A systematic approach to managing pregnant dialysis patients—the importance of an intensified haemodiafiltration protocol

Michael Haase1, Stanislao Morgera1, Christian Bamberg2, Horst Halle2, Sebastian Martini1, Berthold Hocher1, Fritz Diekmann1, Duska Dragun1, Harm Peters1, Hans-H. Neumayer1 and Klemens Budde1

Departments of 1 Nephrology and 2 Obstetrics and Gynaecology, Charité University Hospital CCM, Berlin, Germany

Correspondence and offprint requests to: Michael Haase, MD Medizinische Klinik mit Schwerpunkt Nephrologie Campus Charité Mitte Schumannstrasse 20/21 10117 Berlin, Germany. Email: michael.haase{at}charite.de



   Abstract
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 Conclusions
 References
 
Background. Pregnancy is still uncommon in women on maintenance dialysis; and their outcomes is reported to have improved to 40% to 85% live births. Here, we report the successful multidisciplinary management of five consecutive pregnant dialysis patients.

Methods. In our centre, we treated each of five patients with a systematically intensified haemodiafiltration protocol, increased erythropoeitin dosages, a generous administration of water-soluble vitamins and trace elements, and a multidisciplinary clinical management approach with a very low threshold for hospitalization.

Results. All patients received haemodiafiltration at least 6 times/week, an average of 28.6±6.3 h/week. We achieved a mean weekly Kt/Vdp of 9.6±1.4 and urea reduction rates of 54.8±29.4%. The mean erythropoeitin dose was increased from 169±94 IU/kg/week prior to admission at our centre to 314±111 IU/kg/week after the initiation of intensified haemodiafiltration. Haemoglobin levels increased from 8.9±1.9 g/dl to 10.7±0.5 g/dl. Mean gestational age at delivery was 32.8±3.3 weeks and mean birth weight was 1765±554 g. The length of hospital stay amounted to 85±61 days for the mothers and 26±18 days for the newborns, and all were discharged healthy.

Conclusions. These modified management guidelines led to favourable outcomes in all our patients, and may help to guide therapy in other pregnant dialysis patients.

Keywords: haemodiafiltration; multidisciplinary management; pregnancy



   Introduction
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 Conclusions
 References
 
For women on maintenance dialysis, pregnancy is still uncommon [1] which may be related to uremia or to comorbidities of chronic renal failure [2]. The outcome of pregnancies in such patients has markedly improved from approximately 20% live births during the 1980s [3] to 40–85% surviving infants from a registry and recent case reports [1,4,5]. Nevertheless, fetal mortality in pregnant women on dialysis is still much higher than in the general population [1,6]. Polyhydramnios—possibly due to fetal solute diuresis caused by high placental blood urea nitrogen (BUN) concentration [4], maternal hypertension and premature rupture of the fetal membranes are suspected of causing premature delivery [6]. Shifts in acute fluid volume, electrolyte imbalance, and hypotension also could constitute major dialysis-related complications that impair the utero-placental circulation.

To date, a systematic nephrological and prenatal/gynaecological/obstetric treatment approach cannot be found in the literature. Based on previous recommendations [7,8], a joint treatment protocol was developed by nephrologists in order to maintain near-physiological blood urea nitrogen and gynaecologists for optimal timing of delivery. Here, we report the first prospective study and successful multidisciplinary management of five consecutive pregnant dialysis patients in our centre. Each patient received intensified haemodiafiltration, increased erythropoeitin dosages, generous amounts of water-soluble vitamins and trace elements and close prenatal observation with a low threshold for hospital admission.



