Short Term Sequelae of Preeclampsia: A Single Center Cohort Study
Short Term Sequelae of Preeclampsia: A Single Center Cohort Study
Short Term Sequelae of Preeclampsia: A Single Center Cohort Study
Abstract
Background: Data on the prevalence of persistent symptoms in the first year after preeclampsia are limited.
Furthermore, possible risk factors for these sequelae are poorly defined. We investigated kidney function, blood
pressure, proteinuria and urine sediment in women with preeclampsia 6 months after delivery with secondary
analysis for possible associated clinical characteristics.
Methods: From January 2007 to July 2014 all women with preeclampsia and 6-months follow up at the University
Hospital Basel were analyzed. Preeclampsia was defined as new onset of hypertension (≥140/90 mmHg) and either
proteinuria or signs of end-organ dysfunction. Hypertension was defined as a blood pressure ≥ 140/90 mmHg or
the use of antihypertensive medication. Proteinuria was defined as a protein-to-creatinine ratio in a spot urine
> 11 mg/mmol. Urine sediment was evaluated by a nephrologist. Secondary analyses were performed to
investigate for possible parameters associated with persistent symptoms after preeclampsia.
Results: Two hundred two women were included into the analysis. At a mean time of follow up of 172 days
(+/− 39.6) after delivery, mean blood pressure was 124/76 mmHg (+/− 14/11, range 116–182/63–110) and the mean
serum-creatinine was 61.8 μmol/l (33–105 μmol/l) (normal < 110 μmol/l). Mean estimated glomerular filtration rate
using CKD-EPI was 110.7 mml/min/1.73m2 (range 59.7–142.4 mml/min/1.73m2) (normal > 60 mml/min/1.73m2).
20.3% (41/202) had a blood pressure of 140/90 mmHg or higher (mean 143/89 mmHg) or were receiving
antihypertensive medication (5.5%, 11/202). Proteinuria was present in 33.1% (66/199) (mean 27.5 mg/mmol).
Proteinuria and hypertension was present in 8% (16/199). No active urine sediment (e.g. signs of
glomerulonephritis) was observed. Age and gestational diabetes were associated with persistent proteinuria and
severe preeclampsia with eGFR decline of ≥ 10 ml/min/1.73m2.
Conclusion: Hypertension and proteinuria are common after 6 months underlining the importance of close follow
up to identify those women who need further care.
Keywords: Preeclampsia, Follow-up, Sequelae
© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
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Girsberger et al. BMC Pregnancy and Childbirth (2018) 18:177 Page 2 of 7
present in 18% after 2 years [11]. In one study almost squared test was used to compare frequencies. Different
29% of patients were hypertensive after 5 years, although denominators in the results section are due to missing
sample size was small [12]. Therefore, the time to define data in a few patients.
chronicity of symptoms remains unclear. In regard to
the few existing studies, we hypothesized that a signifi- Results
cant part of patients still show sequelae of preeclampsia Of the 225 women referred to our nephrology clinic, 23
6 months after pregnancy. The aim of the study was to were lost to follow-up (10%). Two hundred two were in-
determine the frequency of hypertension, proteinuria cluded in the analysis. The mean time of the follow up
and eGFR (estimated glomerular filtration rate) decline visit was 172 days (+/− 39.6) after delivery. Mean age
6 months after preeclampsia and to search for possible of the 202 women was 32 years (18–45 years). 58.2%
parameters associated with these endpoints. (117/201) were pregnant for the first time (primigrav-
ida). In 22.2% (43/194) of the patient’s preeclampsia
Methods occurred before 34 weeks of gestation. Severe pre-
From January 2007 to July 2014 all women with pre- eclampsia was observed in 67% (132/197) and eclamp-
eclampsia at the University Hospital Basel referred to our sia as the most severe form was seen in 2% (4/198). 90.1%
nephrology clinic were included into the study. As by our (181/201) had no pre-existing diseases before pregnancy
hospital policy, all patients with preeclampsia are referred (diabetes mellitus, chronic kidney disease or hyperten-
for nephrology follow-up after 6 months. Patients were sion). Baseline characteristics are shown in Table 1.
closely followed by their family doctor or obstetrician and Distribution of blood pressure and urinary protein ex-
referred earlier if necessary. Preeclampsia was defined as cretion at follow-up are shown in Fig. 1a and b. The mean
new onset of hypertension (≥140/90 mmHg) after the blood pressure at 6-months follow up was 124/76 mmHg
20th gestational week or worsening hypertension (defined (+/− 14/11, range 116–182/63–110) and the mean
as blood pressure values ≥20/10 mmHg higher than previ- serum-creatinine was 61.8 μmol/l (33–105 μmol/l)
ously measured during pregnancy) in patients with pre- (normal < 110 μmol/l). Mean estimated glomerular
existing elevated blood pressure and either proteinuria or filtration rate (eGFR) using CKD-EPI (chronic kidney
other signs of end-organ dysfunction. The gynaecology disease epidemiology collaboration) was 110.7 ml/min/
department of the University Hospital of Basel had been 1.73m2 (59.7–142.4 ml/min/1.73m2) (normal > 60 mml/
in the practice of defining preeclampsia without the pro- min/1.73m2). 20.3% (41/202) had a blood pressure of
teinuria requirement, as was later confirmed by the 140/90 mmHg or higher (mean 143/89 mmHg) or
ACOG 2013 guidelines [13]. Hypertension was defined as received antihypertensive medication (5.5%, 11/202).
