Nephrol Dial Transplant (2012) 27 (Supple 3): iii111–iii118
doi: 10.1093/ndt/gfs302
Advance Access publication 6 July 2012
Original Article
Pregnancy in CKD: whom should we follow and why?
Giorgina Barbara Piccoli1,2, Federica Fassio2, Rossella Attini2, Silvia Parisi2, Marilisa Biolcati2,
Martina Ferraresi1, Arianna Pagano2, Germana Daidola1, Maria Chiara Deagostini1, Piero Gaglioti2
and Tullia Todros2
1
2
SS Nefrologia Department of Clinical and Biological Sciences, ASOU San Luigi Gonzaga, University of Torino, Italy, and
Materno-Fetal Unit, Department of Obstetrics, ASOU OIRM S Anna, University of Torino, Italy
Correspondence and offprint requests to: Giorgina Barbara Piccoli; E-mail: [email protected], [email protected]
Abstract
Background. Chronic kidney disease (CKD) has a high
prevalence in pregnancy. In a period of cost constraints,
there is the need for identification of the risk pattern and
for follow-up.
Methods. Patients were staged according to K-DOQI
guidelines. The analysis was prospective, January 2000–
June 2011. Two hundred and forty-nine pregnancies were
observed in 225 CKD patients; 176 singleton deliveries
were recorded. The largest group encompasses stage 1
CKD patients, with normal renal function, in which 127
singleton deliveries were recorded. No hard outcomes occurred (death; dialysis); therefore, surrogate outcomes
were analysed [caesarean section, prematurity, need for
neonatal intensive care unit (NICU)]. Stage 1 patients
were compared with normal controls (267 low-risk pregnancies followed in the same setting) and with patients
with CKD stages 2–4 (49 singleton deliveries); two referral patterns were also analysed (known diagnoses; new
diagnoses).
Results. The risk for adverse pregnancy rises significantly in stage 1 CKD, when compared with controls:
odds ratios were caesarean section 2.73 (1.72–4.33);
preterm delivery 8.50 (4.11–17.57); NICU 16.10 (4.42–
58.66). The risks rise in later stages. There is a high
prevalence of new CKD diagnosis (overall: 38.6%; stage
1: 43.3%); no significant outcome difference was found
across the referral patterns. Hypertension and proteinuria
are confirmed as independent risk factors.
Conclusions. CKD is a risk factor in pregnancy; all
patients should be followed within dedicated programmes
from stage 1. There is need for dedicated interventions
and educational programmes for maximizing the diagnostic and therapeutic potentials in early CKD stages.
Keywords: caesarean section; CKD; glomerular filtration rate;
pregnancy; preterm delivery
Introduction
Chronic kidney disease (CKD) is a growing and often undiagnosed health care problem; its full dimension has
only recently been acknowledged because of its wider
definition and the frequent lack of symptoms [1]. The redefinition of CKD focuses attention on the earlier, usually
asymptomatic, stages of the disease [2]. The CKD staging
and definition system is undergoing extensive criticism, in
particular in the elderly, due to the risk of over-diagnosis
of CKD [3]. However, in younger individuals, the risks of
over-diagnosis of CKD are counterbalanced by the advantages of early interventions. According to the present
broad disease definitions, it has been calculated that the
prevalence of CKD may reach 3% in women of childbearing age [4, 5]. However, the prevalence of CKD is still
often underappreciated in pregnancy, few settings offer an
integrated nephrological and obstetric follow-up and a
systematic approach to the early diagnosis of CKD is not
yet part of the routine follow-up of pregnant women.
There are at least two reasons that may impair an early
diagnosis of CKD in pregnancy: the physiological increase in the renal clearances from the early stages of
pregnancy and the clinical and laboratory overlap with
pre-eclampsia (PE). In fact, PE shares the presence of
proteinuria and hypertension with several forms of CKD
[6, 7]. Conversely, the relationship between PE and CKD
is far from being completely known [8].
CKD is a relevant outcome modifier in pregnancy.
Even though the outcome has improved over the last
decades, recent studies, including a previous one from our
group, show increased materno-fetal morbidity starting
from the first CKD stages [9–18]. Overall, the risk of
negative materno-fetal outcomes is inversely related to
renal function and is increased in the presence of baseline
proteinuria and hypertension and in systemic diseases
[19–22].
© The Author 2012. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
For Permissions, please e-mail: [email protected]
iii112
The wider recognition of the impact of early-stage
CKD on pregnancy outcomes could have a strong organizational and economic impact on the health care system,
requiring integrated teams and dedicated structures, a difficult task at a time of substantial cost constraints.
Therefore, the present study was aimed at analysing the
outcomes of pregnancy in a large cohort of women referred to a tertiary care setting for the presence of CKD,
with particular attention to the cases with normal renal
function. As the great heterogeneity of kidney diseases
did not allow stratification according to the different diagnoses, the patients were stratified according to the CKD
stage and, for the largest subset of CKD stage 1, according to referral pattern, dividing the patients into two main
categories: ‘know diagnoses’ and ‘new diagnoses’.
The availability of both a ‘low-risk’ group and a of
patients in more advanced CKD stages allows definition
of the risks and contextualization of the results, facilitating comparison with data reported in other settings, more
often regarding the late CKD stages [10–12, 14–19].
The study may add information for the planning of interventions aimed at improving pregnancy-related outcomes in CKD women.
Materials and methods
Study setting and inclusion criteria
The study was conducted in the Maternoetal Medicine Unit of Sant’Anna University Hospital (150 beds for obstetric patients) in Turin, Italy
[9]. From 2000, all patients referred with kidney disease were followed
by the same obstetric and nephrological team (from 2002 in a dedicated
outpatient unit). Main baseline and outcome data were gathered prospectively from the start of the activity. The patients were referred from
different nephrology units and regional prenatal care centres and, since
2007, from general physicians.