   Material and methods
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 Conclusions
 References
 
Dialysis protocol
We tried to capture pregnant dialysis patients as early in pregnancy as possible to enhance their treatment as soon as possible. Once pregnancy was confirmed, biochemical, haematologic and metabolic parameters were targeted to be maintained near their physiological levels in all five of our prospectively-observed pregnant dialysis subjects. When pregnancy was diagnosed, all drugs were evaluated and potentially dangerous medications were stopped. We prescribed as much dialysis per week as the women were able to tolerate, but at least 24 h/week. In all patients, we used biocompatible non-reusable high-flux dialysers with a surface area of 1.7 m2 (Gambro Dialysatoren Hechingen, Germany) and 500 ml/min dialysate flow in combination with a bicarbonate haemodiafiltration modus with 9 l of postdilutional multiBic solution (Fresenius, Bad-Homburg, Germany) per session. The dialysate was modified as follows: bicarbonate content was reduced to 28 mmol/l. The other dialysate components were sodium 138 mmol/l, potassium 3.0 mmol/l, calcium 1.25 mmol/l, chloride 110 mmol/l, and magnesium 0.5 mmol/l. Each patient was treated with intravenously administered recombinant human erythropoietin (Epo) beta (NeoRecormon®, Hoffmann-LaRoche, Grenzach-Wyhlen, Germany). The Epo dose was adjusted to maintain the maternal haematocrit above 35%. In addition, we administered iron intravenously (sodium ferric gluconate complex, Ferrlecit®, Aventis, Bad-Soden, Germany) adjusted to achieve a transferrin-saturation between 30% and 50%, which was measured weekly. Iron was given during re-transfusion as a short infusion, over a period of 15 min, of 1 ampoule (40 mg) diluted in 100 ml NaCl 0.9%. In case of a severe anaemia refractory to Epo, blood transfusions were performed to achieve acceptable haematocrit values. For anticoagulation we used unfractionated heparin. The Kt/V corrected for double-pool urea kinetics (Kt/Vdp) was repeatedly calculated in all patients throughout their pregnancies [9]. We collected the last blood sample directly after haemodiafiltration. We closely monitored all dialysis sessions, with blood pressure measured every 15 min to avoid hypotensive periods. For better cardiovascular stability, blood flow was gradually increased during the first 15 min of haemodiafiltration to the highest blood flow rate that could be achieved safely. To provide adequate nutrition for mother and fetus, we encouraged a high-protein diet with more than 100 g of protein and 3000 kcal/day. No dietary or fluid restrictions were imposed on our patients. Additionally, trace elements (Inzolen infantibus®, 1 ampoule containing 2.5 mmol magnesium, 0.015 mmol zinc, 0.015 mmol copper, 0.005 mmol manganese, 0.0015 mmol chromium), vitamin B12 (Cytobion®, 1 ampoule containing 1000 µg cyanocobalamin), and folate (Folat-Injektopas®, 1 ampoule containing 5 mg folate) were administered intravenously to keep their values within their specific normal ranges. Vitamin B12 and folate were adjusted to keep mean corpuscular volume within the normal range. Vitamin B-complex (Polybion N®, 1 ampoule containing 10 mg Thiamin, 4 mg Riboflavin, 40 mg Nicotinamid, 6 mg Dexpanthenol, 0.5 mg Biotin and 4 mg Pyridoxin) was routinely given to compensate for the loss of water-soluble subtypes of vitamin B. The estimated maternal dry weight was increased by 200–400 g every 10 days if judged appropriate based on the mother's clinical condition, blood pressure and hydramnios.

Protocol of gynaecological and obstetric management
All patients were also followed by the Department of Gynaecology and Obstetrics. The first ultrasound, before and after dialysis was performed immediately after pregnancy was diagnosed. Thereafter, fetal ultrasonography was performed every 10 days, even during a stable uneventful pregnancy, or more frequently if clinically indicated. The following parameters were measured: fetal biometry; estimated fetal weight; Doppler velocity indices of uterine umbilical and medial cerebral arteries; signs of fetal stress such as gut distension. Moreover, the extent of hydramnios and cervical length, to calculate the risk of preterm labor, were determined regularly. Cardiotocography (CTG) was performed on admission and at regular intervals, if necessary daily, after the 25th week of gestation. CTG was evaluated as an indicator of fetal cardiac activity and labor activity of the mother. Tocolysis, if necessary, comprised betamimetics (fenoterol 4 µg/h IV) and magnesium (1–3 mmol/h IV). Fetal lung maturity was induced as clinically indicated, with two 24-mg doses of dexamethasone (Celestan®).



