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Pregnancy in advanced chronic kidney disease and end-stage renal disease

Alkhunaizi, Ahda; Melamed, Nirb; Hladunewich, Michelle A.a,b

Current Opinion in Nephrology and Hypertension: May 2015 - Volume 24 - Issue 3 - p 252–259
doi: 10.1097/MNH.0000000000000119
EPIDEMIOLOGY AND PREVENTION: Edited by Navdeep Tangri

Purpose of review This article reviews the available literature about the incidence, outcomes, and the management of pregnancy in women with advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) who require renal replacement therapy.

Recent findings Pregnancy in women with advanced CKD and ESRD can result in serious adverse maternal and fetal outcomes, but improved outcomes have been noted in recent years, likely secondary to intensified dialysis regimens. More intensive dialysis allows for the gentle removal of water, solutes, and uremic toxins, which theoretically results in near-normal maternal renal physiology, an improvement in placental blood flow, and therefore a better environment for fetal growth and development. As management remains complex, a close joint collaboration between the high-risk obstetrical team and nephrology is essential.

Summary Pregnancy on dialysis is becoming a viable option for women with advanced CKD and ESRD who do not have immediate access to transplantation.

aDivision of Nephrology, Department of Medicine

bDepartment of Obstetrics and Gynecology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada

Correspondence to Michelle A. Hladunewich, MD, BSc, MSc, FRCP, Sunnybrook Health Sciences Centre A139 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada. Tel: +1 416 480 5954; fax: +1 416 480 5755; e-mail: michelle.hladunewich@sunnybrook.ca

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INTRODUCTION

Pregnancy becomes increasingly challenging as young women progress through the stages of chronic kidney disease (CKD). Potential untoward outcomes include the progression of underlying renal dysfunction, worsening of urine protein, and hypertension, as well as untoward fetal outcomes including intrauterine growth restriction and preterm delivery. It is known that the risk increases with the degree of renal insufficiency and is further heightened by coexisting hypertension and proteinuria [1]. As such, pregnancies occurring in young women with advanced renal insufficiency (CKD stages 4 and 5) can result in significantly compromised maternal and fetal well-being.

Furthermore, advanced CKD is also a powerful form of contraception. As a young woman's kidneys fail, a number of hormonal changes compromise fertility [2]. Most female patients on dialysis suffer from amenorrhea, whereas those who continue to menstruate tend to have anovulatory cycles. Sexual dysfunction is also commonly encountered in advanced CKD patients, primarily due to decreased sexual interest likely as a result of the cumulative effects of depression, fatigue, medication side-effects, and altered body image, all of which are common in patients with end-stage renal disease (ESRD) [3–5]. As such, young women who approach ESRD during their reproductive years often miss the opportunity to have a child unless kidney transplantation is imminent, which remains the best renal replacement therapy for ESRD patients, including the subgroup contemplating pregnancy. Compared with women on dialysis, transplant recipients have restored fertility and a higher incidence of successful pregnancies with fewer complications [6,7]. However, long transplant waiting times, in particular, for young women with a limited reproductive window, may prevent this as a viable strategy for having a child.

Dialysis, therefore, remains the most readily available method of renal replacement therapy, but the literature concerning pregnancy while on dialysis is generally scarce, and it has long been considered to be challenging to manage pregnancy when it occurs on dialysis. Recently, intensive hemodialysis has been shown to improve fertility as well as pregnancy outcomes, and may prove a therapeutic strategy for young women with advanced CKD and ESRD. In this article, we will review pregnancy incidence and outcomes among women on dialysis and incorporate our experience and recommendations for treating this vulnerable group of young women. Finally, we will discuss potential concerns that require ongoing multicenter collaboration to better understand risk and management strategies.

Box 1

Box 1

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INCIDENCE OF PREGNANCY IN WOMEN WITH ADVANCED CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE

Given the impaired fertility and increased sexual dysfunction that progresses in young women as their kidneys fail, it is not surprising that the incidence of pregnancy is low. There are no population-based registries that are able to capture pregnancy incidence in young women with advanced CKD, and it would be profoundly difficult to assess fertility in this population in the absence of a prospectively followed cohort. In women with ESRD on dialysis, conception rates have been determined from registry data and are often incomplete. Furthermore, given the menstrual irregularities inherent to this population, pregnancy is difficult to diagnose and early losses could conceivably be missed. Irrespective, pregnancy is strikingly uncommon compared with both the age-matched transplant population and the general population [8▪] with the incidence of pregnancy documented to range from less than 1% to approximately 7% [9–14].

