsia,

• worsening anemia,

• and increased risk of abruptio placentae

Patients with lupus also have an increased risk of disease flare during pregnancy, especially in those with a recent flare within six months of conception.

Fetal outcomes

Fetal survival in kidney failure pregnancies has steadily increased over the years, with recent reports of successful deliveries of around 61.4-86.4% with more intensive dialysis treatment. Nonetheless, the majority of these new-borns are:

• preterm (<37 weeks)

• average birth weight of 2118g

• high requirement of neonatal ICU admission

There is also an increased risk of polyhydramnios, with reports between 29% and 67% of pregnancies in CKD.

Table 1. Maternal and fetal outcomes by CKD from Oliverio et al., Am J Kidney Dis. 2021

Table 2. Summary of pregnancy counseling by CKD stage from Burgner et al., Am J Kidney Dis. 2019

Table 3. Maternal and fetal complications in renal failure and pregnancy from Fisher et al., Critical Care Obstetrics, Sixth Edition 2018

Management of pregnant dialysis patient

Preconception care: Detailed information regarding the maternal and fetal risks encountered in pregnant dialysis patients should be provided. The need for multidisciplinary effort should be emphasized.

Contraception: The readiness of a dialysis patient who desires to become pregnant depends on several parameters like the physical condition of women, age of the woman, wait time for a donor kidney, and anemia. Women who are anticipated to undergo transplantation can plan pregnancy post-transplantation as the outcomes are better in transplant patients than those on dialysis. Hence detailed advice regarding contraception must be provided to the woman and the family. Check this tweetorial thread about contraception in chronic kidney disease and our contraception blog here

Anemia: This is an important complication in women on dialysis and requires intravenous iron and erythropoietin administration. Erythropoietin-stimulating agents do not cross the placenta and are safe in pregnancy. 25 % of pregnant dialysis patients might require blood transfusion, which sensitizes the patient and impacts transplantation in the future.

Infections: Pregnant women on dialysis are at risk for tunneled catheter and access-related infections. Asymptomatic bacteriuria in patients who are not anuric should be periodically screened and treated accordingly.

Prevention of Preeclampsia: Many systematic reviews, including Lelia et al documented the benefit of low dose Aspirin 75mg in the prevention of preeclampsia in high-risk women. The same benefit can probably be extrapolated to dialysis pregnant women.

Medications: Women on dialysis who are planning to conceive should be advised to

discontinue ACEI and ARBS for fear of fetal anomalies. But women who are not on dialysis and receiving these drugs for proteinuria can continue using drugs until conception. It is recommended to avoid diuretics during pregnancy, and adequate ultrafiltration can be achieved through regular dialysis. Immunosuppression like mycophenolic acid, cyclophosphamide, methotrexate,rituximab, sirolimus, and everolimus are contraindicated in pregnancy. It is prudent to start aspirin 75mg for prevention of preeclampsia. Drugs like low molecular weight heparin, prednisolone, azathioprine, tacrolimus, and hydroxychloroquine are safe to continue.Recommended antihypertensive drugs during pregnancy include labetalol, nifedipine, and methyldopa.It is suggested to double the dose of folic acid and water-soluble vitamins as they are removed through dialysis.Magnesium sulfate loading and maintenance dose is reduced to half in preeclamptic dialysis women as magnesium is excreted through the kidneys. Phosphate binders are stopped as they decrease absorption of folic acid, and also adequate dialysis would not mandate the use of these drugs during pregnancy. Cinacalcet and non-calcium carbonate phosphate binders are better avoided due to lack of safety data in pregnancy.

Maternal monitoring:Pregnant dialysis women should be assessed at periodic intervals, at least monthly in the first trimester, twice monthly in the second trimester, and weekly once in the third trimester. Cervical length between 18 to 20 weeks helps rule out cervical incompetence as hemodialysis patients are at risk for cervical incompetence.Measurement of blood pressure for evidence of preeclampsia is recommended.Proteinuria by spot urine protein creatinine ratio in patients who are not dialysis dependent should be monitored.Hemodynamic stability of the mother should be ensured during dialysis sessions. Hypotension during dialysis is predominant in the last 30 minutes of dialysis, which may cause uteroplacental insufficiency and premature uterine contractions.Serial blood chemistry are monitored to see for evidence of anemia, serum calcium, phosphorus, and parathormone for bone disease, liver function tests for HELLP syndrome, serum proteins and albumin to assess the overall nutritional status.