   Results
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 Conclusions
 References
 
Between 2000 and 2004 we treated five consecutive pregnant dialysis patients in our hospital (Tables 1–4GoGoGo). Here, we report the detailed treatment and dialysis protocol used during those pregnancies. All patients were treated in outpatient dialysis units prior to admission to our centre. The mean age at the conception was 28±6.6 years. One patient had conceived before starting dialysis, while the pregnancies of four were established while they were on regular dialysis. At the time of conception, those patients had been on dialysis for 37.5±20.4 months (Table 1). Two patients showed well-preserved diuresis throughout their pregnancies, whereas two patients were, and one patient became anuric during their pregnancies. Cervical insufficiency and pre-term labour were the most frequent reasons for hospitalization. In four of the five patients, pregnancy was diagnosed late, after a mean of 17.8±5.2 weeks (Table 1). The hospital stays throughout the pregnancy amounted to 85±61 days for the mothers. All patients received haemodiafiltration at least 6 times/week for an average of 4.6±0.9 h/session, totalling 28.6±6.3 h/week (Table 2). The average maternal weight gain was 282±193 g/week (Table 2). Intradialysis blood flow reached an average of 270±16 ml/min. Using this protocol, we achieved a mean weekly Kt/Vdp of 9.6±1.4 and urea reduction rates of 54.8±29.4%. As a consequence, interdialytic urea levels decreased from 94±49 mg/dl to 36±14 mg/dl at the end of pregnancy (Table 3), and serum creatinine dropped from 5.3±1.6 mg/dl to 2.8±1.1 mg/dl. The mean dose of Epo prior to admission was 169±94 IU/kg/week, and it was increased during the course of the pregnancy to 314±111 IU/kg/week (Table 2). Haemoglobin levels increased from 8.9±1.9 g/dl at the beginning of our intensified treatment to 10.7±0.5 g/dl; haematocrit values increased from 27±3.8% to 33.2±1.9% (Table 3). The reticulocyte count at the beginning was 2.2±0.5; shortly prior to delivery it was 3.9±1.3. Anaemia refractory to Epo necessitated the administration of two units of red blood cells in one patient. This led to acceptable haemoglobin levels, which did not again drop below 9 mg/dl. During pregnancy, iron was given intravenously at a dosage of 1.3±0.9 mg/kg/week, which increased transferrin saturation from 16±3.4% to 32±2.5%. Using our intensified haemodiafiltration protocol, phosphate levels decreased from 1.9±0.5 mmol/l to 1.3±0.2 mmol/l (Table 3). Before admission, two patients were on a phosphate binding medication, both on 3 g of calcium acetate per week. We were able to reduce this medication in both patients to 1.5 g/week. In the first patient we even had to replace phosphate, 100 mmol/week, to correct the phosphate loss due to intensified haemodiafiltration. Calcium levels were kept stable in a physiologic range at an average of 2.38±0.19 mmol/l; pH too did not change remarkably between start, 7.43±0.07, and end, 7.41±0.02. Intact parathormone (88±78 ng/l) did not exceed 200 ng/l throughout the pregnancies of all patients. Under the encouraged high-protein intake diet we observed a slight increase of plasma albumin from 3.0±0.4 g/dl to 3.24±0.3 g/dl (Table 3). On average, 3 to 4 ampoules of trace elements, 10 mg folate, 500 µg vitamin B12, and 4 ampoules of vitamin B-complex were given intravenously per patient per week. Folate and vitamin B12 levels of all patients were kept within their physiologic ranges, between 2.8 and 13.5 µg/l and from 199 to 730 ng/l, respectively, throughout the pregnancies. Two patients only needed oral administration of vitamin D (1,25 OH) to keep their vitamin D levels within physiologic levels ranging from 70 to 150 µmol/l. The mean gestational age at delivery was 32.8±3.3 weeks and mean birth weight at delivery was 1765±554 g. Out of five newborns, four were delivered by caesarean section and developed respiratory distress syndrome requiring CPAP and, in one case, mechanical ventilation. The length of hospital stay amounted to 26±18 days for the newborns, and all were discharged healthy (Table 4).