There are data to suggest that pregnancy rates have improved over time, possibly related to the widespread use of erythropoietin-stimulating agents and more intensive hemodialysis regimens employed in more recent decades. A slightly higher rate of 2.4% of hemodialysis patients became pregnant over a 4-year period (1992–1995) [12] in contrast to earlier data from the same group wherein the pregnancy rate in hemodialysis patients was only 1.5% over a 2-year period (1990–1992) [13]. Similarly, the Australian and New Zealand Dialysis and Transplantation (ANZDATA) registry published data on all pregnancies occurring in dialysis patients spanning 1966–2008. They noted, in fact, no reported pregnancies prior to 1976 with the rate increasing significantly to 0.54 from 1976 to 1985, to 0.67 from 1986 to 1995, and to 3.3 pregnancies per 1000 person-years from 1996 to 2008 [8▪]. Not surprisingly, pregnancy was most common in women between the ages of 25–29 years (5.61 pregnancies per 1000 person-years) as well as more likely to occur in women with glomerulonephritis as a cause of ESRD compared with other causes of ESRD, in particular, diabetes (2.67, 1.87, and 0.88 pregnancies per 1000 person-years, respectively). However, data from our own experience, wherein we augment clearance with more intensive nocturnal hemodialysis, note the highest reported conception rates (≈15–20%) [15,16▪]. The majority of these women were previously on conventional hemodialysis, but none conceived, suggesting that fertility can be improved with more intensive clearance.

Although few studies have systematically collected this data, the potential to conceive appears significantly lower on peritoneal dialysis as compared with hemodialysis. In the US dialysis registry that reported data from 930 dialysis centers including 1699 women of childbearing age on peritoneal dialysis, the pregnancy rate was only 1.1% [12]. Similarly, the ANZDATA study noted an overall rate of 1.06 compared with 2.54 pregnancies per 1000 person-years in young women on peritoneal dialysis and hemodialysis, respectively [8▪]. In addition to the aforementioned hormonal and functional causes of infertility in ESRD patients, experts in the field have speculated about additional causes for the decreased conception rates in peritoneal dialysis patients, including the effect of the large volume of hypertonic solution in the intraperitoneal space, which may interfere with ovum transport from the ovaries to the fallopian tubes or impair implantation [17,18].

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OUTCOME OF PREGNANCY IN WOMEN WITH ADVANCED CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE

Historically, the available data about pregnancy outcomes for patients on renal replacement therapy came from case reports and small, single center, case series. More recently, larger registries have published data spanning a number of decades. Irrespective, there remains more available data with respect to the pregnancy outcomes on hemodialysis than for patients managed on peritoneal dialysis, which we will now review.

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Hemodialysis

A recently published study from Italy compared pregnancy outcomes in women on dialysis to transplant recipients and the general population, estimating that women on dialysis have a 10-fold lower probability of delivering a live-born baby than those who have undergone renal transplantation, who, in turn, have a 10-fold lower probability of delivering a live-born baby as compared with the general population [7]. Fortunately, similar to the noted increase in pregnancy incidence over the decades, pregnancy outcomes have also improved over time.

Confortini et al. [19] reported the first successful pregnancy in a woman on chronic hemodialysis in 1971. With the exception of the need for repeated blood transfusions, the pregnancy was largely uncomplicated and she delivered a healthy baby at term, weighing 1950 g. However, subsequent reports from the European Dialysis and Transplant Association were less encouraging with high rates of elective termination and a live birth rate of only 23% [9]. Subsequent data from the USA, wherein termination was unlikely, did not reflect a much better outcome with a live birth rate of only 37% in the 1980s, improving to 52% in pregnancies occurring after 1990 [13]. This effect of era is again demonstrated by data collected within the ANZDATA registry wherein the live birth rate increased from 0.54 (1976–1985) to 0.67 (1986–1995) to 1.84 (1996–2008) pregnancies per 1000 person-years, albeit these differences did not meet statistical significance [8▪]. More recently published series, however, do note much higher live birth rates, now in excess of 85% [20,21] as it has become standard practice to augment the dose of delivered dialysis.