a blood pressure ≥ 140/90 mmHg or the use of antihyper- Proteinuria was present in 33.1% (66/199) (mean
tensive medication. This definition was used for inclusion 27.5 mg/mmol, range 12–261 mg/mmol). Proteinuria
into the study as well as at follow up. The presence of se- and hypertension were present in 8% (16/199) (Fig. 2).
vere hypertension (≥160/110 mmHg), acute renal failure 54.3% (108/199) had none of the investigated sequelae
or oliguria, eclamptic seizure, pulmonary lung oedema, at follow up. No active urine sediment (e.g. glomerular
signs of HELLP-Syndrome, hyperreflexia, severe head-
Table 1 Baseline characteristics
aches, visual disturbances or intra uterine growth retard-
Age mean (±SD) 32 (± 5.9)
ation with or without pathological Doppler ultrasound
resulted in a diagnosis of severe preeclampsia [14]. Acute Onset of preeclampsia (gestational week) 36 + 3 (± 3.9 weeks)
mean (±SD)
kidney injury was defined as a rise in serum creatinine
concentration of more than 50% from baseline during Early Onset (< 34 weeks of gestation) (43/195) 22.1%
hospitalisation. The presence of pre-existing conditions Nulliparous (150/199) 75.4%
like hypertension, diabetes mellitus or kidney disease was Multiple pregnancy (twins, triplets) (27/202) 13.4%
gathered from medical records. Proteinuria was defined as In vitro fertilisation (13/202) 6.4%
a protein-to-creatinine ratio in a spot urine > 11 mg/mmol Diabetes before pregnancy (4/201) 1.99%
[15]. Decline of kidney function was defined as a decrease
Gestational diabetes (19/202) 9.4%
in eGFR ≥10 ml/min/1.73m2. Urine sediments were
evaluated by a staff nephrologist. For secondary analyses, Previous hypertension (16/202) 7.9%
a multivariate logistic regression model was applied. HELLP (41/198) 20.7%
Univariate analysis was conducted in all variables with at Eclampsia (4/198) 2.0%
least 15 observations and variables with a p-value < 0.2 Severe preeclampsia (132/197) 67%
were added to the model. Wilcoxon Mann Whitney test Acute kidney injury (17/197) 8.6%
was used to compare medians due to skewed distribution
Chronic kidney disease (4/201) 1.99%
of the baseline characteristics in the subgroups; chi-
Girsberger et al. BMC Pregnancy and Childbirth (2018) 18:177 Page 3 of 7
a b
Fig. 1 a and b Distribution of urinary protein excretion and blood pressure at follow-up
microhematuria, casts, signs of glomerulonephritis) was in life [2–4]. To our knowledge, our study is the largest on
observed. short term sequelae after preeclampsia. It shows that a
Baseline characteristics in women with sequelae at significant part of patients with preeclampsia have
follow-up are shown in Tables 2, 3 and 4. Multivariate ongoing sequelae 6 months after delivery. 20% remain
logistic regression analyses showed an association of age hypertensive and one third have persistent proteinuria. 8%
and gestational diabetes with proteinuria > 11 mg/mmol have combined hypertension and proteinuria. If hyperten-
and proteinuria ≥30 mg/mmol at follow-up, respectively. sion or proteinuria persists 6 months after delivery,
Additionally, severe preeclampsia was associated with an different guidelines state that referral for internal medicine
eGFR decline ≥10 ml/min/1.73m2. None of the or nephrology and further diagnostics should be
investigated parameters were associated with persistent considered [9, 10].
hypertension (Table 5). Berks et al. [11] reported proteinuria in 14% of pa-
tients after 3 months and 8% after 2 years. When apply-
Discussion ing, a proteinuria cut off of 0.3 g/d as done by this
Persistent proteinuria and hypertension after pre- group, proteinuria was present in 8% in our study after
eclampsia have been reported in several studies. Pro- 6 months, which is consistent with the 14% after
teinuria in the first few months after preeclampsia is 3 months in Berks’ study. However, Berks et al. mea-
common [11, 16, 17], and can be detected up to several sured proteinuria by 24-h urine collection, whereas a
years. Hypertension can also persist for months and creatinine-protein ratio to estimate proteinuria was used
even for years [11, 12, 18]. Decreased kidney function is in this study, which makes a direct comparison of this
uncommon even after short term follow up in contrast to low range proteinuria results more difficult. In a study
persistent hypertension and proteinuria [4, 12, 16, 19]. by Chua et al. [20], proteinuria was absent after
However, there is data indicating that the risk of chronic 3 months, but a relatively high cut off of 0.5 g/24 h was
kidney disease after preeclampsia might be increased later used. Again, proteinuria was measured with 24-h urine
Fig. 2 Prevalence of hypertension, proteinuria and eGFR decline at mean follow-up of 172 days (± 39.6) after delivery
Girsberger et al. BMC Pregnancy and Childbirth (2018) 18:177 Page 4 of 7
collection. Another study reported persistent Microal- findings suggest that there is no further resolution of
buminuria in up to 60% of patients 2–4 months after hypertension after 6 months in contrast to proteinuria
preeclampsia and in still 40% after 3–5 years using a which was only present in 2% after 2 years. Another ex-
considerably low cut off for microalbuminuria of planation might be the difference in severe preeclampsia
14 mg/24 h [19]. Overall, despite conflicting evidence of 67% in our study to 89% in the study by Berks et al.