PE and Hemolysis, Elevated Liver enzymes, Low Platelet (HELLP)
syndrome are routinely managed by the obstetricians of the MaternoFetal Unit. They are not referred to our unit unless there is the need for
differential diagnosis with CKD; these were identified as ‘other/PE’, and
not included in the present series.
Patient and control population
In total, 249 pregnancies were observed in 225 women with CKD
(1 January 2000–30 June 2011): 18 women had 2 pregnancies; 3 women
had 3 pregnancies. Referrals to the unit increased since the reorganization in 2009, and possibly as an effect of the publication of our previous results regarding 120 pregnancies and 91 singleton deliveries in
the period January 2000–May 2009 [9] (Figure 1).
The study included all patients referred to the Outpatient Unit or admitted to the Obstetrics Ward who had a diagnosis of CKD before or
during pregnancy. In the present study, each pregnancy was considered a
separate ‘case’. The patients lost to follow-up (three cases), ongoing
pregnancies (27 singletons, 1 twin pregnancy), twin deliveries [13], miscarriages [17] and pregnancy terminations [12] were excluded, thus
leaving 176 singleton deliveries for the statistical analysis.
The historical control group of ‘low-risk pregnancies’ gathered in
1999–2007 was employed for comparison. The control group consisted
of a cohort of 297 singleton low-risk pregnancies cared for in the same
Materno-Fetal Unit, as described elsewhere [9]. The type of care was felt
to be more important than a precise age and ethnicity match; therefore,
all patients were included and the differences for age and ethnicity (singleton delivery: 29 versus 30 years and 77 versus 87% non-Caucasians)
were not considered as clinically relevant [9].
The following data were considered in all patients: age, parity, race,
week of the first visit, educational level, body mass index (BMI),
number of admissions, gestational age at delivery, type of delivery, clinical complications in the mother, fetal weight, Apgar index, sex, admission to Intensive Care Unite, outcome; for the pathological pregnancies,
G.B. Piccoli et al.
CKD stage, serum creatinine, proteinuria, kidney disease, previous
follow-up, referral to the unit were recorded.
Definitions employed
GFR measurement. CKD was classified according to K-DOQI guidelines [2, 4]. The most widely used formulae (Cockcroft and Gault,
MDRD and Epidemiology Collaboration (EPI)) have important limits or
are not validated in pregnancy; thus, glomerular filtration rate (GFR) calculation was based on preconception data, when available within 3
months prior to conception
[23–25]. When the preconception data were not available, data at first
control in pregnancy were used, possibly leading to underestimation of
the severity of kidney disease due to the physiological decrease of serum
creatinine during pregnancy [2, 4, 23–25]. The Cockcroft and Gault
formula was chosen because of the adjustment for weight, partially accounting for underweight or obesity, both of which are represented in
our population. We also applied the MDRD and EPI formulae, controlling for cases that would have been classified otherwise. After referral,
creatinine clearance calculated on 24-h urine collection was considered as
approximating GFR. Proteinuria was assessed on 24-h urine collection.
Diagnostic categories. The patients were stratified into two main diagnostic referral categories: patients in whom the diagnosis of CKD was
known and identified as a risk factor for pregnancy (known diagnoses);
patients in whom the diagnosis of CKD was either made in pregnancy or
in whom the diagnosis of CKD was known but not identified as a risk
factor for pregnancy (new diagnoses). The patients with known diagnoses are referred by nephrology teams, and the new ones are by definition first seen by a nephrologist during pregnancy, and are usually
referred by the obstetrical teams.
Obstetric definitions. Hypertension was defined as systolic blood
pressure ≥140 and/or diastolic blood pressure ≥90, or anti-hypertensive
therapy; patients on anti-hypertensive therapy prior to conception were
included even when anti-hypertensive therapy was discontinued in
pregnancy.
PE was strictly defined as hypertension accompanied by proteinuria
≥300 mg/24 h after 20 weeks of gestational age in a previously normotensive, non-proteinuric woman, in the absence of other signs or symptoms indicating a different nephrological diagnosis; the presence of
Doppler flow alterations was considered to support a PE diagnosis [26].
This diagnosis applied only to women who were normotensive and nonproteinuric at referral and during the first 20 gestational weeks (for
example, affected by a glomerulonephritis (GN) in full remission, or by
pyelonephritic kidney scars); since the definition of ‘superimposed PE’
(that is PE superimposed either on hypertension or on proteinuria
already present at baseline) is not unequivocal and the overlap with
CKD is higher, we did not employ it in this study.
A newborn was defined as small for gestational age (SGA) when the
birthweight was below the 10th centile according to Italian birthweight
references [27, 28]. Preterm delivery was defined as delivery before 37
completed weeks of gestational age; a further analysis was performed for
‘early’ preterm deliveries, defined as deliveries before 34 completed
weeks [29].
Prenatal and intrapartum care. Prenatal and intrapartum care of lowrisk pregnancies followed the current guidelines [9, 27, 30]. The frequency of nephrological and obstetric control visits for CKD patients
was individualized (weekly-monthly).
On each clinical consultation, the blood pressure was measured at
least once and weight was recorded; fetal growth was controlled by serial
measurements of symphysis fundus height. Ultrasound biometry and
Doppler study of uterine and umbilical arteries were individualized. In
patients at risk for proteinuria and urinary infections, urinalysis and urine
cultures were performed weekly or every two weeks. In pyelonephritis,
stone disease, reflux nephropathy and other malformations, ultrasounds
of the mother’s kidneys were scheduled every 3 months.
The blood pressure therapeutic goal was ≤130/80. Drugs of choice
were nifedipine or α-methyldopa, the latter preferred in the case of
intense proteinuria or peripheral oedema. Beta blockers or doxazosine
were employed in the case of insufficient response or severe side effects
with the above drugs. All patients were instructed to measure blood
pressure at home (in hypertensive cases, 2–3 measurements/day).