Pregnancy success appears to be directly related to enhanced clearance of urea and other solutes. In an early study prior to the use of widespread dialysis, fetal mortality was noted to be directly related to the blood urea nitrogen (BUN) level with no documented successful pregnancies once the BUN exceeded 60 mg/dl (21.4 μmol/l) [22]. Furthermore, there has been a consistent difference in outcome between women who initiated dialysis during pregnancy and those who conceived on dialysis, with the majority of successful pregnancies noted to have residual renal function. In the US registry data, infant survival was 40.2% in women who conceived on hemodialysis compared with 73.6% who conceived prior to initiating hemodialysis [12]. A similar discrepancy in outcome between established dialysis patients (live birth rate 50%) and those who started dialysis after conception (live birth rate 80%) was noted in the Belgian registry [10]. In addition, this study noted a correlation between birth weight and dose of dialysis. Again, recent data from the ANZDATA registry that included 77 pregnancies between 2001 and 2011 noted superior live birth rates among women who conceived prior to dialysis initiation compared with those already established on dialysis at the time of conception (91 versus 63%; P = 0.03) [23▪]. This study further noted that this significant difference in live birth rates was secondary to early pregnancy losses (<20 weeks gestation) in established dialysis patients. However, beyond 20 weeks, these pregnancies were similar with no significant difference in gestational age or birth weight.

In the absence of residual renal function, adequate dialysis becomes increasingly important. In a series of 28 pregnant women receiving hemodialysis with 18 surviving infants, a significant negative relationship was noted between BUN and birth weight (r = −0.533, P = 0.016) as well as gestational age (r = −504, P = 0.023) [24]. A birth weight of at least 1500 g was achieved at a BUN less than 49 mg/dl (17.9 μmol/l) and a gestational age of at least 32 weeks was achieved at a BUN less than 48 mg/dl (17.1 μmol/l). Thus, the authors recommended adequately intensified dialysis to maintain the BUN at less than 48 mg/dl. We compared pregnancy outcomes from 21 pregnancies in the Toronto Pregnancy and Kidney Disease (PreKid) Clinic and Registry (2000–2012) to 71 pregnancies in the American Registry for Pregnancy in Dialysis patients (1990–2011) [16▪]. The overall live birth rate was significantly higher in the Canadian as compared with the American cohort at 85.7 compared with 61.4% (P = 0.038). The difference was further augmented among established ESRD patients with a live birth rate of 82% compared with 53% (P = 0.028). The Canadian ESRD patients received significantly more dialysis than the American patients (43 ± 6 versus 17 ± 5 h/week, respectively). Furthermore, the duration of pregnancy was longer in the more intensively dialyzed PreKid cohort at 36 (32–38) as compared with 27 (21–35) weeks in the American Registry for Pregnancy in Dialysis patients (P = 0.001) along with a trend toward higher birth weights. A dose response between dialysis intensity and pregnancy outcomes emerged with live birth rates of 48% in women receiving less than 20 h of hemodialysis per week, increasing to 73% in women receiving 21–36 h of hemodialysis per week, and further increasing to 85% in women dialyzed in excess of 36 h a week (P = 0.027).

Despite improved live birth rates over time, pregnancies in young woman on dialysis have proven complex. In the early studies, overall maternal and fetal outcomes were poor with documented maternal deaths, high rates of severe uncontrolled hypertension, eclampsia, hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome, and frequent transfusions, as well as high rates of prematurity, growth restriction, polyhydramnios, and stillbirth [9,10,13]. Even in the study with the highest documented live birth rate [20], the mean gestational age was noted to be only 32.7 ± 3.1 weeks with a mean gestational weight of 1554 ± 663 g. Furthermore, significant rates of complications, including preeclampsia (19%), polyhydramnios (40%), transfusions (25%), and hypertension (70%), were reported. Although the live birth rate was similar in the intensively dialyzed Toronto PreKid cohort (86%), pregnancy complications, to date, have been few and manageable [15,16▪].

