Dialysis and pregnancy: no longer the impossible Free

Pregnancy in women with renal disease provokes anxiety in nephrologists and obstetricians alike. Chronic kidney disease (CKD) is associated with some of the highest rates of adverse maternal and neonatal outcomes compared with other pre-existing medical conditions in women of childbearing age. Women with advanced CKD also are at risk of disease progression, hastening the requirement for renal replacement therapy, shortening their life expectancy and potentially restricting their ability to care for their children, who may have complex health needs secondary to prematurity. Thus, many women with advanced CKD have been advised strongly not to conceive [1] or to wait for a kidney transplant before contemplating pregnancy.

Following the first live birth reported in a woman receiving haemodialysis in 1971 [2], the number of successful pregnancy outcomes in women with end-stage renal disease (ESRD) has been increasing, and a recent exponential rise in reported pregnancies is highlighted by Piccoli et al. in this issue of NDT [3]. Ninety pregnancies in women receiving haemodialysis were identified between 2000 and 2008 [4], and in the following 6 years an additional 464 pregnancies have been reported, representing an approximately 7-fold rise. Whilst reporting bias may be partially contributory, these findings are likely to reflect several changes in clinical practice.

First, there have been substantial improvements in pregnancy outcomes for women receiving dialysis during the last two decades. For example, infant survival in pregnancies of women already established on haemodialysis from US registry data was only 40.2% in 1992–1995 [5], compared with a 100% live birth rate in a small case series of women receiving nocturnal haemodialysis in 2008 [6]. Urea was historically used to perform fetocide, and prior to widespread use of haemodialysis, fetal death occurred if maternal urea was greater than 21.4 µmol/L [7]. Several authors have now described a relationship between pre-dialysis urea and fetal outcomes [8, 9]. In 2004, Hou was first to demonstrate a significant improvement in live births between women established on haemodialysis receiving less than and greater than 20 h of dialysis per week during pregnancy [10]. Thus, over the last decade, augmentation of dialysis hours during pregnancy has become standard practice.

Evidence for further intensification of dialysis in pregnancy has recently been provided by a single Canadian centre, promoted by an increase in pregnancy incidence associated with enhanced provision of nocturnal haemodialysis. The number of dialysis hours was extended (mean 43 ± 6 h per week) in 19 pregnancies [11] and comparison with a historic cohort of 70 pregnancies (mean 17 ± 5 h per week) from the USA confirmed an association between increased dialysis hours and a higher proportion of live births, reduced preterm delivery and improved birthweight.

Other single-centre studies have supported the hypothesis of intensive dialysis leading to prolongation of gestation, but small numbers have prohibited robust analysis of this effect. Piccoli et al. report a well-conducted systematic review and meta-analysis of maternal and neonatal outcomes of 574 pregnancies in 543 women with ESRD with exclusion of duplicates and partial duplicated studies, although a formal assessment of publication bias was not performed. Studies of pregnancies in women established on dialysis prior to conception or commencing dialysis before 20 weeks' gestation published after 2000 were included with appropriate independent analysis of cohort studies and case reports [3]. Heterogeneity of reporting between studies precluded assessment of residual renal function, parity, age and maternal disease. However, overall the live birth rate was 82% and meta-regression demonstrated a significant relationship between number of hours of dialysis and rate of preterm delivery before 37 weeks' and small for gestational age infants (<10th centile), supporting the role of intensive dialysis in pregnancy.

Second, advances in neonatal care, e.g. exogenous surfactant and neurocritical care units, have led to improved outcomes of preterm infants [12] and are likely to have contributed to better neonatal survival and reduced number of terminations in women with ESRD in recent decades [13]. The severity and nature of neonatal morbidity reported by Piccoli et al. reflected preterm delivery with no increased risk of congenital abnormalities. One of the limitations of the systematic review performed by Piccoli et al. was the lack of chronological assessment of perinatal mortality, which was prohibited by the absence of individual data. Some pregnancies included in the meta-analysis occurred several decades ago, and it is probable that perinatal mortality is even lower for the infants of women on haemodialysis with current antenatal and neonatal care, but prospective data are needed.

Third, qualitative research has revealed that many women are traumatized by their clinician warning them against pregnancy and feel a devastating loss about being denied motherhood [14, 15]. Recognition of the consequences of didactic pre-pregnancy counselling and a more supportive shared decision-making culture regarding conception for women with advanced CKD [4] will further augment the number of pregnancies in women with ESRD. Finally, reproductive technologies can now overcome the burden of infertility in women with CKD [16–18], enabling pregnancies in women that were previously impossible.