Fetal monitoring:Pregnancy on dialysis is considered a high-risk pregnancy. It should include first and second-trimester screening for fetal chromosomal anomalies, which includes nuchal translucency and quadruple test.Recent advances have been the assessment of cell-free fetal DNA and invasive testing like chorionic villus sampling and amniocentesis, which are offered to the patient who had repeated pregnancy losses.

Fluid shifts during dialysis can have an impact on uteroplacental flow. Hence fetal monitoring should include fetal heart monitoring during dialysis, fetal growth, and amniotic fluid volume every 2-4 weeks.

Now the most important part is about the mode and adequacy of dialysis.

Dialysis

Modality

A small study by Moumita et al. reported higher pregnancy rates in patients on nocturnal hemodialysis, which is probably related to a higher dialysis dose. Shahir et al. analyzed the data from ANZDATA. They found that the pregnancy rate is lower in patients on peritoneal dialysis compared to those on hemodialysis(2.54 pregnancies per 2,000 patient-years among HD patients vs. 1.06 pregnancies among PD patients).Although there are advantages of peritoneal dialysis (PD) like physiological ultrafiltration, preserved residual renal function, avoidance of anticoagulation, and better control of urea levels which decrease the risk of polyhydramnios, continuing PD during pregnancy has increased incidence of small for gestational age babies compared to hemodialysis. Therefore, women should be given informed choices about the modality of dialysis. The ideal timing for shifting to hemodialysis is immediately after the pregnancy is confirmed or in the first trimester. If women wish to continue PD, hybrid therapy with intermittent HD can be offered to the women to ensure adequate dialysis.

The following infographic summarizes advantages and disadvantages of hemodialysis and peritoneal dialysis in pregnant women.

Figure 3. Pros and cons of different dialysis modalities in pregnancy

Dialysis dose

PD prescription should be individualized according to the patient and gestational age. As the gestational age advances, reduced dwell volumes and times with multiple exchanges are recommended. Automated Peritoneal dialysis is a good alternative to CAPD during pregnancy. Tidal PD nullifies abdominal symptoms like drain pain and gastroesophageal reflux.

Hemodialysis needs modification of prescription during pregnancy. Biocompatible membranes are recommended in view of lesser amounts of protein catabolism. Low flux dialysers with longer dialysis duration offer better hemodynamic stability by minimizing fluid and osmotic shifts, mitigating hypotensive episodes.The frequency of dialysis should be titrated to achieve the pre-dialysis urea less than 50 mg/dl.Prolonged dialysis helps achieve a better uremic milieu for the fetus, allows the liberal intake of protein, potassium, and fluid intake to the mother, and eases dry weight and fluid removal, thereby having minimal effect on uteroplacental flow.Increasing dialysis timing also optimizes blood pressure control, blood transfusion requirements for the mother and decreases the likelihood of preterm delivery, small for gestational age and low birth weight infants.Live birth rate is 85% in women who are on dialysis for >37 hours/week compared to women who are on dialysis for less than 20 hours/week.

The advantages of intensive hemodialysis in pregnancy include better clinical parameters(Blood pressure, edema), improved blood chemistry(urea,hemoglobin, calcium, phosphorus) and greater biologic variables (inflammation and endothelial function).Therefore intensive hemodialysis remains the standard of care for pregnant dialysis women.

Ultrafiltration goals are difficult to ascertain in pregnancy. Maternal dry weight is adjusted periodically as per estimated fetal weight. Maternal weight gain is usually between 1 to 1.5kg in the first trimester and thereafter increases by 0.3-0.5kg per week. Hence estimated dry weight should be increased by 400 gm/ week after the first trimester to accommodate for the fetal weight of about 500 gm/week in second and third trimester.Isolated ultrafiltration can be considered in case of excessive weight gain during pregnancy.

Calorie intake in pregnancy should be increased by 35 kcal/kg in women on hemodialysis(HD) and 25 kcal/kg in women on peritoneal dialysis(PD). Lower energy diet in women on PD is compensated for the dialysate glucose absorption.The protein intake should be 1.2g/kg/day in women on HD and a little higher around 1.4gm/kg/day in women on PD to account for the higher protein losses during PD because of increased frequency of exchanges.

Dialysate potassium between 3 to 3.5mmol/L is recommended to avoid hypokalemia.Low bicarbonate dialysate is suggested to avoid exaggerated alkalosis in addition to progesterone-generated alkalosis in pregnancy.Calcium dialysate around 2.5 mmol/L with 1-2 grams of oral calcium carbonate is recommended to control hyperphosphatemia and secondary hyperparathyroidism.Weekly monitoring of serum calcium, phosphorus, and serum electrolytes should be done to ensure eu electrolytic milieu.

AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.