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Peritoneal dialysis

Although a successful pregnancy on peritoneal dialysis is certainly a possibility, especially in a woman with significant residual kidney function, there are remarkably fewer cases reported in the literature as compared with women on intermittent hemodialysis [18,25]. One might anticipate that peritoneal dialysis would be equivalent if not superior to hemodialysis as a treatment mode of choice, because of the preservation of residual kidney function, as well as the less drastic metabolic and fluid shifts that results in less hypotension, together with a general tendency toward higher hemoglobin levels. However, there is the potential for added risks unique to peritoneal dialysis. Abdominal fullness, discomfort, catheter drainage difficulties, and polyhydramnios, necessitating a progressive decline in fill volumes, have been described [25–30]. Bloody dialysate can indicate an obstetrical catastrophe including placental abruption [31] or can be secondary to trauma to the expanding uterus from the peritoneal dialysis catheter [30,32] and has been documented to be severe resulting in significant maternal morbidity with fetal demise [32,33]. Preterm delivery, premature rupture of membranes, and stillbirth have also been documented to occur secondary to acute peritonitis [34–36]. Even in a recent small series of five women, wherein peritoneal dialysis was prescribed to women with advanced CKD to augment clearance, complications were noted, including exit-site infections, catheter malposition, and peritonitis [37]. Should peritoneal dialysis be the only available renal replacement option, it seems appropriate to increase the frequency of dialysis delivered to help match the increase in maternal metabolism and to compensate for the loss of residual renal function that may ensue as the pregnancy progresses. Recent publications provide a prescription for effective management in the third trimester, which may include a reduction in the volume of exchanges while increasing the frequency or the use tidal exchanges to enhance clearance and alleviate abdominal symptoms [38,39].

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MANAGEMENT OF PATIENTS RECEIVING INTENSIVE HEMODIALYSIS

Given the infrequency of pregnancy in patients with ESRD, few clinicians will have the opportunity to manage this difficult patient population. Despite significant recent improvements in the live birth rate, the risks to both mother and baby remain high. Therefore, collaboration between nephrology and the obstetrical team is essential, and these patients are best managed in a clinic that includes nephrology, maternal fetal medicine specialists, or high-risk obstetricians as well as a full multidisciplinary staff of nurses comfortable with the management of dialysis patients, dietitians, and pharmacists. Fetal follow-up includes careful screening for congenital abnormalities, follow-up of fetal growth, and placental health. Amniotic fluid and cervical status also need careful assessment and follow-up. Issues for maternal follow-up include regular medication reviews, careful follow-up and supplementation of electrolytes, vitamins, and minerals, the management of anemia, as well as the management of volume status and blood pressure (Table 1).

Table 1

Table 1

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Early pregnancy management

The diagnosis of pregnancy can be challenging in women with advanced CKD and ESRD and pregnancy is often diagnosed late in these women, as periods are irregular and common symptoms, such as nausea and vomiting, are also present in patients with advanced CKD. Approximately 30% of human chorionic gonadotropin is cleared by the kidneys whereas another fraction is metabolized [40]. As such, false-positive serum pregnancy tests have been documented in women with advanced CKD [41]. Furthermore, the interpretation of the first trimester screening tests for Down's syndrome should be done with caution given that the serum levels of beta human chorionic gonadotropin (βhCG) and pregnancy-associated plasma protein-A are known to be elevated in women with advanced CKD [42,43]. Amniocentesis may be required if these tests are unclear. All chronic medications should be reviewed, those that are contraindicated in pregnancy should be discontinued or changed, and high-dose folic acid supplementation should be initiated at that time along with ample water-soluble vitamins. Although aspirin has been shown as effective in decreasing the risk of severe early preeclampsia in women with underlying kidney disease [44], there is no evidence as to whether a similar benefit is present in the specific subgroup of women who are on dialysis. Moreover, aspirin has the potential to increase the risk of bleeding given the possible underlying platelet dysfunction and concomitant use of heparin, which is considered to be well tolerated during pregnancy.

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Antenatal management

Intensified dialysis allows for better and gentle salt and water management, which results in reduction of interdialytic weight gain, maintenance of stable, normal blood pressure with fewer hypotensive episodes, and less need for antihypertensive medications. This should also hypothetically minimize shifts in maternal intravascular volume and improve fetoplacental blood flow. Higher doses of dialysis also result in aggressive reduction of urea levels as well as uremic toxins. This, together with improved volume management, will decrease rates of polyhydramnios, which has long been thought to result from fetal solute diuresis and fluid overload. Controlling polyhydramnios will secondarily result in less premature rupture of membranes and labor. Finally, intensive dialysis has also been noted to improve endothelial function, which may be important for placental health [45]. Based on our previous work, which noted improved live birth rates, gestational age, and fetal growth in more aggressively dialyzed women, we attempt at least 36 h of hemodialysis per week in young women with ESRD [16▪]. However, the benefit of intensive hemodialysis may be less obvious in young women who initiate dialysis during pregnancy and likely still have significant residual renal function, as our work did not reveal significant differences in the live birth rate, gestational age or fetal size when compared with the American cohort, despite significantly more hours of weekly dialysis [16▪], which implies the importance of tailoring dialysis dose to residual kidney function, avoiding a potentially burdensome number of dialysis hours. Routine blood work should include screening for anemia, which has been shown to be associated with adverse pregnancy outcome in patients on dialysis [20], and should be managed by adequate iron supplementation and significantly increased doses of erythropoietin-stimulating agents. Calcium and phosphate levels typically require supplementation. The diet can be liberalized to ensure adequate caloric and protein intake.