Another substantial achievement by Piccoli et al. was to provide a direct comparison of pregnancy outcomes from case reports between women receiving peritoneal dialysis (PD) and haemodialysis. Women receiving PD during pregnancy were more likely to deliver small for gestation infants than those receiving haemodialysis (31.0 versus 66.7%, respectively), but there were no differences in proportion of infants delivered preterm or live birth rates. Inadequate reporting prohibited assessment of the effect of PD regimes on pregnancy outcomes, and it is not possible to equate dialysis dose provided between modalities; however, these data suggest that haemodialysis supports better placental function than PD, despite presumed greater fluctuations in blood pressure.

An attempt was made to quantify maternal mortality, which the authors reported to be low (0.4%), although compared with the general population (e.g. UK maternal mortality 9 per 100 000 births, 2011–3) the rate of maternal death in women receiving dialysis is alarming (4000 per 100 000 births) and emphasizes the high-risk nature of pregnancy in women with ESRD. However, Piccoli et al. were unable to address longer-term maternal outcomes (e.g. will the woman be alive when her child starts school), which are relevant for comprehensive pre-pregnancy counselling, due to inadequate reporting of follow-up, nor was it possible to determine whether hypertensive complications during pregnancy accelerate pre-existing cardiovascular disease in this high-risk group.

Several questions regarding optimum management of pregnant women with severe renal impairment remain. Piccoli et al. excluded pregnancies in women who commenced dialysis after 20 weeks' gestation, hence thresholds for starting haemodialysis during pregnancy and how to adjust dose according to residual renal function remain undetermined. Jesudason et al. described better pregnancy outcomes in women starting dialysis during pregnancy compared with those established on dialysis prior to conception [19]; however, this benefit was not observed by Hladunewich et al. following intensive dialysis [11] and a further prospective study of targets for urea and other renal parameters (e.g. haemoglobin and phosphate) for optimum pregnancy outcomes is needed.

Similarly, the timing of increments in dialysis dose in pregnancy is unknown. Optimization of the maternal milieu during placental development early in pregnancy seems logical but is offset by potential loss of remaining kidney function. Other adverse consequences reported in women with increments in dialysis dose during pregnancy include reactivation of previously quiescent lupus [20] and cervical shortening in women [11], and the relationship between dialysis dose and these events, and their underlying mechanisms, remain unclear.

Pre-eclampsia is estimated to affect up to 75% of women on haemodialysis [21]. However, confirmation in women with pre-existing anuria, proteinuria or hypertension is challenging. Case reports describe exclusion of pre-eclampsia in women on haemodialysis through monitoring anti-angiogenic factor concentrations (soluble fms-like tyrosine kinase-1, endoglin) [22, 23], and a recent study demonstrated high-diagnostic performance of low placental growth factor for diagnosis of superimposed pre-eclampsia in women with CKD [24]. Thus, serial assessment of placental biomarkers in women with ESRD may prevent unnecessary preterm iatrogenic delivery but requires confirmation in a larger cohort.

Another consideration for women with severe renal impairment contemplating pregnancy is the development of HLA antibodies, which are identifiable in nearly a third of women after delivery [25], contributing to disproportionate representation of women on transplant waiting lists. Encouragingly only 3/46 (5.9%) women with renal transplants developed de novo donor-specific antibody after pregnancy, which may reflect antenatal immunosuppression use [26]; however, other methods to prevent sensitization in women who are not immunosuppressed remain unknown.

The systematic review and meta-analysis by Piccoli et al. provide further support for the role of augmentation of dialysis during pregnancy to enhance neonatal outcomes and, for the first time, provide evidence for haemodialysis as the modality of choice in pregnancy. These findings are welcomed in the light of an anticipated rise in the number of women with ESRD contemplating pregnancy due to cultural changes in delaying childbearing, longer waiting times for allografts and advances in assisted conception, together with a more supportive approach for the desire to have children in women with CKD by health professionals.

CONFLICT OF INTEREST STATEMENT

None declared.

(See related article by Piccoli et al. Pregnancy in dialysis patients in the new millennium: a systematic review and meta-regression analysis correlating dialysis schedules and pregnancy outcomes. Nephrol Dial Transplant 2016; 31: 1915–1934)

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