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Table 1. Characteristics of patients and pregnancy

 

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Table 2. Characteristics of intensified haemodiafiltration

 

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Table 3. Important laboratory data during pregnancy on intensified haemodiafiltration

 

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Table 4. Characteristics of neonates

 


   Discussion
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 Conclusions
 References
 
To date, only retrospective evaluations from registries and a few case reports or reports on small series of cases touch on the management of pregnant women on dialysis. Most published reports hint at better pregnancy outcomes in haemodialysis patients undergoing intensified dialysis regimens. Still, only 40–85% of pregnancies in women on dialysis result in a surviving infant [5]. This may be related to an increased incidence of preterm labour and frequently observed polyhydramnios. Additionally, the mother is at risk of anaemia and worsening hypertension.

However, existing reports do not propose a systematic treatment approach. Here, we report on the pregnancies of five women on haemodiafiltration that ended with a success rate of 100% live births. According to previously published guidelines and recommendations [1,7], we developed an intensified dialysis protocol—including close gynaecological observation, which was prospectively applied to all five pregnant dialysis patients. Haemodiafiltration (HDF) was chosen to further increase the effectiveness and safety of the dialysis prescription, for even in critically ill patients daily haemodiafiltration enjoys excellent cardiovascular tolerance [10]. All five pregnant dialysis patients tolerated HDF very well; episodes of hypotension were very rare and brief. As evidenced by our laboratory results, HDF helped to substantially improve the elimination of larger solutes, such as phosphate, while preserving a high clearance for small solutes, such as urea and creatinine.

Moreover, compared with protocols previously published, ours prescribed one of the highest dialysis doses in a standardized haemodiafiltration protocol. Our weekly Kt/Vdp amounted to 9.6—other centres using intensified dialysis have reported a Kt/V of 8.9 [11], or 5.3 [7] in single patients. This result was mainly achieved by increasing the weekly dialysis frequency, and may have contributed to the favourable clinical outcome of our patients (an effect seen also in regular patients on daily haemodialysis) [12,13]. No data on the use of equilibrated Kt/Vdp to estimate the quality of longer dialysis sessions during pregnancy are available. This may be related to the undue discomfort caused by the additional postdialytic blood samples necessary for that calculation. Thus, the amount of postdialytic urea rebound after prolonged dialysis sessions in these pregnant patients is unknown. We used double-pool Kt/Vdp in an attempt to prevent an overestimation of Kt/Vdp.

By maintaining a lower targeted ultrafiltration per treatment, daily dialysis allows better fluid management—with less hypotension, decreased fluid restrictions and decreased interdialytic weight gains [7,8,12]. It also allows maintaining stable arterial blood pressures with a reduction of antihypertensive medications [13]. Thus, episodes of compromised fetoplacental blood flows can largely be reduced. These improvements are hypothetically attributable to less extreme fluctuations of solutes and fluid and may help to minimize shifts in maternal intravascular volume. Nevertheless, significant fluid shifts, electrolyte imbalances and hypotension influence the amniotic fluid pool during haemodialysis, which emphasizes the need for close fetal surveillance. Regular fetal ultrasound examinations helped to set ultrafiltration goals for each session as well as determine the optimal timing of semi-elective deliveries in these high-risk pregnancies. Increasing dialysis dosage reduces predialysis BUN levels; and intensified ultrafiltration may reduce the occurrence of polyhydramnios, and thus lower the risk of premature labour and rupture of membranes in the later stages of pregnancy. This is particularly important as this subgroup of patients has a high or even higher risk of prematurity than any other group. More frequent and intense dialysis treatments also allow a higher protein intake (approximately 1.5 g/kg/day), which is important for both the pregnant women and the unborn child. All our pregnant women enjoyed the liberal intake of fluid and food, and we observed reasonable weight gains, improvements of the albumin levels as well as very well controlled predialysis BUN levels.