Ongoing obstetrical follow-up should be focused on stratification of the risk of placental dysfunction by means of biochemical markers and assessment of placental morphology and uterine artery Doppler readings. Serial ultrasound examinations are important for the early detection of fetal growth restriction, disorders of amniotic fluid volume, and cervical length for the prediction of cervical incompetence and preterm birth, which was a documented issue in our series for unclear reasons [16▪]. One of the challenges in pregnancies complicated by CKD, with or without hemodialysis, is the management of worsening hypertension, which may be due to superimposed preeclampsia, but may also be secondary to fluid overload. Such a distinction is critical as false diagnosis of preeclampsia may lead to an unnecessary indicated delivery and iatrogenic prematurity. At the same time, the management of hypertension with ultrafiltration, due to presumed fluid overload being the cause of the hypertension, may result in end-organ hypoperfusion (including placental hypoperfusion). Nevertheless, distinguishing between these different causes is difficult given that many of these patients have underlying chronic hypertension and the presence of proteinuria (as a marker of preeclampsia) cannot be determined in the absence of urine output. Instead, the diagnosis of the most likely cause for the hypertension should be based on clinical assessment of fluid status and laboratory evidence of hemolysis, elevated liver enzymes, and low platelets syndrome. In addition, there is now evidence that the diagnosis of preeclampsia can be based on either single or serial measurements of serum levels of angiogenic markers such as soluble fms-like tyrosine kinase-1 (sFlt1) and placental growth factor (PlGF) as well as by noninvasive assessment of hemodynamic variables such as peripheral vascular resistance, but these are not as yet widely available [46].

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Labor and delivery

With respect to the timing of delivery, we believe that in cases in which adequate monitoring is available and there is no evidence of maternal or fetal complications, patients can be induced after 37 weeks of gestation. With respect to mode of delivery, the vaginal route is preferred and Cesarean section should be reserved for the usual obstetrical indications. For these reasons, as well as the metabolic and hemodynamic disorder that may complicate the perioperative course of patient on hemodialysis, preoperative anesthetic assessment is recommended. Special precaution should be taken with regard to treatment with intravenous magnesium sulfate (for seizure prophylaxis in patients with severe preeclampsia or fetal neuroprotection in the case of early preterm labor, two conditions that are more common in these patients) given the lack of renal clearance of magnesium. The neonatology team should become familiar with the parents, ideally before delivery, to facilitate adequate evaluation and monitoring of the newborn who may have elevated levels of creatinine and urea, and may be at risk of dehydration due to osmotic diuresis. Finally, our women can breastfeed as desired, but caution should be exercised against over aggressive ultrafiltration and dehydration, which can hamper milk production.

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CONCLUSION

In summary, pregnancy incidence and outcomes for women with advanced CKD and ESRD have improved over time. Intensive dialysis, along with careful multidisciplinary care, can decrease both maternal and fetal morbidity. However, further study is required to ensure that this is a safe long-term practice. It is well known that patients with ESRD have a decreased life expectancy, which was noted among the young women who died during follow-up in the ANZDATA registry while their children were still quite young [8▪]. Pregnancy is also a potential reason for sensitization [47], which might hamper future transplantation. Intensified hemodialysis is not without increased risks notably bacteremia, vascular access issues, and loss of residual renal function [48]. Finally, little is currently known about the future development and well-being of children born on dialysis. As such, ongoing collaborative research is required to better advise and manage these unique patients.

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Acknowledgements

None.

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Financial support and sponsorship

None.

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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REFERENCES

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Keywords:

chronic kidney disease; dialysis; end-stage renal disease; pregnancy

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