Besides the routine laboratory controls of pregnancy, CKD patients
underwent a monthly measurement of renal function and proteinuria,
Pregnancy, CKD, need for follow-up
iii113
Fig. 1 The flow chart of patients and controls.
urinalysis and urinary culture, serum electrolytes, coagulation and blood
cell counts; other laboratory tests were on demand.
Hospitalization was required in the presence of poorly controlled hypertension, worsening of renal function, proteinuria of new onset or with
rapid worsening, severe upper urinary tract infection and for any other
problem of the mother and/or fetus.
In singletons, the aim was to delay delivery at least until 36 weeks;
indications for early delivery were severe worsening of maternal and/or
fetal conditions until 32 weeks of gestational age or less severe worsening after 32 weeks. In addition to the classic hallmarks of PE or HELLP
syndrome, worsening of the maternal conditions included poorly controlled hypertension, rapidly increasing nephrotic proteinuria, rapid increase in serum creatinine, alone or in combination. Fetal worsening
included abnormal fetal heart rate tracings at any gestational age, absent
end diastolic flow velocities at Doppler study of the umbilical arteries at
or after 32 weeks of gestational age, no fetal growth over two weeks at
later gestational ages. In these cases, betamethasone for induction of
lung maturation was routinely administered at standard doses. Caesarean
section was performed for fetal indications, before or during labour, or
in cases of unfavourable conditions or lack of response to induction. The
main indications for admission to the Neonatal Intensive Care Unit
(NICU) were birthweight <1500 g, gestational age <34 weeks, Apgar
score below 7 at 5′, need for intubation.
Statistical analysis
The data were collected prospectively and periodically entered into the
electronic database; start of observation: referral to the unit; end of observation: 1 month after delivery. Since no maternal or fetal deaths were
observed in the singleton cohort and none of the patients needed dialysis
during pregnancy or in the first month after delivery, we limited our
analysis to the following surrogate outcomes: preterm delivery (<37 and
<34 weeks), SGA baby, admission to the NICU, Caesarean section.
Common parameters were analysed in CKD patients in comparison
with the control group of ‘low-risk pregnancies’; these analyses included
referral to the unit before or after 12 weeks of gestational age; maternal
age, dichotomized at the median; parity ( primiparous versus other); educational level ( primary school versus others); race (Caucasian versus
others).
As for the CKD cohort, the analysis took into account the CKD stage
and referral pattern, the presence of hypertension and the presence and
level of proteinuria (<300 mg/day; 300 mg to <1 g/day; ≥1 g/day).
The following groups were considered as reference: CKD stage 1
versus other stages; known diagnosis versus other diagnostic patterns;
proteinuria <0.3 versus other levels; no hypertension versus hypertension. A descriptive analysis was performed as appropriate (mean and
standard deviation for parametric data; median and range for nonparametric data). Paired t-test, chi-square test, Fisher’s test, Kruskal–
Wallis test, Mann–Whitney U-test, ANOVA and t-test with Bonferroni
were used for comparisons between cases and controls and among groups.
Significance was set at <0.05. Multivariate logistic regression analysis was
used to control for simultaneous effects of covariates. Adjusted odds ratio
(OR) and 95% confidence intervals were derived from the estimated
regression coefficients. Statistical analyses were performed with SPSS
vers18.0 for Windows (SPSS, Chicago, IL, USA) [31].
Results
Baseline data
The baseline data are reported in Table 1 for all patients
and for singleton deliveries, in order to control for attrition biases. No significant difference was found,
suggesting no or irrelevant attrition bias.
The largest subset of the study population is represented by patients with normal renal function: 127 singleton deliveries in stage 1 CKD patients.
No significant demographic baseline difference was
found across CKD stages; as expected by definition, the
prevalence of hypertension, proteinuria and median creatinine and GFR levels are different (Table 2). The lower
prevalence of the late CKD stages reflects the distribution
of CKD stages in the overall population in a setting of
systematic recruitment of CKD patients. No case on dialysis was referred.
Overall, 19 miscarriages and 13 pregnancy terminations
were recorded. Two patients terminated pregnancy by
their own volition; in two cases, the decision reflected
both a high clinical risk and personal preferences (nephrotic syndrome, later diagnosed as membranous nephropathy, and stage 4 CKD patient, both without family
support). Pregnancy termination was decided for clinical
reasons in eight cases: fetal malformations (four cases),
severe early PE (three cases, who were by definition
neither hypertensive nor proteinuric during the first gestational weeks), while in one case, worsening of renal function played a role, supporting the choice to terminate
pregnancy in the setting of severe intrauterine growth restriction and severe pregnancy-induced hypertension.
Differences between cases and controls: all cases versus all controls: age (P = 0.000); Caucasian race (P = 0.002); educational level (P = 0.001); only cases who delivered a singleton: age (P = 0.003); Caucasian
race (P = 0.006); educational level (P = 0.001).
GN, glomerulonephritis; BMI, body mass index.
a
Three cases were lost to follow-up (not staged).
Statistical analysis:
*Student t-test.
**Chi-square test.
°Mann-Whitney test.