Using an intensified dialysis regimen that goal can be achieved much easier. However, the intensified haemodiafiltration protocol must be adjusted to avoid hazardous effects, such as as alkalosis [8], hypokalaemia, and hypo- or hyper-calcaemia. So, we used a reduced-bicarbonate dialysate and individually adjusted its potassium and calcium content. Frequent monitoring of magnesium levels in patients on magnesium-containing tocolytic IV drips must be strongly advised to avoid hypermagnaesemia—seen in one of our patients after infusion of 2 mmol/h magnesium over 48 h. Replacement of water-soluble vitamins and trace elements should also be continued during the pregnancy of women on dialysis [8]. We adopted an extensive regimen for vitamin and Epo therapy. Folate supplementation is required, particularly early in fetal neural development. The average Epo dosage of 314 IU/kg/week we used was higher than of previous studies or case reports that also used high Epo doses [14]. It has been suggested that pregnancy-induced increased vascular volume, with subsequent haemodilution [7] and possibly Epo resistance due to enhanced cytokine production, which also occurs during high-risk pregnancies, may contribute to increased Epo requirements in pregnancy. Respecting our patients’ need for higher Epo doses, we achieved haemoglobin levels recently recommended for pregnant dialysis patients [15]. Using high Epo doses in combination with intravenous iron supplementation and a high dialysis dose, we had to transfuse only two units of blood in one of the five patients, which helped us avoid the undesirable effects of transfusions in pregnancy.

In order to increase the chances for favourable outcome for the mother and the child, pregnant women on dialysis should be followed and treated in a specialized centre that can provide expert nephrologic, obstetric and gynaecologic services from the moment that the pregnancy is detected. The threshold for hospital admission was very low in our centre; and in retrospect we believe that the close monitoring was extremely important for some of our patients. It allowed better control of cervix cerclage and tocolysis, and most importantly, making an early decision for planned delivery by Caesarean section, which may have contributed to the favourable outcomes of all five pregnancies in our centre. In the era of short hospital stays, driven by hospital administrators, we feel strongly that the hospitalizations not only provided the basis for the close surveillance of our patients and facilitated the intense dialysis regimen, but also allowed additional bed rest for the pregnant women, another potentially under-recognized factor in the care of these patients.

At this stage we believe that outcomes of pregnant dialysis patients can be improved using an intensified haemodiafiltration protocol. Whether such a protocol will lead to a higher rate of conception in dialysis patients is unknown. However, the best option for young female patients with end stage renal disease who want to become pregnant may still be a successful renal transplantation. A major advantage of the latter approach would be, at least, the higher rate of fertility and possibly better outcomes, compared with those of dialysis patients.



   Conclusions
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 Conclusions
 References
 
This is one of the world's largest prospective case series of patients on maintenance dialysis during pregnancy, and clearly with the best outcomes. For the first time, a standardized haemodiafiltration and supplementation protocol was prescribed to all of the patients. We presume that the high quality of blood purification, effective Epo treatment and generous supplementation of vitamins and trace elements, as well as close prenatal/obstetric monitoring and management for the optimal timing of delivery, may have contributed to this success. These modified management guidelines led to favourable outcomes in all our patients, and may help to guide therapy in other pregnant dialysis patients. We hope to have provided a reasonable basis for a multicentric approach on this extremely important issue for a small minority of dialysis patients.



   Acknowledgments
 
We thank our dialysis team for their compassionate technical assistance.

Conflict of interest statement. None declared.



   References
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 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 Conclusions
 References
 

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Received for publication: 11. 5.05
Accepted in revised form: 5. 7.05





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