proteinuria seems to be a relevant short-term sequela and thereby a faster resolution of symptoms in our
after preeclampsia. In our secondary analysis, older age at study. In another study from Japan [16] 17% (9/52) of
baseline was associated with proteinuria > 11 mg/mmol, women with preeclampsia still had hypertensive blood
but not with proteinuria > 30 mg/mmol. Gestational dia- pressure values or received antihypertensive medication
betes was associated with proteinuria > 30 mg/mmol. after 2 years. This value is close to the 18% of women
However, given the large confidence interval with the with hypertension after 2 years in the study by Berks et
lower range close to 1, this finding might be significant by al., although the percentage of patients with severe pre-
chance. Furthermore, as we know from diabetic kidney eclampsia was not reported in the Japanese study. In a
disease, it usually takes years of abnormal glucose metab- third study from Iran [12], 29% (10/35) were still hyper-
olism to result in kidney damage with proteinuria, making tensive after a median follow up of 5.7 years. We could
this finding also clinically unlikely. not identify any clinical parameters associated with per-
In our study, 20% of women were hypertensive after sistent hypertension in our secondary analysis. In a sub-
6 months. In the study by Berks et al., 39% of women group analysis in 129 women with available data on peak
had hypertensive blood pressure values after 3 months hypertensive values at baseline, peak systolic blood pres-
and 18% were still hypertensive after 2 years [11]. These sure was significantly associated (p = 0.04) with
Table 4 Baseline characteristics (median (IQR)) of women with decline in eGFR ≥10 ml/min/1.73 m2 at follow-up
No eGFR decline (n = 170) eGFR decline (n = 27) p-value
Age 33 (28–37) 31 (27–35) 0.20
Onset (d) 258 (240–272) 261 (241–273) 0.64
Early onset 21.8% (36/165) 18.5% (5/27) 0.70
Nulliparous 75.7% (128/169) 66.7% (18/27) 0.32
Time to f/u (d) 180 (152–190) 179 (154–190) 0.93
MD 15.3% (26/170) 3.7% (1/27) 0.10
IVF 7.7% (13/170) 0% (0/27) 0.14
GD 8.8% (15/170) 14.8% (4/27) 0.33
HELLP 21.2% (36/170) 18.5% (5/27) 0.75
Severe PE 70% (119/170) 48.2% (13/27) 0.03
AKI 10.1% (17/169) 0% (0/27) 0.09
HT Hypertension, BP Blood pressure in mmHg, PE Preeclampsia, AKI Acute kidney injury, GD gestational diabetes, f/u follow-up; d days
eGFR delcine in our study, thus the clinical significance Ethics approval and consent to participate
remains unclear. This study was approved by the Swiss Ethic Committee of northwest and
central Switzerland as part of the swissethics association to be conducted
Our study has several strengths. To the best of our under Art. 34 HFG, ART. 37-40 HFV of Swiss Federal Law waiving the need
knowledge, this is the largest study on short term seque- for consent.
lae of preeclampsia. Furthermore, information on urine
sediments has not been reported in this setting before. Competing interests
The authors declare that they have no competing interests.
Due to a standardized protocol for follow-up after pre-
eclampsia at our clinic, a low number of patients were
lost to follow-up. The collection of several baseline char- Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in
acteristics allowed for secondary analysis for risk factors. published maps and institutional affiliations.
There are also several limitations. Being designed as a
cohort study, there is no control group as a reference. Author details
1
Clinic for Transplantation Immunology and Nephrology, University Hospital
We did not have information on GFR during pregnan- Basel, Petersgraben 4, 4031 Basel, Switzerland. 2Department of Gynaecology
cies, since there were no routine blood tests before pre- and Obstetrics, University Hospital Basel, Spitalstrasse 21, 4031 Basel,
eclampsia symptoms occurred with mostly initiation of Switzerland.
delivery short thereafter. An analysis on possible socio- Received: 12 October 2017 Accepted: 30 April 2018
demographic differences between the patients lost to
follow-up and the patients included in our study would
have been of interest, but was not possible due to un- References
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