23.2 ± 4.5
23.1 ± 4.5
23.4 ± 4.7
23.7 ± 4.8
21.7 ± 4.1
21.4 ± 4.2
22.6 ± 3.08
22.1 ± 2.99
22.5 ± 5.0
20.39 ± 1.79
22.54 ± 3.61
22.51 ± 3.63
62.6
66.3
57.4
58.8
57.7
61.9
80
85.7
60
75
45.4
46
12 (4–38)
13 (4–38)
12 (4–38)
14 (4–38)
9 (5–38)
14 (6–38)
8 (5–33)
8 (5–33)
6 (4–28)
7 (6–28)
12 (4–32)
12 (4–32)
All cases (N = 249)a
Singleton delivery (N = 176)
Stage 1 (N = 175)
Stage 1 singleton delivery (N = 127)
Stage 2 (N = 45)
Stage 2 singleton delivery (N = 28)
Stage 3 (N = 21)
Stage 3 singleton delivery (N = 17)
Stage 4 (N = 5)
Stage 4 singleton delivery (N = 4)
All controls (N = 297)
All controls singleton delivery (N = 267)
31.24 ± 5.74
30.93 ± 5.04
31.4 ± 5.33
30.7 ± 5.2
32.0 ± 7.1
31.4 ± 4.6
33.3 ± 4.48
32.8 ± 4.5
27.4 ± 4.51
28.0 ± 4.97
29.44 ± 5.31
29.41 ± 5.31
59
59.7
58
56.7
62.2
60.7
71.4
76.5
60
75
60.3
61.4
87.6
87.5
88.6
88.2
82.2
85.7
95.2
94.1
40
50
77.4
77.2
BMI
(mean, std)*
Educational
level > 8th grade, %**
Caucasian race, %**
Week of referral
(median, range)°
Nulli-parous, %**
Maternal age, years
(mean, std)*
Table 1. The main characteristics of the overall CKD population referred and of the low-risk controls: comparison between all referred cases and cases who delivered a singleton
GN 45 (18.1%)
GN 32 (18.2%)
GN 29 (16.6%)
GN 21 (16.5%)
GN 11 (24.4%)
GN 7 (25%)
GN 4 (19.1%)
GN 4 (23.5%)
GN 1 (20%)
none
–
–
G.B. Piccoli et al.
GN, %
iii114
Univariate outcome analysis: CKD stage 1 versus
controls and CKD stages 2–4.
Table 3 reports the main materno-fetal outcomes in CKD
patients and in controls; of note, the differences between
CKD stage 1 and controls are significant for all the tested
outcomes except SGA, a parameter influenced by the
policy of delivery in the presence of flattening of the
growth curve; thus, a lower prevalence of SGA may
reflect a policy of early delivery.
The trends across stages suggest a continuous increase
of risk for adverse outcomes in parallel to the decreasing
kidney function. The differences between stage 1 and
stages 2–4 are significant for all the tested outcomes,
except for SGA, even if a trend towards increase in prevalence of SGA is observed; the comparison between stage
1 and stage 2 CKD reaches statistical significance as for
gestational age and birthweight (Table 3).
Table 4 reports the changes in renal function and proteinuria in the different stages, from referral to delivery in a
subset of 127 CKD cases referred before the 20th week of
gestation.
In the large subset of CKD stage 1 cases (89 patients
referred before the 20th gestational week), proteinuria significantly increases, although the data are very scattered,
as shown by the wide ranges and the median value
remains in a ‘normal’ range; creatinine data show a small
increasing trend throughout pregnancy; only one patient
(type 1 diabetic, stage 2 CKD at the start of pregnancy)
doubled serum creatinine during gestation.
PE superimposed on CKD was diagnosed in 6 cases, 3
of which underwent pregnancy termination before the
23rd gestational week; hence, the prevalence is 6/188
(3.2%) considering the 176 singleton deliveries, plus the
12 pregnancy terminations, occurred after the 12th week.
The incidence of PE was 1.1% in our low-risk control
population, in line with the literature data obtained in lowrisk patients, such as kidney transplant donors [9, 32–34].
Univariate analysis: stage 1 CKD patients according to
referral patterns
Table 5 reports the univariate analysis regarding the main
materno-fetal short-term outcomes in the subset of stage 1
CKD patients (127 singleton deliveries), with patients
sorted according to the two main referral patterns (known
and new diagnoses).
In keeping with the results obtained in the overall stage
1 CKD population (Table 3), the differences between
CKD patients and the controls are significant for most of
the tested outcomes in all subsets (SGA being confirmed
as the exception), without significant differences between
known and new diagnoses (Table 5).
Multivariate logistic regression analysis
Table 6 shows the multivariate logistic regression analysis
between CKD stage 1 patients and controls. The analysis
confirms a highly significant effect of being in the CKD
stage 1 cohort for all the tested outcomes. The relative
risk of being affected by stage 1 CKD ranges from
2.73 for caesarean section, to 8.50 for preterm delivery
Pregnancy, CKD, need for follow-up
iii115
Table 2. Main laboratory and clinical data in CKD patients who delivered a singleton
CKD stage 1
(N = 127)
CKD stage 2
(N = 28)
CKD stage 3
(N = 17)
CKD stage 4
(N = 4)
P
9 (33.3%)
0.88 (0.70–1.68)
12 (70.6%)
1.40 (1.23–1.99)
1 (25%)
2.82 (2.0–3.8)
77.6 ± 9.0
50.3 ± 6.3
22.8 ± 3.3
0.11 (0–8.28)
0.13 (0–6.80)
0.63 (0–2.25)
0.56 (0.3–0.65)
P¹ = 0.000; P² = 0.028
P¹ = 0.000; P² = 0.000; P³ = 0.000;
P4 = 0.001; P5 = 0.001; P6 = 0.002
P¹ = 0.000; P³ = 0.000; P4 = 0.000;
P5 = 0.033
P¹ = 0.001; P4 = 0.037
93 (73.2%)
18 (64.3%)
5 (29.4%)
0
Proteinuria >0.3 g ≤1 g/24 h, %
20 (15.8%)
4 (14.3%)
8 (47.1%)
4 (100%)
Proteinuria >1 g/24 h, %
Main diagnoses: GN
Referral pattern: known diagnoses
Referral pattern: new diagnoses
14 (11%)
21 (16.5%)
72 (56.7%)
55 (43.3%)
6 (21.4%)
7 (25%)
19 (67.9%)
9 (32.1%)
4 (23.5%)
4 (23.5%)
14 (82.4%)
3 (17.6%)
0
0
3 (75%)
1 (25%)
Hypertension, %
Creatinine, mg/dL
(median, range)
GFR (mean, std)
28 (22%)
0.60 (0.3–1.10)
139.4 ± 42.6
Proteinuria, g/24 h
(median, range)
Proteinuria ≤0.3 g/24 h, %
P¹ = 0.000; P² = 0.050; P4 = 0.008;
P5 = 0.028
P¹ = 0.002; P² = 0.034; P4 = 0.000;
P5 = 0.002
n.s.
n.s.
n.s.
n.s.
P¹ = stage 1 versus 3; P² = stage 2 versus 3; P³ = stage 1 versus 2; P4 = stage 1 versus 4; P5 = stage 2 versus 4; P6 = stage 3 versus 4.
GFR, glomerular filtration rate.
Table 3. Main materno-fetal outcomes in the study group
Caesarean
section, %
Preterm delivery
< 37 weeks, %
Preterm delivery
< 34 weeks, %
Weeks of gestation
(mean, std)
Birthweight
(mean, std)
SGA, % (<10th
centile)
Need for NICU, %
Controls
(n = 267)
CKD
stage 1
(N = 127)
CKD
stage 2
(N = 28)
CKD
stage 3
(N = 17)
CKD
stage 4
(N = 4)
CKD All
stages
(N = 176)
P stage 1
versus
stage 2
P stage 1
versus
controls
P stage 1
versus
stages 2–4
66 (24.7%)
59 (46.4%)
17 (60.7%)
11 (64.7%)
3 (100%)
90 (51.1%)
n.s.
P = 0.000
P = 0.045
13 (4.9%)
36 (28.3%)
12 (42.9%)
14 (82.4%)
4 (100%)
66 (37.5%)
n.s.
P = 0.000
P = 0.000
4 (1.5%)
13 (10.2%)
5 (17.9%)
7 (41.2%)
2 (50%)
27 (15.3%)
n.s.
P = 0.000
P = 0.002
39.2 ± 1.9
37.3 ± 2.8
36 ± 3.7
34.5 ± 2.3
32 ± 3.2
36.7 ± 3.1
P = 0.038
P = 0.000
P = 0.000
3268.3 ±
500.4
28 (10.5%)
2855.1 ±
694.5
18 (14.2%)
2543.0 ±
782.7
4 (14.3%)
2180.6 ±
572.9
5 (29.4%)
1246.2 ±
397.1
3 (75.0%)
2703.7 ±
755.2
30 (17%)
P = 0.037
P = 0.000
P = 0.000
n.s.
n.s.
n.s.
3 (1.1%)
18 (14.2%)
7 (25%)
8 (47.1%)
4 (100%)
37 (21%)
n.s.
P = 0.000
P = 0.003
Table 4. Variations over time (first versus last control) in 127 cases referred before the 20th gestational week
stage (n)
Proteinuria first
control (median,
range), g/24 h
Proteinuria last
control (median,
range), g/24 h
First versus last
control
(Wilcoxon test)
Creatinine first
control (median,
range) mg/dL
Creatinine last
control (median,
range) mg/dL
First versus last
control
(Wilcoxon test)
CKD stage 1 (89)
CKD stage 2 (19)
CKD stage 3 (16)
CKD stage 4–5 (3)
All stages (127)
0.10 (0–5.21)
0.12 (0–6.80)
0.57 (0–2.25)
0.63 (0.30–0.65)
0.12 (0–6.80)
0.18 (0–9.40)
0.35 (0.10–17.29)
2.64 (0.54–7.90)
2.03 (0.67–2.6)
0.31 (0–17.29)
P = 0.000
P = 0.013
P = 0.000
Ns
P = 0.001
0.62 (0.30–1.10)
0.88 (0.73–1.68)
1.41 (1.23–1.99)
2.74 (2.02–3.80)
0.70 (0.30–3.80)
0.67 (0.36–1.44)
0.86 (0.69–4.98)
1.59 (0.80.2.56)
2.87 (1.73–3.67)
0.73 (0.36–4.98)
P = 0.003
n.s.
n.s.
n.s.
P = 0.000
(<37 completed gestational weeks). There is also a mild
protective effect for Caucasian race and an increase in OR
for prematurity in older women, similar to that observed
in the overall population.
Table 7 reports the risks of later stages of CKD versus
stage 1: the OR for caesarean section is not significant,
while the OR preterm delivery and for the need for NICU
significantly rises in the subsequent CKD stages (2.84 for
preterm delivery and 2.59 for the need for NICU).
Hypertension and proteinuria are confirmed as relevant
risk factors: statistical significance is reached in the first
case for caesarean section and preterm, or early preterm
iii116
G.B. Piccoli et al.
Table 5. Main materno-fetal outcomes in the study group
Caesarean section, %
Preterm delivery < 37 weeks, %
Early preterm delivery < 34 weeks, %
Gestational age (mean, std)
Birthweight, g (mean, std)
SGA, % (<10th centile) (Parazzini)
Need for NICU, %
Controls
(n = 267)
Known diagnosis
(n = 72)
New diagnosis
(n = 55)
All cases
(n = 127)
Statistical significance
66 (24.7%)
13 (4.9%)
4 (1.5%)
39.2 ± 1.91
3268.3 ± 500.4
28 (10.5%)
3 (1.1%)
36 (50.0%)
19 (26.4%)
7 (9.7%)
37.3 ± 2.6
2853.9 ± 669.9
9 (12.5%)
10 (14.1%)
23 (41.8%)
17 (30.9%)
6 (10.9%)
37.2 ± 2.88
2856.6 ± 731.64
9 (16.4%)
8 (14.6%)
60 (41.4%)
38 (26.2%)
14 (9.7%)
37.4 ± 2.7
2915.4 ± 697.1
18 (12.4%)
20 (13.9%)
P¹ = 0.000; P² = 0.009 P³ = n.s.
P¹ = 0.000; P² = 0.000 P³ = n.s.
P¹ = 0.002; P² = 0.001 P³ = n.s.
P¹ = 0.000; P² = 0.000 P³ = n.s.
P¹ = 0.000; P² = 0.000 P³ = n.s.
n.s. in all subsets
P¹ = 0.000; P² = 0.000 P³ = n.s.
Stage 1, CKD patients.
P¹ = known versus controls; P² = new versus controls; P³ = known versus new.
Table 6. Summary data from the multivariate logistic regression analyses, comparing CKD stage 1 cases and controls for the chosen outcomes
Outcomes
Cesarean sections
(N = 125)
Preterm delivery < 37 weeks
(N = 49)
Early preterm delivery
< 34 weeks (N = 17)
Need for NICU
(N = 21)
Stage 1 CKD patients
Maternal age > 30 years
Pluriparous
Caucasian
Referral > 12 weeks
2.73 (1.72–4.33)
1.07 (0.68–1.68)
0.80 (0.51–1.28)
0.99 (0.55–1.78)
0.94 (0.60–1.47)
8.50 (4.11–17.57)
2.49 (1.26–4.90)
0.86 (0.44–1.68)
0.53 (0.23–1.25)
1.03 (0.53–2.0)
7.33 (2.25–23.84)
3.89 (1.20–12.52)
1.04 (0.37–2.90)
0.48 (0.14–1.69)
0.91 (0.32–2.57)
16.10 (4.42–58.66)
2.16 (0.82–5.7)
0.32 (0.10–0.95)
0.38 (0.11–1.24)
1.25 (0.48–3.25)
Odds ratio and 95% confidence interval.
Table 7. Summary data from the multivariate logistic regression analyses, including CKD patients in all stages and both referral patterns, for the
chosen outcomes
Outcomes
Cesarean section
(N = 91)
Preterm delivery < 37 weeks
(N = 66)
Early preterm delivery < 34 weeks
(N = 27)
Need for NICU
(N = 37)
CKD stage 2–3–4
Age > 30 years
Pluriparity
Caucasian
Referral > 12 weeks
Hypertension yes/no
Proteinuria >0.3 ≤1 g
Proteinuria > 1 g
New diagnosis
1.51 (0.71–3.21)
0.95 (0.49–1.85)
0.84 (0.43–1.62)
1.20 (0.41–3.52)
1.34(0.66–2.73)
2.68 (1.20–5.95)
1.73 (0.75–4.02)
2.73 (0.89–8.40)
0.75 (0.35–1.60)
2.84 (1.30–6.20)
1.67 (0.80–3.48)
0.64 (0.30–1.34)
0.41 (0.13–1.27)
1.17 (0.54–2.57)
2.84 (1.26–6.38)
1.85 (0.76–4.50)
2.58 (0.85–7.86)
1.00 (0.43–2.31)
2.02 (0.77–5.30)
1.51 (0.57–3.98)
0.57 (0.21–1.55)
0.68 (0.18–2.52)
1.25 (0.44–3.58)
3.54 (1.31–9.54)
2.06 (0.66–6.41)
2.64 (0.73–9.50)
0.81 (0.25–2.59)
2.59 (1.10–6.06)
1.45 (0.62–3.39)
0.39 (0.16–0.98)
0.55 (0.17–1.81)
1.26 (0.50–3.17)
1.31 (0.52–3.29)
2.20 (0.80–6.01)
4.40 (1.38–14.07)
0.65 (0.23–1.79)
Odds ratio and 95% confidence interval.
delivery (OR: 2.68, 2.84 and 3.54, respectively) and
for the need for NICU in the presence of proteinuria
(OR 4.4).
Discussion
The broader definition of CKD, according to the K-DOQI
guidelines, is leading to the recognition of an increasing
number of cases with early CKD in several settings, including pregnancy [1, 2, 4, 5]. At this time of cost constraints, the recognition of increasing needs may be seen
as an unbearable challenge for the health care system.
In our setting, one of the first Italian outpatient units
dedicated to pregnancy and kidney diseases, referrals
doubled in the last 2 years (in 2000–2009: 120 pregnancies referred, 110 in CKD patients; in 2009–2011: 158 referred, 137 in CKD patients) [9]. This led to a re-analysis
of our population to try to answer the question whether
we should follow all cases and for which specific risks.
One of the characteristics of our cohort is the high prevalence of CKD patients with normal renal function (127
singleton deliveries in CKD stage 1 patients). From a
health care point of view, this is an interesting cohort,
both because the prevalence of CKD stage 1 was calculated as high as 3% of pregnancies, and because stage 1
CKD patients were less studied as for pregnancy outcomes, particularly in the past when CKD was considered
synonymous with decreased kidney function or severe
proteinuria [4, 35, 36].
Thus, the analysis was focussed on CKD stage 1
patients, both in comparison with a cohort of 267 lowrisk pregnancies and with 49 patients in later CKD stages,
followed in the same setting.
In an attempt to identify specific subsets of patients,
on whom tailoring dedicated interventions, the stage 1
Pregnancy, CKD, need for follow-up
patients were also stratified according to referral for
known or new CKD diagnosis.
The main results of our study can be summarized in
two main points:
The first one is in regard to the overall cohort of CKD
stage 1 patients. The present study confirms on a larger
scale the previous experience of our group, further supporting that stage 1 CKD patients are at increased risk for
adverse pregnancy outcomes, with an OR ranging from
2.7 for Caesarean section to 8.50 for preterm delivery and
16.10 for need for NICU (Table 6) [9]. These data are in
line with a growing body of literature data [32, 33, 37–39]
(Tables 2, 3 and 6).
The risk for adverse pregnancy-related events increases
along with the CKD stage. In our population, being in
stage 2–4 CKD increases the OR by about 2, for preterm
delivery and need for NICU, when compared with stage 1
CKD (Table 7). Even though a lack of a common language
still prevents a precise contextualization, our results
compare favourably with the recent literature, mainly obtained in later CKD stages [27–36,40–42].
In contrast to our previous study, in which the results
recorded in stage 1 and stage 2 CKD were almost equal,
the stepwise increase along stages is more clear and statistical difference is reached between stage 1 and 2 CKD
as for birthweight and gestational age, underlining the
importance of an even ‘minor’ decrease in kidney function (Tables 2 and 6) [9].
The second point is in regard to an attempt to analyse
CKD stage 1 patients according to diagnostic pattern.
The prevalence of new diagnosis was high (over 40% in
stage 1), underlying the importance of pregnancy as a
valuable occasion for early diagnosis of CKD and for
specific interventions (Table 2).
No difference was found between new and known diagnoses, confirming hypertension and proteinuria as adjunctive risk factors for adverse pregnancy-related outcomes,
and underlining that until multi-centre cohort studies
will allow precise stratification according to the different
kidney diseases, all CKD patients should be considered at
risk for pregnancy-induced complications (Tables 5 and 7)
[40–42].
Two practical suggestions can be derived from this
analysis: first, kidney function data, including at least
creatinine, electrolytes and urinalysis and, if possible,
kidney ultrasounds, should be performed to timely identify patients with pre-existing kidney diseases; secondly,
educational interventions should stress the importance of
interstitial nephropathies and of kidney malformations, including pyelonephritis scars and single kidney, as they share
with the better-known glomerular nephropathies, an increased risk of adverse pregnancy-related events (Table 5).
Our study has weaknesses and strengths, in part
common to clinical studies on CKD and pregnancy. One
of the limits is heterogeneity of disease, with a frequent
lack of preconception data, thus impairing precise staging
of CKD at the start. The assessment of renal function in
pregnancy remains a challenge, as all the established formulas display important limits in pregnancy; we continued with our working choice of the Cockcroft-Gault
formula, applying it whenever possible to preconception
iii117
data, while being aware of the limits of both the formula
and the CKD staging in pregnancy [3, 9, 23–25, 40].
One of the strengths of our study is the availability of a
‘low-risk’ control population with the same follow-up.
A second strength is the very low incidence of loss to
follow-up in the study group (three cases) and in the
control group, assuring against attrition biases after referral. A third one is the same nephrological and obstetric
team from the beginning, ensuring continuity and a relatively homogeneous approach (even with the obvious
changes and improvements over time) in a field such as
pregnancy in which differences among centres are very
important.
In a new and developing field, nothing is trivial; our
results, which favourably compare with the recent literature, reflect a combination of underlying kidney disease
and intervention which may impact on the outcome; for
example, the surrogate outcome of caesarean section is
linked with preterm delivery and may reflect a more aggressive policy towards the preservation of maternal
kidney function. Such a policy may be possible only in
settings, such as ours, where an excellent neonatology
ward is present, and only multicentre studies will shed
light on the role of the different factors that influence
outcome. Furthermore, a referral bias cannot be excluded,
leading to referral of pregnant women with the more
severe manifestations to the specialized Unit.
Even if a detailed discussion goes far beyond the aim
of the present study, a further practical suggestion can be
derived from our experience: as morbidity is mostly
related to prematurity, referral to a tertiary care centre,
with skilled neonatologists, is a key for success. The fact
that, despite our efforts, the prognosis is still different
from that of the control population underlines the need for
interventional studies in this delicate context.
Conclusions
Our data indicate an increased risk for adverse pregnancyrelated morbidity in all CKD patients in all stages, starting
form CKD stage 1. Even minor differences in kidney
function (stage 2 versus stage 1) increase the risk for
adverse pregnancy-related outcomes.
Within the limits of each context-sensitive analysis, our
study supports a dedicated follow-up programme for pregnant women, starting from stage 1 CKD. Only a broader,
multi-centre study, allowing stratification for specific diseases, will allow more precise tailoring of diagnostic and
management protocols.
Acknowledgements. Dr. P. Christie is acknowledged for his careful
language editing.
Conflict of interest statement. The results presented in this paper have
not been published previously in whole or part, except in abstract format
(EDTA 2011).
References
1. Graves JW. Diagnosis and management of chronic kidney disease.
Mayo Clin Proc 2008; 83: 1064–1069.
iii118
2. National Kidney Foundation. K/DOQI clinical practice guidelines
for chronic kidney disease: evaluation, classification and stratification. Am J Kidney Dis 2002; 39 (Suppl 1): S1–S266.
3. Ikizler TA. CKD classification: time to move beyond KDOQI. J Am
Soc Nephrol 2009; 20: 929–930.
4. Williams D, Davison J. Chronic kidney disease in pregnancy. BMJ
2008; 336: 211–215.
5. Hou S. Historical perspective of pregnancy in chronic kidney
disease. Adv Chronic Kidney Dis 2007; 14: 116–118.
6. Steegers EAP, von Dadelszen P, Duvekot JJ et al. Pre-eclampsia.
Lancet 2010; 376: 631–644.
7. Young BC, Levine RJ, Karumanchi SA. Pathogenesis of preeclampsia. Annu Rev Pathol Mech Dis 2010; 5: 173–192.
8. Vikse BE, Irgens LM, Leivestad T et al. Preeclampsia and the risk
of end-stage renal disease. N Engl J Med 2008; 359: 800–809.
9. Piccoli GB, Attini R, Vasario E et al. Pregnancy and chronic kidney
disease: a challenge in all CKD stages. Clin J Am Soc Nephrol
2010; 5: 844–855.
10. Chopra S, Suri V, Aggarwal N et al. Pregnancy in chronic renal insufficiency: single centre experience from North India. Arch
Gynecol Obstet 2009; 279: 691–695.
11. Cavallasca JA, Laborde HA, Ruda-Vega H et al. Maternal and fetal
outcomes of 72 pregnancies in Argentine patients with systemic
lupus erythematosus (SLE). Clin Rheumatol 2008; 27: 41–46.
12. Imbasciati E, Gregorini G, Cabiddu G et al. Pregnancy in CKD
stages 3 to 5: fetal and maternal outcomes. Am J Kidney Dis 2007;
49: 753–762.
13. Carr DB, Koontz GL, Gardella C et al. Diabetic nephropathy in
pregnancy: suboptimal hypertensive control associated with preterm
delivery. Am J Hypertens 2006; 19: 513–519.
14. Trevisan G, Ramos JG, Martins-Costa S et al. Pregnancy in patients
with chronic renal insufficiency at Hospital de Clínicas of Porto
Alegre. Brazil. Ren Fail 2004; 26: 29–34.
15. Fischer MJ, Lehnerz SD, Hebert JR et al. Kidney disease is an independent risk factor for adverse fetal and maternal outcomes in pregnancy. Am J Kidney Dis 2004; 43: 415–423.
16. Misra R, Bhowmik D, Mittal S et al. Pregnancy with chronic kidney
disease: outcome in Indian women. J Women Health 2003; 12:
1019–1025.
17. Khoury JC, Miodovnik M, LeMasters G et al. Pregnancy outcome
and progression of diabetic nephropathy. What’s next? J Matern
Fetal Neonatal Med 2002; 11: 238–244.
18. Rossing K, Jacobsen P, Hommel E et al. Pregnancy and progression
of diabetic nephropathy. Diabetologia 2002; 45: 36–41.
19. Bar J, Ben-Rafael Z, Padoa A et al. Prediction of pregnancy
outcome in subgroups of women with renal disease. Clin Nephrol
2000; 53: 437–444.
20. Germain S, Nelson-Piercy C. Lupus nephritis and renal disease in
pregnancy. Lupus 2006; 15: 148–155.
21. Rahman FZ, Rahman J, Al-Suleiman SA et al. Pregnancy outcome
in lupus nephropathy. Arch Gynecol Obstet 2005; 271: 222–226.
22. Clark CA, Spitzer KA, Nadler JN et al. Preterm deliveries in
women with systemic lupus erythematosus. J Rheumatol 2003; 30:
2127–2132.
23. Alper AB, Yi Y, Webber LS et al. Estimation of glomerular filtration
rate in preeclamptic patients. Am J Perinatol 2007; 24: 569–574.
G.B. Piccoli et al.
24. Smith MC, Moran P, Ward MK et al. Assessment of glomerular filtration rate during pregnancy using the MDRD formula. BJOG
2008; 115: 109–112.
25. Alper AB, Yi Y, Rahman M et al. Performance of estimated glomerular filtration rate prediction equations in preeclamptic patients. Am
J Perinatol 2011; 28: 425–430.
26. ACOG Committee on Obstetric Practice. ACOG practice bulletin.
Diagnosis and management of preeclampsia and eclampsia. Int J
Gynaecol Obstet 2002; 77: 67–75.
27. National Collaborating Centre for Women’s and Children’s Health:
Antenatal Care: Routine Care for the Healthy Pregnant Woman.
Clinical Guideline. London, UK: Royal College of Obstetricians
and Gynaecologists Press, 2008.
28. Parazzini F, Cortinovis I, Bortolus R et al. Standards of birth weight
in Italy. Ann Ostet Ginecol Med Perinat 1991; 112: 203–246.
29. Lachelin GCL, McGarrigle HG, Seed PT et al. Low saliva progesterone concentrations are associated with spontaneous early preterm
labour (before 34 weeks of gestation) in women at increased risk of
preterm delivery. BJOG 2009; 116: 1515–1519.
30. Intrapartum Care: Care of Healthy Women and Their Babiesduring
Childbirth. NICE Clinical Guideline 55. London, UK: National Institute for Health and Clinical Excellence, 2007.
31. SPSS vers18.0 for Windows. Chicago, IL: SPSS, 2009.
32. Ibrahim HN, Akkina SK, Leister E et al. Pregnancy outcomes after
kidney donation. Am J Transplant 2009; 9: 825–834.
33. Reisaeter AV, Roislien J, Henriksen T et al. Pregnancy and birth after
kidney donation: the Norwegian experience. Am J Transplant 2009;
9: 820–824.
34. Todros T, Verdiglione P, Oggé G et al. Low incidence of
hypertensive disorders of pregnancy in women treated with spiramycin for toxoplasma infection. Br J Clin Pharmacol 2005; 61:
336–340.
35. Lindheimer MD, Davison JM. Pregnancy and CKD: any progress?
Am J Kidney Dis 2007; 49: 729–731.
36. Epstein FH. Pregnancy and renal disease. N Engl J Med 1996; 335:
277–278.
37. Alsuwaida A, Mousa D, Al-Harbi A et al. Impact of early chronic
kidney disease on maternal and fetal outcomes of pregnancy. J
Matern Fetal Neonatal Med 2011; 24: 1432–1436.
38. Stehman-Breen CO, Levine RJ, Qian C et al. Increased risk of preeclampsia among nulliparous pregnant women with idiopathic hematuria. Am J Obstet Gynecol 2002; 18: 703–708.
39. Brown MA, Holt JL, Mangos GJ et al. Microscopic hematuria in
pregnancy: relevance to pregnancy outcome. Am J Kidney Dis 2005;
45: 667–673.
40. Piccoli GB, Conijn A, Attini R et al. Pregnancy in chronic kidney
disease: need for a common language. J Nephrol 2011; 24:
282–299.
41. Maynard SE, Thadhani R. Pregnancy and the kidney. J Am Soc
Nephrol 2009; 20: 14–22.
42. Nevis IF, Reitsma A, Dominic A et al. Pregnancy outcomes in
women with chronic kidney disease: a systematic review. Clin J Am
Soc Nephrol 2011; 6: 2587–2598.
Received for publication: 30.12.11; Accepted in revised form: 5.6.12